Clinical trial NCT05256134
Conditions: Alzheimers Disease
Sponsor: Hoffmann-La Roche
Start date: 2022-04-19; Completion date: 2023-03-13
Enrollment: 25 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A study to evaluate the efficacy and safety of gantenerumab in amyloid-positive, cognitively unimpaired participants at risk for or at the earliest stages of AD. The planned number of participants for this study is approximately 1200 participants randomized in a 1:1 ratio to receive either gantenerumab or placebo (600 participants randomized to gantenerumab and 600 participants randomized to placebo).

Detailed description:

Arms: arm 1: Gantenerumab will be administered as subcutaneous (SC) injection with gradual uptitration. arm 2: Placebo will be administered as SC injection with gradual uptitration.
Interventions: intervention 1: Gantenerumab intervention 2: Placebo
Intervention descriptions: intervention 1: Gantenerumab will be administered as per the dosing schedule described in the Arm description. intervention 2: Placebo will be administered as per the dosing schedule described in the Arm description.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: A Phase III, Multicenter, Randomized, Parallel-Group, Double-Blind, 
Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
Gantenerumab in Participants at Risk for or at the Earliest Stages of 
Alzheimer’s Disease 
NCT Number: NCT05256134 
Document Dates: Protocol Version 2: 02-November-2021 
 
 
 


PROTOCOL AMENDMENT APPROVAL
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unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and; therefore, is 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 WN42444, Version 2
PROTOCOL
PROTOCOL TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
PARALLEL-GROUP, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF 
GANTENERUMAB IN PARTICIPANTS AT RISK 
FOR OR AT THE EARLIEST STAGES OF 
ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
WN42444
STUDY NAME
SKYLINE
VERSION NUMBER:
2
TEST COMPOUND:
Gantenerumab
(RO4909832)
STUDY PHASE:
III
EUDRACT NUMBER:
2021-001184-25
IND NUMBER:
102,266
NCT NUMBER:
To be determined
MEDICAL MONITOR:
, M.D.
SPONSOR’S NAME 
AND LEGAL 
REGISTERED 
ADDRESS:
F. Hoffmann-La Roche Ltd
Grenzacherstrasse 124
4070 Basel, Switzerland
APPROVAL DATE:
See electronic date stamp below.
Company Signatory
Approver's Name
Title
Date and Time (UTC)
02-Nov-2021 18:07:57


Gantenerumab—F. Hoffmann-La Roche Ltd
2/Protocol WN42444, Version 2
PROTOCOL HISTORY
Protocol
Version
Date Final
2
See electronic date stamp on title page
1
24 September 2021


Gantenerumab—F. Hoffmann-La Roche Ltd
3/Protocol WN42444, Version 2
PROTOCOL AMENDMENT, VERSION 2
RATIONALE
Protocol WN42444 has been amended to address a health authority (HA) requirement to 
include a coronavirus disease 2019 (COVID-19) vaccination risk assessment, clarify 
magnetic resonance imaging (MRI) monitoring requirements, the requirements for 
starting the post-progression dose escalation period, the assessment schedule related to 
the post-progression escalation period, the process of rescreening, and to add plasma 
samples as specified below.  Substantive changes to the protocol, along with a rationale 
for each change, are summarized below.

Sections 2.3 and 6.8.1 have been updated to address a HA requirement to include a 
COVID-19 vaccination risk assessment

Section 8.2.7 has been updated to clarify the MRI safety monitoring schedule for 
each study period (initial dose escalation, maintenance dosing, and 
post-progression dose escalation periods) and dosing schedule (every week [Q1W],
every 2 weeks [Q2W], every 4 weeks [Q4W])

Table A3-1 has been updated to clarify timing of MRIs related to amyloid-related 
imaging abnormality (ARIA) management for each study period and dosing 
schedule

Footnotes have been added to Tables 2, 3, 5 and 6 to clarify the assessment 
schedule during and following the post-progression dose escalation

Text has been updated to clarify that, before a participant enters the 
post-progression dose escalation period based on having clinically progressed, they
need to be on target dose; it has also been clarified that, in order to conclude on 
clinical progression, the change in diagnostic classification must be confirmed on a 
second visit, approximately 6 months later so that the diagnosis can be considered 
stable

Pharmacokinetic samples at Week 131 and Week 183 have been added in Table 2 
and Table 5 because they are needed for the valid assessment of anti-drug 
antibodies (ADAs) at these timepoints

Tables 16 and A24-1 have been updated to clarify prothrombin time collection 
timepoints

The process for rescreening has been clarified
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
4/Protocol WN42444, Version 2
TABLE OF CONTENTS
1.
PROTOCOL SUMMARY............................................................................. 13
1.1
Synopsis................................................................................ 13
1.2
Study Design ......................................................................... 19
1.3
Schedule of Activities ............................................................ 20
2.
INTRODUCTION ........................................................................................ 48
2.1
Study Rationale ..................................................................... 48
2.2
Background ........................................................................... 48
2.3
Benefit–Risk Assessment...................................................... 50
3.
OBJECTIVES AND ENDPOINTS AND ESTIMANDS................................. 52
4.
STUDY DESIGN......................................................................................... 55
4.1
Overall Design ....................................................................... 55
4.1.1
Screening Period................................................................... 56
4.1.1.1
Optional Blood-Based Biomarker Prescreening .................... 56
4.1.1.2
Main Screening...................................................................... 57
4.1.2
Maintenance Treatment Period ............................................. 58
4.1.3
Dosing in the Double-Blind Treatment Period........................ 59
4.1.4
Follow-Up Period................................................................... 60
4.2
Rationale for Study Design.................................................... 60
4.2.1
Rationale for Study Population .............................................. 60
4.2.2
Rationale for Control Group................................................... 62
4.2.3
Rationale for Biomarker Assessments................................... 63
4.2.3.1
Rationale for PET-, CSF- and Blood-Based 
Biomarker Assessments........................................................ 63
4.2.3.2
Rationale for MRI-Based Biomarker 
Assessments ......................................................................... 64
4.3
Justification for Dose and Schedule ...................................... 65
4.4
End of Study Definition .......................................................... 68
4.5
Duration of Participation ........................................................ 68
5.
STUDY POPULATION................................................................................ 68
5.1
Inclusion Criteria.................................................................... 68


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5.1.1
Optional Blood-Based Biomarker Prescreening 
Procedure.............................................................................. 68
5.1.2
Main Study............................................................................. 69
5.2
Exclusion Criteria................................................................... 70
5.2.1
Exclusions Related to CNS Disorders ................................... 70
5.2.2
Exclusions Related to Imaging Findings................................ 71
5.2.3
Exclusions Related to Cardiovascular Disease ..................... 72
5.2.4
Exclusions Related to Hepatic and Renal 
Disorders ............................................................................... 72
5.2.5
Exclusions Related to Infections and Immune 
Disorders ............................................................................... 72
5.2.6
Exclusions Related to Metabolic and Endocrine 
Disorders ............................................................................... 72
5.2.7
Exclusions Related to Medications........................................ 73
5.2.8
Additional Exclusions............................................................. 74
5.3
Lifestyle Considerations......................................................... 75
5.3.1
Meals and Dietary Restrictions.............................................. 75
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 75
5.3.3
Activity ................................................................................... 75
5.3.4
Contraception Requirements................................................. 76
5.4
Screen Failures ..................................................................... 76
6.
STUDY TREATMENT(S) AND CONCOMITANT THERAPY ...................... 76
6.1
Study Treatments Administered ............................................ 77
6.1.1
Gantenerumab....................................................................... 78
6.1.2
Placebo.................................................................................. 81
6.1.3
Positron Emission Tomography Tracers................................ 81
6.2
Preparation, Handling, Storage, and 
Accountability ........................................................................ 82
6.3
Treatment Assignment and Blinding...................................... 83
6.3.1
Treatment Assignment........................................................... 83
6.3.2
Blinding.................................................................................. 83
6.4
Study Treatment Compliance ................................................ 84
6.5
Dose Modification.................................................................. 84


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6.6
Continued Access to Study Treatment after the 
End of the Study.................................................................... 84
6.7
Treatment of Overdose.......................................................... 85
6.8
Concomitant Therapy ............................................................ 86
6.8.1
Permitted Therapy................................................................. 86
6.8.1.1
COVID-19 Vaccination........................................................... 87
6.8.2
Cautionary Therapies ............................................................ 88
6.8.2.1
Herbal Therapies................................................................... 88
6.8.3
Prohibited Therapy ................................................................ 88
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL .......................... 89
7.1
Discontinuation of Study Treatment....................................... 89
7.2
Participant Discontinuation or Withdrawal from 
the Study ............................................................................... 90
7.3
Participants Lost to Follow-Up............................................... 91
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 92
8.1
Efficacy Assessments............................................................ 93
8.1.1
Clinical Outcome Assessments ............................................. 93
8.1.2
Pharmacodynamic Assessments........................................... 94
8.2
Safety Assessments .............................................................. 94
8.2.1
Physical Examinations........................................................... 94
8.2.2
Vital Signs.............................................................................. 94
8.2.3
Electrocardiograms................................................................ 95
8.2.4
Clinical Safety Laboratory Tests............................................ 95
8.2.5
Pregnancy Testing................................................................. 96
8.2.6
Monitoring for Suicidal Ideation and Behavior ....................... 96
8.2.7
Brain Magnetic Resonance Imaging...................................... 96
8.3
Adverse Events, Serious Adverse Events, and 
Other Safety Reporting.......................................................... 97
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 98
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ................................................................... 100


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8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ................................................................... 100
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ................................................................... 100
8.3.5
Pregnancy ........................................................................... 101
8.3.6
Death Events....................................................................... 102
8.3.7
Anticipated Events Not Qualifying for Expedited 
Reporting............................................................................. 102
8.3.8
Adverse Events of Special Interest and Selected 
Adverse Events ................................................................... 102
8.3.8.1
Adverse Events of Special Interest...................................... 102
8.3.8.2
Selected Adverse Events..................................................... 102
8.3.9
Reporting Requirements for Medical Device 
Complaints........................................................................... 102
8.3.10
Medical Monitors and Emergency Medical 
Contacts .............................................................................. 103
8.4
Pharmacokinetics ................................................................ 103
8.5
Pharmacodynamics ............................................................. 104
8.5.1
Plasma Biomarker Samples ................................................ 104
8.5.2
Clinical Genotyping Sample................................................. 104
8.5.3
CSF Sample (only for Participants who are 
Enrolled by CSF Amyloid Assessment) ............................... 104
8.5.4
Brain Magnetic Resonance Imaging.................................... 105
8.6
Genetics .............................................................................. 106
8.7
Biomarker Assessments...................................................... 106
8.8
Immunogenicity Assessments ............................................. 107
8.9
Health Status Utility ............................................................. 108
8.10
Clinical Outcome Assessments ........................................... 108
8.10.1
Data Collection Methods for Clinical Outcome 
Assessments ....................................................................... 109
8.10.2
Description of Clinical Outcome Assessment 
Instruments.......................................................................... 111
8.10.2.1
Preclinical Alzheimer’s Cognitive Compositive-5................. 111
8.10.2.2
Clinical Dementia Rating Scale ........................................... 113
8.10.2.3
Amsterdam Instrumental Activity of Daily Living 
Questionnaire Short Version................................................ 114


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8.10.2.4
Cognitive Function Instrument acute ................................... 114
8.10.2.5
Geriatric Depression Scale-30............................................. 114
8.10.2.6
Clinician Global Impression of Cognitive Function............... 115
8.10.2.7
Participant Global Impression of Cognitive 
Function............................................................................... 115
8.10.2.8
Study Partner Global Impression of Cognitive 
Function............................................................................... 115
8.10.2.9
EuroQol EQ-5D-5L .............................................................. 116
8.10.2.10
Repeatable Battery for the Assessment of 
Neuropsychological Status .................................................. 116
8.10.2.11
Diagnostic Classification Form ............................................ 116
8.11
Additional Assessments and Procedures 
Requiring Separate Consent at Participating 
Sites..................................................................................... 117
8.11.1
Optional Blood-Based Biomarker Prescreening .................. 117
8.11.2
Optional Longitudinal Amyloid PET Imaging 
(Only for Participants Who Enrolled via Amyloid 
PET at Screening) ............................................................... 118
8.11.2.1
Participants.......................................................................... 118
8.11.2.2
Design ................................................................................. 118
8.11.2.3
Preparation and Administration of the 
Radioligand.......................................................................... 118
8.11.2.4
Amyloid PET-Specific Assessments.................................... 119
8.11.2.5
Imaging Processing and Analysis........................................ 119
8.11.3
Tau PET Imaging................................................................. 120
8.11.3.1
Participants.......................................................................... 120
8.11.3.2
Design ................................................................................. 120
8.11.3.3
Preparation and Administration of [18F]MK-
6240..................................................................................... 120
8.11.3.4
Tau PET-Specific Assessments .......................................... 120
8.11.3.5
Imaging Processing and Analysis........................................ 121
8.11.4
Optional Longitudinal Cerebrospinal Fluid 
Sampling (Only for Participants Enrolled via CSF 
at Screening) ....................................................................... 121
8.11.5
Overview of the Research Biosample Repository 
and External Research Entities ........................................... 122


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8.11.5.1
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 123
8.11.5.2
Sample Collection................................................................ 123
8.11.5.3
Data Protection, Use, and Sharing ...................................... 123
8.11.5.4
Consent to Participate in the Research 
Biosample Repository.......................................................... 124
8.11.5.5
Withdrawal from the Research Biosample 
Repository ........................................................................... 125
8.11.5.6
Monitoring and Oversight..................................................... 125
9.
STATISTICAL CONSIDERATIONS .......................................................... 126
9.1
Statistical Hypotheses ......................................................... 126
9.2
Sample Size Determination ................................................. 126
9.3
Analysis Sets....................................................................... 127
9.4
Statistical Analyses.............................................................. 127
9.4.1
General Considerations....................................................... 128
9.4.2
Primary Endpoint................................................................. 128
9.4.2.1
Primary Estimand ................................................................ 128
9.4.2.2
Primary Estimator................................................................ 129
9.4.3
Secondary Endpoints .......................................................... 130
9.4.4
Safety Endpoints ................................................................. 130
9.4.5
Other Analyses.................................................................... 130
9.4.5.1
Summaries of Conduct of Study.......................................... 130
9.4.5.2
Summaries of Demographics and Baseline 
Characteristics..................................................................... 131
9.4.5.3
Pharmacokinetic Analyses................................................... 131
9.4.5.4
Immunogenicity Analyses.................................................... 131
9.5
Interim Analysis ................................................................... 132
9.5.1
Optional Interim Analysis..................................................... 132
9.6
Independent Data Monitoring Committee ............................ 132


Gantenerumab—F. Hoffmann-La Roche Ltd
10/Protocol WN42444, Version 2
LIST OF TABLES
Table 1
Schedule of Activities:  Week 17 to Week 37; Dose 
Escalation to Target Dose of 255 mg Q1W................................. 20
Table 2
Schedule of Activities:  Week 38 to End of Study; 255 mg 
Q1W............................................................................................ 26
Table 3
Schedule of Activities:  Post-Progression Dose Escalation 
with Q1W Study Drug Administration Frequency; 
Dosing Weeks 1P37P ............................................................... 29
Table 4
Schedule of Activities:  Week 17 to Week 37; Dose 
Escalation to Target Dose of 510 mg Q2W................................. 34
Table 5
Schedule of Activities:  Week 38 to End of Study; 510 mg 
Q2W............................................................................................ 39
Table 6
Schedule of Activities:  Post-Progression Dose Escalation 
with Q2W Study Drug Administration Frequency; 
Dosing Weeks 1P37P ............................................................... 42
Table 7
Objectives and Endpoints ........................................................... 53
Table 8
Study Treatment Description....................................................... 77
Table 9
Distinct Study Rater Roles at Sites ........................................... 110
Table 10
Analysis Sets and Description................................................... 127
Table 11
Primary Estimand and Estimand Framework............................ 129
LIST OF FIGURES
Figure 1
Study Design Schematic............................................................. 19
Figure 2
Biomarker Abnormalities Detected Over Time............................ 61
Figure 3
Evolution of the Nomenclature of Alzheimer’s Disease 
Staging Since 2010..................................................................... 62
Figure 4
Median Amyloid PET Over Time Comparing Different Dosing 
Regimens (Q1W vs. Q2W).......................................................... 67
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations......... 141
Appendix 2
Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-Up, and Reporting....................................... 148
Appendix 3
Safety Plan:  Management of Identified and Potential Risks..... 168
Appendix 4
Contraceptive and Barrier Guidance......................................... 181
Appendix 5
Reporting Requirements for Medical Device Complaints.......... 184
Appendix 6
Mini-Mental State Examination (Preclinical Alzheimer’s 
Cognitive Composite5) Form A, B, and C........................... 185
Appendix 7
FCSRTIRDR (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C .......................................... 198


Gantenerumab—F. Hoffmann-La Roche Ltd
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Appendix 8
LM III WMSIV (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C .......................................... 211
Appendix 9
Coding WAISIV (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C .......................................... 224
Appendix 10
Category Fluency (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C .......................................... 232
Appendix 11
Clinical Dementia Rating Scale................................................. 251
Appendix 12
Amsterdam Instrumental Activity of Daily Living 
QuestionnaireShort Version (A-IADL-Q-SV) Participant 
Version...................................................................................... 262
Appendix 13
Amsterdam Instrumental Activity of Daily Living 
QuestionnaireShort Version (A-IADL-Q-SV) Study Partner 
Version...................................................................................... 280
Appendix 14
CFIa Participant Version ........................................................ 298
Appendix 15
CFIa Study Partner Version ................................................... 300
Appendix 16
Geriatric Depression Scale30 ................................................. 302
Appendix 17
Alzheimer’s Disease Clinical Global Impression of Cognitive 
Function Severity (AD-CGI-S)................................................ 305
Appendix 18
Alzheimer’s Disease Participant Global Impression of 
Cognitive Function (AD-PGI-S)................................................. 308
Appendix 19
Alzheimer’s Disease Study Partner Impression of Cognitive 
Function (AD-SPGI-S) .............................................................. 312
Appendix 20
EuroQol EQ-5-D-5L IA .............................................................. 316
Appendix 21
EuroQol EQ-5D-5L IA Proxy ..................................................... 319
Appendix 22
Repeatable Battery for the Assessment of 
Neuropsychological Status........................................................ 323
Appendix 23
Diagnostic Classification Form (DCF) ....................................... 338
Appendix 24
Clinical Safety Laboratory Tests ............................................... 344
Appendix 25
Abbreviations ............................................................................ 346


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PROTOCOL AMENDMENT ACCEPTANCE FORM
PROTOCOL TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
PARALLEL-GROUP, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF 
GANTENERUMAB IN PARTICIPANTS AT RISK FOR 
OR AT THE EARLIEST STAGES OF 
ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
WN42444
STUDY NAME: 
SKYLINE
VERSION NUMBER:
2
TEST COMPOUND:
Gantenerumab
(RO4909832)
MEDICAL MONITOR:
, M.D.
SPONSOR’S NAME:
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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1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, PARALLEL-GROUP, 
DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
EVALUATE THE EFFICACY AND SAFETY OF GANTENERUMAB 
IN PARTICIPANTS AT RISK FOR OR AT THE EARLIEST STAGES 
OF ALZHEIMER’S DISEASE
Study Rationale
The primary purpose of this secondary prevention study is to evaluate the efficacy, safety, 
pharmacodynamics, and pharmacokinetics of gantenerumab, an anti-amyloid antibody, in 
amyloid-positive, cognitively unimpaired participants at risk for or at the earliest stages of 
Alzheimer’s disease (AD).
Alzheimer’s disease, a debilitating and progressive neurodegenerative disease, represents a 
significant unmet medical need with no fully approved therapeutics to halt, slow, or prevent the 
onset of symptoms.  The currently available treatment options primarily include symptomatic 
medications and are only approved for the overtly symptomatic stages of AD.
The amyloid hypothesis postulates that amyloid may be an early, key driver of 
AD pathophysiology.  If this hypothesis is true, then early intervention at the amyloid-positive, 
cognitively unimpaired stage (i.e., at-risk stage of disease), may result in a high efficacy 
potential for an anti-amyloid antibody (i.e., gantenerumab), to slow the disease process and 
preserve the cognitive and functional abilities of affected individuals.  This is the main 
hypothesis Study WN42444 (SKYLINE) aims to test.
Objectives and Endpoints and Estimands
Study WN42444 will evaluate the efficacy and pharmacodynamics of gantenerumab treatment 
compared with control treatment as well as the safety and pharmacokinetics of gantenerumab 
treatment compared with placebo in cognitively unimpaired participants, aged 6080 years, at 
risk for or at the earliest stages of AD who are amyloid-positive based on evaluations of either 
cerebrospinal fluid (CSF) sampling or amyloid positron emission tomography (PET) imaging.
Study WN42444 is a randomized, double-blind, placebo-controlled study.  Eligible participants 
will be randomized in a 1:1 ratio to receive either gantenerumab or placebo.  If, in the course of 
the study, a participant progresses to a clinical diagnosis of mild cognitive impairment (MCI) or 
dementia due to AD, a ‘post-progression dose escalation’ period will commence.  During the 
post-progression dose escalation period, participants who were randomized to placebo will 
switch to gantenerumab in a double-blinded manner.  Participants who were randomized to 
gantenerumab will continue with gantenerumab (255 mg SC every 1 week [Q1W] or 510 mg SC 
every 2 weeks [Q2W]).  All participants who progress to a clinical diagnosis of MCI or dementia 
due to AD must comply with all aspects of the post-progression dose escalation schedules of 
activities.
The study treatment duration is 211 weeks regardless of the dosing regimen (i.e., Q1W or 
Q2W) or whether a participant progresses to a clinical diagnosis of MCI or dementia due to AD.
The primary comparison for efficacy will be between the following arms:

Experimental arm:  participants randomized to gantenerumab at the beginning of the study

Control arm:  participants randomized to placebo at the beginning of the study, irrespective 
of whether they progressed during the study and thus, started gantenerumab
The primary objective of this study is to evaluate the difference between the experimental and 
control arms in the change from baseline to Year 4 in cognition, as measured by the 
Preclinical Alzheimer’s Cognitive Composite-5 (PACC-5) score.
For pharmacodynamic measures, the primary comparison will be between gantenerumab and 
control.  For safety measures, the primary comparison will be between gantenerumab and 
placebo.


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Primary Objective
Corresponding Endpoint

To evaluate the efficacy of 
gantenerumab compared with control 
on cognition

Change from baseline to Year 4 in the 
Preclinical Alzheimer’s Cognitive 
Composite-5 score
Secondary Objectives
Corresponding Endpoints

To evaluate the efficacy of 
gantenerumab compared with control
on clinical progression

Time from randomization to clinical 
progression to mild cognitive impairment or 
dementia due to Alzheimer’s disease based 
on the diagnosis of the independent Clinical 
Adjudication Committee

To evaluate the efficacy of 
gantenerumab compared with control 
on clinical progression

Time to onset of confirmed clinical 
progression, defined as the time from 
randomization to the first occurrence of 
two consecutive visits 
(approximately 6 months apart) with a 
Clinical Dementia Rating Global Score 0

To evaluate the efficacy of 
gantenerumab compared with control 
on cognition and/or function

Change from baseline to Year 4 in the 
Amsterdam Instrumental Activities of Daily 
Living Questionnaire Short Version and the 
Cognitive Function Instrument acute

Change from baseline to Year 4 in the 
Clinical Dementia Rating Sum of Boxes

To evaluate the safety of 
gantenerumab compared with placebo

Nature, frequency, severity, and timing of 
adverse events, serious adverse events, and 
adverse events of special interest

Physical examinations (including neurological 
systems), vital signs, blood tests, ECGs, and 
Columbia-Suicide Severity Rating Scale

Nature, frequency, severity, and timing of 
magnetic resonance imaging (MRI) findings:  
amyloid-related imaging 
abnormalitiesedema/effusion and 
amyloid-related imaging 
abnormalitieshemosiderin deposition

Nature, frequency, severity, and timing of 
injection-site reactions

Presence of anti-drug antibodies (ADAs)
during the study relative to the presence of 
ADAs at baseline
Pharmacodynamic Biomarker Objective
Corresponding Endpoints

To evaluate biomarkers 
of pharmacodynamics of 
gantenerumab compared with control

Change in brain amyloid load over time, as 
measured by amyloid positron emission 
tomography (PET) in a subset of participants

Change in brain tau load over time, as 
measured by tau PET in a subset of 
participants


Gantenerumab—F. Hoffmann-La Roche Ltd
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Pharmacodynamic Biomarker Objective
Corresponding Endpoint

Change in cerebrospinal fluid (CSF) 
biomarkers, including, but not limited to, 
A1-42, A1-40, neurofilament light (NfL), pTau, 
and tTau in a subset of participants

Change in blood-based biomarkers, 
including, but not limited to, A1-42, A1-40, 
NfL, and pTau in all participants

Change in MRI-derived measurements over 
time, including, but not limited to, volumetric 
changes in whole-brain, ventricles, 
hippocampus, or other structures in all 
participants
Exploratory Objectives
Corresponding Endpoints

To evaluate the efficacy of 
gantenerumab compared with control 
on (1) depressive symptoms, 
(2) clinician-rated, participant-rated, 
and study partner-rated global 
impression of overall disease severity, 
and (3) health-related quality of life

(1) Change from baseline to Year 4 in the 
Geriatric Depression Scale-30

(2) Change from baseline to Year 4 in the 
AD Clinical Global Impression of Cognitive 
Function, AD Participant Global Impression 
of Cognitive Function, and AD Study Partner 
Global Impression of Cognitive Function
scales

(3) Change from baseline to Year 4 in the 
EuroQoL 5-Dimension, 5-Level 
Questionnaire index-based and visual 
analogue scores

To evaluate the efficacy of 
gantenerumab compared with control 
on clinical progression

Time from randomization to clinical 
progression to MCI or dementia based on the 
site clinician’s diagnostic classification

To characterize the pharmacokinetic 
(PK) profile of gantenerumab

Trough plasma concentrations of 
gantenerumab at specified timepoints

PK parameters estimated with population 
PK modeling

To evaluate the potential relationships 
between drug exposure and the 
efficacy and safety of gantenerumab

Relationship between plasma concentration 
or PK parameters of gantenerumab and 
pharmacodynamics (PD) as well as efficacy 
endpoints

Relationship between CSF concentration or 
PK parameters of gantenerumab and safety 
endpoints

To evaluate the effect of ADAs

Relationship between ADA status and 
efficacy, safety, PD, as well as PK endpoints


Gantenerumab—F. Hoffmann-La Roche Ltd
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Exploratory Objective
Corresponding Endpoints

To identify biomarkers that are:
(1) predictive of response to 
gantenerumab (i.e., predictive 
biomarkers),
(2) early surrogates of efficacy,
(3) associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers),
(4) associated with acquired 
resistance to gantenerumab,
(5) associated with susceptibility to 
developing adverse events or can lead 
to improved adverse event monitoring 
or investigation (i.e., safety 
biomarkers)
(6) able to increase the knowledge and 
understanding of disease biology and 
drug safety

Relationship between biomarkers in blood 
and CSF and efficacy, safety, PK, 
immunogenicity, or other biomarker 
endpoints

Relationship between biomarkers (such as 
MRI, PET, CSF and blood mentioned in 
secondary objectives) and efficacy, safety, 
PK, immunogenicity, or other biomarker 
endpoints
Overall Design
Study WN42444 is a 4-year and 9-month, Phase III, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study designed to evaluate the efficacy and safety of 
gantenerumab in amyloid-positive, cognitively unimpaired participants at risk for or at the 
earliest stages of AD.
The planned number of participants for the study is approximately 1200 participants randomized 
in a 1:1 ratio to receive either gantenerumab or placebo (600 participants randomized to 
gantenerumab and 600 participants randomized to placebo).
Participants will be selected based on (1) evidence of underlying cerebral Apathology as 
indicated by amyloid PET or by the pTau181/A1-42 ratio in the CSF, and (2) having both 
unimpaired cognitive and functional status as evidenced by a Clinical Dementia Rating (CDR) 
Global Score (CDR-GS 0), and the Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS) Delayed Memory Index (DMI; 80).  Eligible participants 
will be 6080 years of age, inclusive, must not meet the clinical diagnostic criteria for MCI due 
to AD or dementia due to AD, and must meet all the eligibility criteria.
If, in the course of the study, participants, who have reached target dose, progress to a clinical 
diagnosis of MCI or dementia due to AD (as determined by the independent clinical adjudication 
committee [iCAC]), a post-progression dose escalation period will commence.  During the 
post-progression dose escalation period, participants who were randomized to placebo will 
switch to gantenerumab in a double-blinded manner, unless the ongoing Phase III studies of 
gantenerumab in early AD do not demonstrate efficacy.  For study purposes, clinical 
progression to MCI or dementia due to AD is determined by the iCAC.  In order to conclude on 
clinical progression, the diagnostic classification change must be confirmed on the next 
cognitive assessment visit, approximately 6 months later.  Evaluation by the iCAC will be 
triggered by pre-specified trigger criteria.  Details of the trigger and diagnostic criteria for MCI 
and dementia due to AD will be provided in the iCAC Charter.
The study treatment period for each participant is 211 weeks (i.e., baseline to Week 211, 
inclusive) which constitutes the primary efficacy analysis dataset.
Number of Participants
Study WN42444 will enroll approximately 1200 participants aged 6080, who are cognitively 
unimpaired or at risk for or are at the earliest stages of AD during the global enrollment phase of 
this study.
Study Treatment
The active study drug under investigation for this study is gantenerumab.


Gantenerumab—F. Hoffmann-La Roche Ltd
17/Protocol WN42444, Version 2
Gantenerumab
Gantenerumab will be administered by SC injections to all participants.
Participants who choose the Q1W dosing regimen at the target dose, and are randomized to the 
active treatment arm will receive a dose of gantenerumab 120 mg SC every 4 weeks (Q4W) 
three times, 255 mg SC Q4W three times, and 255 mg SC Q2W six times, regardless of 
apolipoprotein E (APOE 4) status, prior to reaching the target dose of 255 mg Q1W 
(i.e., 1020 mg per month).
Participants who choose the Q2W dosing regimen at the target dose, and are randomized to the 
active treatment arm will receive a dose of gantenerumab 120 mg SC Q4W three times, 255 mg 
SC Q4W three times, and 510 mg SC Q4W three times, regardless of APOE 4 status, prior to 
reaching the target dose of 510 mg Q2W (i.e., 1020 mg per month).
Note:  the minimum number of study drug doses, as outlined above, must be administered 
during each titration step prior to dose escalation.
Following the initial dose escalation period, study drug will be administered at a Q1W or Q2W 
dosing regimen.  Participants will use their selected dosing regimen throughout the 
maintenance dosing phase of the study.
For Q4W injections, a visit window of 7 days is allowed for dosing visits.  Once study drug is 
administered Q1W or Q2W, the visit window for dosing visits is 3 days.  It is recommended not 
to administer more than 1020 mg (i.e., 4 255 mg Q1W or 2 510 mg for Q2W) within 28 days.  
Always return to the initial planned dosing regimen for subsequent visits.  If administration is not 
possible on the scheduled dosing day, the study drug should be administered as soon as 
possible within the time window from the scheduled dosing date.  If the study drug cannot be 
administered within the time window, the dose should be skipped, and the participant should 
receive the next dose at the next scheduled time with the study drug dosing resumed in 
accordance with the original dosing schedule.
During the initial dose escalation, the maintenance dosing periods, and the post-progression 
dose escalation period (if applicable), injections will be administered SC into the abdomen as a 
single injection, 2 or 3 injections as any combination of the following:

0.8 mL injection for the 120 mg dose or placebo

1.7 mL injection for the 255 mg dose or placebo
Participants on the Q1W dosing regimen will receive 1 SC study drug injection per dosing visit 
during the initial dose escalation and maintenance dosing periods.  However, participants on the 
Q1W dosing regimen will receive 2 SC study drug injections per dosing visit at Week 1P, 
Week 5P, and Week 9P, and 1 SC study drug injection per dosing visit at all other dosing visits 
during the post-progression dose escalation period.
Participants on the Q2W dosing regimen will receive 1 SC study drug injection per dosing visit 
until Week 25 during the initial dose escalation period.  Starting at Week 25, participants will 
receive 2 SC study drug injections per dosing visit during the initial dose escalation, 
maintenance dosing, and post-progression dose escalation periods with the exception of dosing 
at Week 1P, Week 5P, and Week 9P when they will receive 3 SC study drug injections per 
dosing visit.
During pre-specified visits, the study drug may be administered by the participant or their study 
partner (non-professional caregiver) at the participant’s home or another suitable location
depending on the individual participant’s/study partner’s preference, if appropriately trained and 
certified by the investigator or delegate, and allowed by local regulations.
During the initial dose escalation period, participants will receive SC injections of study drug by 
the investigator or an appointed qualified study staff for the first 3 doses at the clinic.  If the 
participant or their study partner is willing and determined capable of administering 
SC injections by the investigator or delegate, this participant or study partner will receive 
observer and dose administration training at the first 3 dosing visits (i.e., Weeks 1, 5, 9).  At the 
next 4 visits (i.e., Weeks 13, 17, 21, and 25) the injections will be administered by the 
participant or study partner under the site staff’s supervision.  Following the supervised dosing 
visits at the clinic, subsequent dosing may be administered by the participant or study partner at 
home except for doses that coincide with a clinic visit, in which case the participant or study 


Gantenerumab—F. Hoffmann-La Roche Ltd
18/Protocol WN42444, Version 2
partner should administer the injection in the clinic, under investigator/study staff supervision.  
Study staff will document the outcome of the supervised administrations.  Training and 
supportive materials will be provided to the site and the participant and/or their study partner.  
Following the in-person instructional training and supervised administrations at the site, 
adequate supply of study drug will be provided.  Participants should be observed for at least 
2 hours after dosing for the first 4 administrations of study drug (corresponding to the injections 
at Week 1, Week 5, Week 9 and Week 13); the observation time may be reduced to 
at least 1 hour following all other administrations.  However, participants must be observed for a 
minimum of 1 hour after each injection by their study partner or another suitably trained 
individual (i.e., “postdose observer”) even if they are self-administering the study drug.  
Study partners and postdose observers will be trained by the site staff to recognize signs and 
symptoms of allergic reactions and the appropriate actions to be taken if the participant were to 
develop those signs and symptoms.  Postdose observers must also sign the Postdose Observer 
Informed Consent Form prior to the initiation of the training.
At subsequent visits, the investigator or appointed qualified study staff will determine if the 
participant or study partner continues to be qualified to perform home administrations.  If at any 
time the investigator, participant, or study partner determines that home administration by the 
participant or study partner is unqualified, then the study drug must be administered at home or 
in the clinic by an alternative trained study drug administrator.
Starting from the fifth dose, at applicable sites, study drug may also be administered by a 
trained healthcare professional (mobile nurse) at the participant’s home or another suitable 
location, if the participant has given written informed consent.
During the post-progression dose escalation period, participants must be observed for at least 
2 hours after the first 4 ‘definitely active doses’ (i.e., dosing at Week 1P, Week 5P, Week 9P 
and Week 13P).  The observation time may be reduced to at least 1 hour following all other 
administrations.  Participant or study partner administration is prohibited during the 
post-progression dose escalation period.  The study drug administration by the participant or 
their study partner may resume after Week 37P following assessment and adequate training, if 
necessary, by the site.  Sites must verify participant/study partner readiness for study drug
administration.
A vial adapter will be available in countries where it has been approved to withdraw the 
medication from the vial into a disposable syringe (this device will be optional for health care 
professionals and for participants and study partners [non-professional caregivers]).
For study drug administration days that include efficacy assessments, study drug must be 
administered at the clinical site by the site staff or the participants/study partner.  
Study personnel preparing and administering study drug must not be involved with any efficacy 
or safety assessments.
Placebo
A placebo of identical composition (except gantenerumab) and volume to gantenerumab will be 
administered by SC injection to the abdomen.  The dosing schedule of the placebo and 
gantenerumab will also be identical throughout the duration of the study.
Duration of Participation
The total duration of study participation for each participant is expected to be 244 weeks, which 
includes the screening period (up to 17 weeks), the double-blind treatment period (211 weeks), 
and the subsequent safety follow-up visit 16 weeks after the final safety and efficacy 
assessment at Week 211.
Independent Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) is being used.


Gantenerumab—F. Hoffmann-La Roche Ltd
19/Protocol WN42444, Version 2
1.2
STUDY DESIGN
Figure 1
Study Design Schematic
AD Alzheimer’s disease; APOE apolipoprotein E; BBBM blood-based biomarker; ICF Informed Consent Form; Max maximum; MCI mild 
cognitive impairment; Q1W every 1 week; Q2W every 2 weeks; wk week.
a This is a randomized, double-blind, placebo-controlled study. Eligible participants will be randomized in a 1:1 ratio to receive either 
gantenerumab or placebo. If, in the course of the study, participants who are on target dose progress to a clinical diagnosis of MCI or dementia
due to AD, a blinded, post-progression dose escalation period will commence, with participants who were randomized to placebo switching to 
gantenerumab.
b The default dosing regimen is Q2W.










Table 1
Schedule of Activities:  Week 17 to Week 37; Dose Escalation to Target Dose of 255 mg Q1W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
24/Protocol WN42444, Version 2
Participants should be observed for at least 2 hours after dosing for the first 4 administrations of study drug (corresponding to the injections at Week 1, Week 5, Week 9 and Week 13); the observation 
time may be reduced to at least 1 hour following all other administrations.
a
Not applicable for sites where BBBM prescreening is not approved. Participation in the optional BBBM prescreening requires signing of the separate BBBM prescreening ICF.
b
Scope of the unscheduled visit should include all efficacy assessments if they were missed at the preceding, regularly scheduled efficacy assessment visit.  Safety assessments, including physical 
examinations, must also be included if they were missed at the preceding, regularly scheduled safety assessment visit or as clinically indicated.  Unscheduled visits related to the occurrence of 
ARIA-E or ARIA-H are to follow the PK and plasma biomarker sampling rules as detailed below.
c
Return of amyloid test and APOE genotyping results must take place at least 7 days prior to the randomization visit.  Follow-up over disclosures should occur within 1 week of the provision of 
results.
d
Visits, including PK, ADA and plasma biomarker sampling must take place in-clinic.
A PK sample is to be obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) following an MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria.
An additional plasma exploratory biomarkers sample is to 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).
e
Plasma biomarker sample during the main screening period should only be collected if the BBBM prescreening was not completed for the participant.
f
Metabolic tests include hemoglobin A1C, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, folic acid, vitamin B-12, 
methylmalonic acid, total thyroxine, free thyroxine, and thyroid-stimulating hormone levels.  These tests should be collected as fasting samples 
(i.e., at least 4 hours after meals).
g
Tau and amyloid PET scheduling window is 14 days. In an exceptional case of tau or amyloid PET scheduling issue the Sponsor must be notified and the scans may be performed up to 
3 months after the scheduled assessment. For Early Termination visits, tau and amyloid PET scans should only be obtained if the last scan was 6 months earlier.
ADA anti-drug antibody; AD-CGI-S Clinician Global Impression of Cognitive Function; AD-PGI-S Participant Global Impression of Cognitive Function; AD-SPGI-S Study Partner Global 
Impression of Cognitive Function; A-IADL-Q-SV Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version; APOE apolipoprotein E; ARIA-E amyloid-related imaging 
abnormalities edema/effusion; ARIA-H amyloid-related imaging abnormalities hemosiderin deposition; BBBM blood-based biomarker; C in-clinic administration by study staff; 
CDR Clinical Dementia Rating; CFIa Cognitive Function Instrument acute; CRPC-reactive protein; C-SSRS Columbia-Suicide Severity Rating Scale; CS supervised in-clinic 
administration, where applicable; CSF cerebrospinal fluid; DCF Diagnostic Classification Form; Early Term Early Termination; EQ-5D-5L EuroQol 5-Dimension 5-Level Questionnaire; 
GDS-30 Geriatric Depression Scale; H visit appropriate for home administration by participant or study partner, where applicable; HBV hepatitis B virus; HCV hepatitis C virus; 
CF Informed Consent Form; Max. maximum; MN visit appropriate for home administration by mobile nursing professional, where applicable; MRI magnetic 
resonance imaging; PACC-5 Preclinical Alzheimer’s Cognitive Composite-5; PET positron emission tomography; PK pharmacokinetic; Q1W every 1 week; RBANS Repeatable Battery 
for the Assessment of Neuropsychological Status; Unsch unscheduled; Wk week.
x B before study drug administration; visits may be split over 2 consecutive days.
The baseline visit (Week 1) may be split over 5 consecutive business days.  All cognitive and functional assessments must be completed first, and before study drug administration.  All safety 
assessments (e.g., vitals, blood tests, and ECGs) must be completed on the day of dosing and before study drug administration. Study drug administration should be the last baseline visit activity, 
marking the end of Week 1.


Table 1
Schedule of Activities:  Week 17 to Week 37; Dose Escalation to Target Dose of 255 mg Q1W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
25/Protocol WN42444, Version 2
h
Baseline tau PET should be obtained prior to first dose of study drug. However, in an exceptional case, and with the notification of the Sponsor, the baseline tau PET may be obtained within 
3 months of randomization.
i
Cerebrospinal fluid collection 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.
For Early Termination visits, CSF sampling should only be obtained if the last CSF sampling was 6 months earlier.
j
Every 4 weeks, except when there is an in-clinic visit, the investigator or an appointed qualified study staff member will have a telephone conversation with the participant and study partner to elicit, 
in a non-leading way, information on medication errors, adverse events, and changes to concomitant medications that may have occurred in the home setting.  Therefore, there will be contact 
between the study staff and the participant/study partner at least every 4 weeks.  The study staff is encouraged to have more frequent calls with a particular participant/study partner if considered 
appropriate by the investigator.  In addition, the participant and study partner must be instructed to contact the investigator and seek approval for continued study drug dosing in the home setting in 
case of onset of any new symptoms or symptom worsening, new or changed concomitant medications, or medication errors.






Table 2
Schedule of Activities:  Week 38 to End of Study; 255 mg Q1W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
28/Protocol WN42444, Version 2
study partner, where applicable; MN visit appropriate for home administration by mobile nursing professional, where applicable; MRI magnetic resonance imaging; PACC-5 Preclinical 
Alzheimer’s Cognitive Composite-5; PET positron emission tomography; PK pharmacokinetic; Q1W every 1 week; Unsch unscheduled; Wk week.
x B before study drug administration; visits may be split over 2 consecutive days.
As per Table 1, participants reach the target dose at Week 37 after which they will continue with the Q1W dosing frequency.  Subsequently, the next dose after Week 37 is given at Week 38, and last 
dose is given at Week 210 during maintenance dosing.
Participants should be observed for at least 2 hours after dosing at Week 1, Week 5, Week 9 and Week 13; the observation time may be reduced to at least 1 hour following all other administrations.
a
Scope of the unscheduled visit should include all efficacy assessments if they were missed at the preceding, regularly scheduled efficacy assessments visit.  Safety assessments, including physical 
examinations, must also be included if they were missed at the preceding, regularly scheduled safety assessments visit or as clinically indicated.  Unscheduled visits related to the occurrence of 
ARIA-E or ARIA-H are to follow the PK and plasma biomarker sampling rules as detailed below.
b
Visits, that include PK, ADA and plasma biomarker sampling must take place in-clinic.
A PK sample is to be obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) following an MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria.  An additional plasma exploratory biomarkers sample is to 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).
c
Metabolic tests include hemoglobin A1C, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, folic acid, 
vitamin B-12, methylmalonic acid, total thyroxine, free thyroxine, and thyroid-stimulating hormone levels.
These tests should be collected 
as fasting samples (i.e., at least 4 hours after meals).
d
Every 4 weeks, except when there is an in-person clinic visit, the investigator or an appointed qualified study staff will have a telephone conversation with the participant and study partner to elicit, 
in a non-leading way, information on medication errors, adverse events, and changes to concomitant medications that may have occurred in the home setting.  Therefore, there will be contact 
between the study staff and the participant/study partner at least every 4 weeks.  The study staff is encouraged to have more frequent calls with a particular participant/study partner if considered 
appropriate by the investigator.  Following the first 2 years of study treatment, the frequency of this telephone surveillance may be reduced to occur at least once, at midtime, between the 6-month 
in-person clinic visits.  However, for participants who enter the post-progression dose escalation period, there will be contact between the study staff and the 
participant/study partner at least every 4 weeks for 2 years after entering the post-progression dose escalation period (Table 3).  Following this 2-year 
period, the frequency of this telephone surveillance can be reduced again as outlined above.  In addition, the participant and study partner must be instructed to contact the 
investigator and seek approval for continued study drug dosing in the home setting in case of onset of any new symptoms or symptom worsening, new or changed concomitant medications, or 
medication errors.
e
Optional post-baseline amyloid and tau PET scans will be administered until the target number of scans is reached.
f
Tau and amyloid PET scheduling window is 14 days.  In an exceptional case of tau or amyloid PET scheduling issues the Sponsor must be notified and the scans may be performed up to 
3 months after the scheduled assessment.  For Early Termination visits, tau and amyloid PET scans should only be obtained if the last scan was 6 months earlier.
g
Optional post-baseline CSF samples will be collected until the target number of samples is reached.  Cerebrospinal fluid collection 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.  For Early Termination visits, CSF sampling should only be obtained if the last CSF sampling was 
6 months earlier.


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Table 3
Schedule of Activities:  Post-Progression Dose Escalation with Q1W Study Drug Administration 
Frequency; Dosing Weeks 1P37P
Neuropsychological efficacy assessments (i.e., Preclinical Alzheimer’s Cognitive Composite-5 [PACC-5], Cognitive Function 
Instrument acute [CFIa], Amsterdam Instrumental Activities of Daily Living Questionnaire Short Version [A-AIDL-Q-SV], 
Clinical Dementia Rating [CDR], Alzheimer’s disease Clinician Global Impression of Cognitive Function [AD-CGI-S], 
Alzheimer’s disease Participant Global Impression of Cognitive Function [AD-PGI-S], Alzheimer’s disease Study Partner Global 
Impression of Cognitive Function [AD-SPGI-S], EuroQol 5-Dimension, 5-Level Questionnaire [EQ-5D-5L], Geriatric Depression 
Scale-30 [GDS-30]), and the Diagnostic Classification Form (DCF), should continue as per the original schedule of activities
(i.e., Table 2).
Participants originally randomized to active treatment will continue with gantenerumab 255 mg SC every 1 week (Q1W).








Table 3
Schedule of Activities:  Post-Progression Dose Escalation with Q1W Study Drug Administration Frequency; 
Dosing Weeks 1P37P (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
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a
Visit weeks and dose numbers only refer to the ‘post-progression dose escalation’ period. Visit weeks are labeled ‘P’ (i.e., post-progression).
b
Visits at Weeks 1P, 5P, 9P, 13P, 17P, 21P, 25P, 27P, 29P, 31P, 33P, 35P, and 37P are defined as ‘definitely active dosing’ visits when both participant previously on placebo and active 
treatment receive an active dose of study drug.
c
Scope of the unscheduled visit should include all efficacy assessments if they were missed at the preceding, regularly scheduled efficacy assessments visit.  Safety assessments, including physical examinations, must also be included if they were 
missed at the preceding, regularly scheduled safety assessments visit or as clinically indicated.  Unscheduled visits related to the occurrence of ARIA-E or ARIA-H are to follow the PK, ADA and plasma biomarker sampling rules as detailed below.
d
Participants should be observed for at least 2 hours after the first 4 ‘definitely active doses’ (i.e., dosing at Week 1P, Week 5P, Week 9P and Week 13P). The observation time may be reduced to at least 1 hour following all other administrations. 
Participant or study partner administration is prohibited during the ‘post-progression dose escalation’ period. Study drug administration by the participant or their study partner may resume after Week 37P following assessment and adequate training, if 
necessary, by the site. Sites must verify participant/study partner readiness for study drug administration.
e
If MRI, 12-lead ECG, metabolic tests, CRP, PT serum chemistry and hematology were obtained within 4-weeks of Week 1P, these assessments do not need to be repeated during the Week 1P visit.
f
Visits, including PK, ADA and plasma biomarker sampling must take place in-clinic. A PK sample is to be obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) following an MRI scan showing new occurrence or worsening 
of ARIA-E or ARIA-H that meets the discontinuation criteria.  An additional plasma exploratory biomarkers sample is to 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).
g
During the post-progression dose escalation period, MRIs must be obtained -at minimum- before the first post-progression dose (Week 1P), after the second (Week 25P) and third (Week 37P)
dose-escalation steps as detailed in Table 3. Once participants have reached target dose, MRIs must be obtained 4 months, then 10 months, then 16 months after the first target dose, after which 
annual MRI monitoring frequency can be initiated.
h
Metabolic tests include hemoglobin A1C, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, folic acid, vitamin B-12, methylmalonic acid, total thyroxine, free 
thyroxine, and thyroid-stimulating hormone levels.  These tests should be collected as fasting samples (i.e., at least 4 hours after meals).
i
Every 4 weeks, except when there is an in-clinic visit, the investigator or an appointed qualified study staff member will have a telephone conversation with the participant and study partner to elicit, in a non-leading way, information on medication errors, 
adverse events, and changes to concomitant medications that may have occurred in the home setting.  Therefore, there will be contact between the study staff and the participant/study partner at least every 4 weeks.  The study staff is encouraged to 
have more frequent calls with a particular participant/study partner if considered appropriate by the investigator.  In addition, the participant and study partner must be instructed to contact the investigator and seek approval for continued study drug 
dosing in the home setting in case of onset of any new symptoms or symptom worsening, new or changed concomitant medications, or medication errors.
j
Optional post-baseline amyloid and tau PET scans will be administered until the target number of scans is reached.
k
Tau and amyloid PET scheduling window is 14 days. In an exceptional case of tau or amyloid PET scheduling issue the Sponsor must be notified and the scans may be performed up to 3 months after the scheduled assessment.
For Early Termination visits, tau and amyloid PET scans should only be obtained if the last scan was 6 months earlier. 
l
CSF sampling, amyloid and tau PET scans must be repeated prior to the first ‘post-progression dose escalation’ dose administration if the last such assessment occurred 6 months earlier. This repeat assessment will then replace the next originally 
scheduled Year 2, Year 3 or Year 4 assessment if this assessment is due in 6 months.
If the last CSF sampling, amyloid and tau PET scan took place 6 months of the first ‘post-progression dose escalation’ dose administration, assessments should be continued as per the original schedule of activities (i.e., Table 2).
m
Optional post-baseline CSF sampling will be continued until the target number of samples is reached.  Cerebrospinal fluid collection 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.








Table 4
Schedule of Activities:  Week 17 to Week 37; Dose Escalation to Target Dose of 510 mg Q2W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
37/Protocol WN42444, Version 2
c
Return of amyloid test and APOE genotyping results must take place at least 7 days prior to the randomization visit.  Follow-up over disclosures should occur within 1 week of the provision of 
results.
d
Visits, including PK, ADA and plasma biomarker sampling must take place in-clinic.
A PK sample is to be obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) following an MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria.  An additional plasma exploratory biomarkers sample is to 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).
e
Plasma biomarker sample during the main screening period should only be collected if the BBBM prescreening was not completed for the participant.
f
Metabolic tests include hemoglobin A1C, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, folic acid, vitamin B-12, 
methylmalonic acid, total thyroxine, free thyroxine, and thyroid-stimulating hormone levels. These tests should be collected as fasting samples (i.e., at least 
4 hours after meals).
g
Tau and amyloid PET scheduling window is 14 days.  In an exceptional case of tau or amyloid PET scheduling issue the Sponsor must be notified and the scans may be performed up to 
3 months after the scheduled assessment.  For Early Termination visits, tau and amyloid PET scans should only be obtained if the last scan was 6 months earlier.
ADAanti-drug antibody; AD-CGI-S Clinician Global Impression of Cognitive Function; AD-PGI-SParticipant Global Impression of Cognitive Function; AD-SPGI-SStudy Partner Global 
Impression of Cognitive Function; A-IADL-Q-SVAmsterdam Instrumental Activities of Daily Living Questionnaire Short Version; APOE apolipoprotein E; ARIA-E amyloid-related imaging 
abnormalities edema/effusion; ARIA-H amyloid-related imaging abnormalities hemosiderin deposition; BBBM blood-based biomarker; C in-clinic administration by study staff; 
CDR Clinical Dementia Rating; CFIa Cognitive Function Instrument acute; CRPC-reactive protein; C-SSRS Columbia-Suicide Severity Rating Scale; CS supervised in-clinic 
administration, where applicable; CSF cerebrospinal fluid; DCFDiagnostic Classification Form; Early TermEarly Termination; EQ-5D-5L EuroQol 5-Dimension 5-Level Questionnaire; 
GDS-30 Geriatric Depression Scale; H visit appropriate for home administration by participant or study partner, where applicable; HBV hepatitis B virus; HCV hepatitis C virus;
ICF Informed Consent Form; Max. maximum; MN visit appropriate for home administration by mobile nursing professional, where applicable; MRI magnetic 
resonance imaging; PACC-5 Preclinical Alzheimer’s Cognitive Composite-5; PET positron emission tomography; PK pharmacokinetic; Q2W every 2 weeks; RBANS Repeatable Battery 
for the Assessment of Neuropsychological Status; Unschunscheduled; Wk week.
x B before study drug administration; visits may be split over 2 consecutive days.
The baseline visit (Week 1) may be split over 5 consecutive business days.  All cognitive and functional assessments must be completed first, and before study drug administration.  All safety 
assessments (e.g., vitals, blood tests, and ECGs) must be completed on the day of dosing and before study drug administration.  Study drug administration should be the last baseline visit activity, 
marking the end of Week 1.
Participants should be observed for at least 2 hours after dosing for the first 4 administrations of study drug (corresponding to the injections at Week 1, Week 5, Week 9 and Week 13); the 
observation time may be reduced to at least 1 hour following all other administrations.
a
Not applicable for sites where BBBM prescreening is not approved. Participation in the optional BBBM prescreening requires signing of the separate BBBM prescreening ICF.
b
Scope of the unscheduled visit should include all efficacy assessments if they were missed at the preceding, regularly scheduled efficacy assessments visit.  Safety assessments, including 
physical examinations, must also be included if they were missed at the preceding, regularly scheduled safety assessments visit or as clinically indicated.  Unscheduled visits related to the 
occurrence of ARIA-E or ARIA-H are to follow the PK and plasma biomarker sampling rules as detailed below.


Table 4
Schedule of Activities:  Week 17 to Week 37; Dose Escalation to Target Dose of 510 mg Q2W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
38/Protocol WN42444, Version 2
h
Baseline tau PET should be obtained prior to first dose of study drug. However, in an exceptional case, and with the notification of the Sponsor, the baseline tau PET may be obtained within 
3 months of randomization.
i
Cerebrospinal fluid collection 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.
For Early Termination visits, CSF sampling should only be obtained if the last CSF sampling was 6 months earlier.
j
Every 4 weeks, except when there is an in-clinic visit, the investigator or an appointed qualified study staff member will have a telephone conversation with the participant and study partner to elicit,
in a non-leading way, information on medication errors, adverse events, and changes to concomitant medications that may have occurred in the home setting.  Therefore, there will be contact 
between the study staff and the participant/study partner at least every 4 weeks.  The study staff is encouraged to have more frequent calls with a particular participant/study partner if considered 
appropriate by the investigator.  In addition, the participant and study partner must be instructed to contact the investigator and seek approval for continued study drug dosing in the home setting in 
case of onset of any new symptoms or symptom worsening, new or changed concomitant medications, or medication errors.






Table 5
Schedule of Activities:  Week 38 to End of Treatment Period (Week 211); 510 mg Q2W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
41/Protocol WN42444, Version 2
x B before study drug administration; visits may be split over 2 consecutive days.
As per Table 4, participants reach the target dose at Week 37 after which they continue with the Q2W dosing frequency.  Subsequently, the next dose after Week 37 is given at Week 39, and last dose is given 
at Week 209 during maintenance dosing.
Participants should be observed for at least 2 hours after dosing at Week 1, Week 5, Week 9 and Week 13; the observation time may be reduced to at least 1 hour following all other administrations.
a
Scope of the unscheduled visit should include all efficacy assessments if they were missed at the preceding, regularly scheduled efficacy assessments visit.  Safety assessments, including physical 
examinations, must also be included if they were missed at the preceding, regularly scheduled safety assessments visit or as clinically indicated.  Unscheduled visits related to the occurrence of ARIA-E or 
ARIA-H are to follow the PK and plasma biomarker sampling rules as detailed below.
b
Visits, including PK, ADA and plasma biomarker sampling must take place in-clinic.
A PK sample is to be obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) following an MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that meets the 
discontinuation criteria.  An additional plasma exploratory biomarkers sample is to 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).
c
Metabolic tests include hemoglobin A1C, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, folic acid, vitamin B-12, methylmalonic 
acid, total thyroxine, free thyroxine, and thyroid-stimulating hormone levels. These tests should be collected as fasting samples (i.e., at least 4 hours after meals).
d
Every 4 weeks, except when there is an in-clinic visit, the investigator or an appointed qualified study staff member will have a telephone conversation with the participant and study partner to elicit, in a non-
leading way, information on medication errors, adverse events, and changes to concomitant medications that may have occurred in the home setting.  Therefore, there will be contact between the study staff 
and the participant/study partner at least every 4 weeks.  The study staff is encouraged to have more frequent calls with a particular participant/study partner if considered appropriate by the investigator.  
Following the first 2 years of study treatment, the frequency of this telephone surveillance may be reduced to occur at least once, at midtime, between the 6-month in-clinic visits.  However, for 
participants who enter the post-progression dose escalation period, there will be contact between the study staff and the participant/study partner at least every 4 
weeks for 2 years after entering the post-progression dose escalation period (Table 6), after which the frequency of this telephone surveillance can be reduced again 
as outlined above.  In addition, the participant and study partner must be instructed to contact the investigator and seek approval for continued study drug dosing in the home setting in case of onset of 
any new symptoms or symptom worsening, new or changed concomitant medications, or medication errors.
e
Tau and amyloid PET scheduling window is 14 days.  In an exceptional case of tau or amyloid PET scheduling issue the Sponsor must be notified and the scans may be performed up to 3 months after 
the scheduled assessment. For Early Termination visits, tau and amyloid PET scans should only be obtained if the last scan was 6 months earlier.
f
Optional post-baseline CSF samples will be collected until the target number of samples is reached.  Cerebrospinal fluid collection 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.  For Early Termination visits, CSF sampling should only be obtained if the last CSF sampling was 
6 months earlier.
g Optional post-baseline amyloid and tau PET scans will be administered until the target number of scans is reached.










Table 6
Schedule of Activities: Post-Progression Dose Escalation with Q2W Study Drug Administration Frequency; 
Dosing Weeks 1P37P (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
46/Protocol WN42444, Version 2
a
Visit weeks and dose numbers only refer to the ‘post-progression dose escalation’ period. Visit weeks are labeled ‘P’ (i.e., post-progression).
b
Visits at Weeks 1P, 5P, 9P, 13P, 17P, 21P, 25P, 29P, 33P, and 37P are defined as ‘definitely active dosing’ visits when both participant previously on 
placebo and active treatment receive an active dose of study drug.
c
Scope of the unscheduled visit should include all efficacy assessments if they were missed at the preceding, regularly scheduled efficacy assessments visit.  Safety assessments, including physical 
examinations, must also be included if they were missed at the preceding, regularly scheduled safety assessments visit or as clinically indicated.  Unscheduled visits related to the occurrence of 
ARIA-E or ARIA-H are to follow the PK, ADA and plasma biomarker sampling rules as detailed below.
d
Participants should be observed for at least 2 hours after after the first 4’ definitvely active doses’ (i.e., at Week 1P, Week 5P, Week 9P and Week 13P); the observation time may be reduced to at 
least 1 hour following all other administrations.  Participant or study partner administration is prohibited during the ‘post-progression dose escalation’ period.  Study drug administration by the 
participant or their study partner may resume after Week 37P following assessment and adequate training, if necessary, by the site.  Sites must verify participant/study partner readiness for study 
drug administration.
e
If MRI, 12-lead ECG, metabolic tests, CRP, PT serum chemistry and hematology were obtained within 4-weeks of Week 1P, these assessments do not need to be repeated during the Week 1P 
visit.
f
Visits, including PK, ADA and plasma biomarker sampling must take place in-clinic.
A PK sample is to be obtained as soon as practicable (e.g., at an unscheduled visit or the next study visit) following an MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria.  An additional plasma exploratory biomarkers sample is to 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).
g
During the post-progression dose escalation period, MRIs must be obtained -at minimum- before the first post-progression dose (Week 1P), after the second 
(Week 25P) and third (Week 37P) dose-escalation steps as detailed in Table 6. Once participants have reached target dose, MRIs must be obtained 
4 months, then 10 months, then 16 months after the first target dose, after which annual MRI monitoring frequency can be initiated.
h
Metabolic tests include hemoglobin A1C, total cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides, folic acid, vitamin B-12, 
methylmalonic acid, total thyroxine, free thyroxine, and thyroid-stimulating hormone levels. These tests should be collected as fasting samples (i.e., at least 
4 hours after meals).
i
Every 4 weeks, except when there is an in-clinic visit, the investigator or an appointed qualified study staff member will have a telephone conversation with the participant and study partner to elicit, 
in a non-leading way, information on medication errors, adverse events, and changes to concomitant medications that may have occurred in the home setting.  Therefore, there will be contact 
between the study staff and the participant/study partner at least every 4 weeks.  The study staff is encouraged to have more frequent calls with a particular participant/study partner if considered 
appropriate by the investigator. In addition, the participant and study partner must be instructed to contact the investigator and seek approval for continued study drug dosing in the home setting in 
case of onset of any new symptoms or symptom worsening, new or changed concomitant medications, or medication errors.
j
Optional post-baseline amyloid and tau PET scans will be administered until the target number of scans is reached.
k
Tau and amyloid PET scheduling window is 14 days. In an exceptional case of tau or amyloid PET scheduling issue the Sponsor must be notified and the scans may be performed up to 
3 months after the scheduled assessment. For Early Termination visits, tau and amyloid PET scans should only be obtained if the last scan was 6 months earlier.


Table 6
Schedule of Activities: Post-Progression Dose Escalation with Q2W Study Drug Administration Frequency; 
Dosing Weeks 1P37P (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
47/Protocol WN42444, Version 2
l
CSF sampling, amyloid and tau PET scans must be repeated prior to the first ‘post-progression dose escalation dose administration if the last such assessment occurred 6 months earlier.  
This repeat assessment will then replace the next originally scheduled Year 2, Year 3, or Year 4 assessment if this assessment is due in 6 months.
If the last CSF sampling, amyloid and tau PET scan took place 6 months of the first ‘post-progression dose escalation’ dose administration, assessments should be continued as per the original 
schedule of activities (i.e., Table 5).
m Optional post-baseline CSF sampling will be continued until the target number of samples is reached. Cerebrospinal fluid collection 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.


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2.
INTRODUCTION
2.1
STUDY RATIONALE
The primary purpose of this secondary prevention study is to evaluate the efficacy, 
safety, pharmacodynamics, and pharmacokinetics of gantenerumab, an anti-amyloid 
antibody, in amyloid-positive, cognitively unimpaired participants at risk for or at the 
earliest stages of Alzheimer’s disease (AD).
Alzheimer’s disease, a debilitating and progressive neurodegenerative disease, 
represents a significant unmet medical need with no fully approved therapeutics to halt, 
slow, or prevent the onset of symptoms. The currently available treatment options
primarily include symptomatic medications and are only approved for the overtly 
symptomatic stages of AD.
The amyloid hypothesis postulates that amyloid may be an early, key driver of 
AD pathophysiology. If this hypothesis is true, then early intervention at the 
amyloid-positive, cognitively unimpaired stage (i.e., at-risk stage of disease), may result 
in a high efficacy potential for an anti-amyloid antibody (i.e., gantenerumab), to slow 
the disease process and preserve the cognitive and functional abilities of affected 
individuals. This is the main hypothesis Study WN42444 (SKYLINE) aims to test.
2.2
BACKGROUND
The neuropathological hallmarks of AD are extracellular amyloid plaques built of 
insoluble amyloid (A) peptide and intraneuronal neurofibrillary tangles consisting of 
hyperphosphorylated tau filaments (Bloom 2014). Recent efforts have focused on 
targeting amyloid as a compelling therapeutic target (Bachurin et al. 2017; 
Graham et al. 2017). These investigational treatments are based on the amyloid 
hypothesis, which postulates that Aaccumulation is a key factor driving 
AD pathogenesis (Selkoe 1991; Hardy and Selkoe 2002; Selkoe and Hardy 2016). 
Accumulation of cerebral Amay begin up to 20 years prior to the emergence of clinical 
symptoms (Bateman et al. 2012) and cause a series of downstream events leading to 
synaptic dysfunction, inflammation, neurodegeneration, and eventually clinical 
symptoms (Jack et. al. 2013).
Growing clinical evidence supports that monoclonal antibodies against amyloid can bind 
aggregated A, promote its clearance (Salloway et al. 2009; Ostrowitzki et. al. 2012; 
Sevigny et al. 2016; Klein et al. 2019), and reduce markers of neurodegeneration in the 
cerebrospinal fluid (CSF; Ostrowitzki et al. 2017). In a Phase I study of aducanumab, 
reduction of amyloid plaques, as seen on brain amyloid positron emission tomography 
(PET) imaging, was suggested to be associated with a time- and dose-dependent
slowing of cognitive decline (Sevigny et al. 2016). Reduction of Aplaques was also 
observed in the subsequent Phase III studies, leading to the accelerated approval of 
aducanumab by the U.S. Food and Drug Administration (FDA) in 2021. Evidence of 


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amyloid reduction and slowing of cognitive decline has also been reported for other 
monoclonal anti-Aantibodies (Eisai Co, Ltd 2018; Mintun et al. 2021).
The ability of gantenerumab to reduce aggregated cerebral Ahas been confirmed in 
2 PET sub-studies in participants with mild cognitive impairment (MCI) due to AD 
(Study WN25203 open-label extension [OLE]) or mild AD dementia (Study WN28745
OLE). Starting from a mean baseline level of 76 centiloids, a mean reduction of 
39 centiloids by the first year and 59 centiloids by the second year was achieved at 
doses titrated up to 1200 mg. Moreover, at Years 1 and 2, 37% and 51% of participants, 
respectively, had cerebral Alevels below the PET amyloid positivity threshold
(Klein et al. 2019). Continued monthly dosing for a third year resulted in 80% of 
participants reaching amyloid levels near centiloid zero, which is considered to be the 
mean amyloid PET value for young healthy individuals (Klein et al. 2021).
Gantenerumab is currently being investigated in a number of other studies in early AD
and in familial AD. However, Study WN42444 is the first to investigate the effects of 
gantenerumab treatment in cognitively unimpaired older participants at risk for or at the 
earliest stages of AD.
On the basis of a meta-analysis that included participants who were at risk for or at the 
earliest stages of AD, it was estimated that the risk of progression to a clinical diagnosis 
of MCI or dementia due to AD is 20% (95% CI: 10%–34%) for individuals with Stage 1 
preclinical AD and 38% (95% CI: 21%–59%) for those with Stage 2 preclinical AD as 
defined by the 2011 NIA-AA criteria (Sperling at al. 2011) during a maximum mean 
follow-up of 10.4 years (Parnetti et al. 2019).
However, not all cognitively unimpaired, amyloid-positive individuals will progress to 
clinically symptomatic stages of AD within the 4-year study period (Hansson et al. 2018), 
and the exact proportion of individuals who will progress to a clinically symptomatic 
stage at any time remains uncertain.
Analyses conducted in 3 observational cohorts (Harvard Aging Brain Study [HABS], 
Australian Imaging, Biomarker and Lifestyle [AIBL] Study of Aging, and 
Alzheimer's Disease Neuroimaging Initiative [ADNI]) with participants of similar age, 
cognitive status, and increased amyloid burden to the target population in 
Study WN42444, showed that subtle cognitive decline on the PACC-5 (between 0.14 
and 0.26 standard deviations/year) was associated with an approximately 5fold 
greater risk of subsequent clinical disease progression (i.e., MCI diagnosis or 
CDR-Global score [CDR-GS]0; Papp et al. 2020) over a period of 3 years.
Detailed information on gantenerumab is provided in the Gantenerumab
Investigator's Brochure.


Gantenerumab—F. Hoffmann-La Roche Ltd
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2.3
BENEFIT–RISK ASSESSMENT
Currently, there are no approved disease-modifying therapies for cognitively unimpaired 
participants at risk for or at the earliest stages of AD.  Study WN42444 will test the 
hypothesis that gantenerumab administration at the target dose of 1020 mg monthly 
(administered as either 510 mg SC Q2W or 255 mg SC Q1W) to cognitively unimpaired, 
amyloid-positive individuals, 6080 years of age, reduces brain amyloid load and slows 
or delays clinical disease progression.
The key benefit–risk considerations for Study WN42444 are summarized below:

According to the amyloid hypothesis of AD, Aaggregation and deposition play an 
important role in the pathophysiology of this disease, in particular, possibly early in 
the disease course. Gantenerumab has shown evidence of amyloid plaque 
reduction as measured by PET in prior studies, and thus, may have the potential to 
slow the progression of AD from the pre-symptomatic to the symptomatic stages of 
the disease.

The target dose of gantenerumab in Study WN42444 is derived from a large body of 
amyloid PET and safety data from the ongoing clinical development program, 
including the ongoing Phase III studies, in early AD. Furthermore, the brain amyloid 
load of participants eligible for Study WN42444 is expected to be similar to the 
baseline cerebral amyloid load of participants of the ongoing studies. Therefore, a 
similar reduction of amyloid plaque is expected in Study WN42444 and similar 
amyloid-related imaging abnormalities (ARIA) risk mitigation measures are 
considered appropriate.

Nonclinical and clinical studies suggest that target engagement, as shown by 
PET standard uptake value reference region amyloid reduction, is not driven by the 
maximum observed concentration (Cmax) but rather depends on average exposure. 
Therefore, it is expected that the two offered dose regimens (i.e., 510 mg Q2W and 
255 mg Q1W) can also be administered in Study WN42444 without altering the 
treatment effect.

Gantenerumab has been generally safe and well-tolerated in healthy volunteers and 
participants with AD.  The identified risks of gantenerumab treatment are ARIAs of 
edema/effusion (ARIA-E) and of microhemorrhage/hemosiderin deposition 
(ARIA-H), as well as injection-site reactions (ISRs) associated with 
SC administration. Both of these risks (i.e., ARIA and ISR) have been 
well-characterized and are clinically manageable with the implemented mitigation 
measures.

Results from the double-blind portions, as well as from the OLEs of 
Studies WN25203 and WN28745, showed that ARIA findings are mostly 
asymptomatic, non-serious, of mild severity, do not require permanent cessation of 
treatment, and are manageable with MRI monitoring and dose intervention 
algorithms.  Injection-site reactions are non-serious, largely mild to moderate in 
severity, and self-resolving.


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
Potential risks of gantenerumab treatment include hypersensitivity, systemic 
injection reaction, and immunogenicity. There have been no reports of serious 
hypersensitivity or serious systemic injection reaction, or clinical findings indicative 
of an immunogenic response to gantenerumab in approximately 2500 participants 
that have been exposed.

No new safety signals have emerged in the ongoing, blinded pivotal 
Studies WN29922 and WN39658 which are overseen by an independent Data 
Monitoring Committee (iDMC).

Offering 2 different dosing frequency regimens (Q1W and Q2W dosing) and home 
administration by participants or their study partners (non-professional caregivers), 
is considered to represent a low risk to the overall safety, data integrity, and the 
benefit-risk profile of Study WN42444. Both regimens are expected to result in a 
comparable ARIA risk as they will provide the same gantenerumab exposure.

Robust mitigation measures will be put in place to ensure and closely monitor the 
safe and correct administration of the study drug by the participant or study partner 
throughout the study in the home setting.  These measures include participant 
and/or study partner training and approval for home administrations by the 
investigator or delegate (including training on the recognition of and action required 
for serious hypersensitivity reactions), an at least 1-hour postdose observation 
period, as well as regular telephone contact between the participant, study partner,
and the clinical site.  The benefit is to provide participants and their study partners 
appropriate opportunities to reduce the burden of study participation.

Overall, a substantial body of evidence exists for the safety of administration of 
gantenerumab up-titrated to the target dose of 1020 mg monthly in amyloid-positive 
individuals, 6080 years of age.  An iDMC will evaluate safety data on a regular 
basis from Study WN42444 in an unblinded fashion, including the incidence, 
severity, and nature of adverse events, serious adverse events, ARIA-E and 
ARIA-H, ISRs, adverse events of special interest, ECGs, laboratory abnormalities, 
and the Mini Mental State Examination (MMSE).

Based on its mechanism of action, there is no reason to believe that gantenerumab 
administration would compromise the immune function of the body.  This notion 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 rationales suggesting 
that gantenerumab administration could increase the risk of infection by severe 
acute respiratory syndrome coronavirus 2 (SARSCoV-2) or the more severe 
coronavirus disease 2019 (COVID-19) outcomes.  Whereas people of advanced 
age, including those with AD, may be at higher risk for COVID-19, participation in 
Study WN42444 is not expected to further increase this risk. Moreover, the Sponsor 
will implement COVID-19 mitigation measures as appropriate and feasible.

Based on the available information, no interactions between gantenerumab 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 


Gantenerumab—F. Hoffmann-La Roche Ltd
52/Protocol WN42444, Version 2
where gantenerumab is being investigated for the treatment of Alzheimer’s disease.
Just as with other vaccinations (e.g., influenza), the administration of COVID-19 
vaccines will be considered as a concomitant medication in this study. Please see
Section 6.8.1.1 for additional information.

Overall, the anticipated benefitrisk profile of the target doses of gantenerumab of 
1020 mg monthly (administered as either 510 mg SC Q2W or 255 mg SC Q1W) 
supports a clinical trial with these dosing regimens in cognitively unimpaired, 
amyloid-positive participants, aged 6080 who are at risk for or at the earliest stages 
of AD.
See Appendix 3 for information on risks for gantenerumab and risk mitigation measures
implemented, including guidelines for managing adverse events associated with 
gantenerumab.
More detailed information about the identified and potential risks of gantenerumab
treatment may be found in the Gantenerumab Investigator’s Brochure.
3.
OBJECTIVES AND ENDPOINTS AND ESTIMANDS
Study WN42444 will evaluate the efficacy and pharmacodynamics of gantenerumab 
treatment compared with control treatment as well as the safety and pharmacokinetics of 
gantenerumab treatment compared with placebo in cognitively unimpaired participants, 
aged 6080 years, at risk for or at the earliest stages of AD who are amyloid-positive 
based on evaluations of either CSF sampling or amyloid PET imaging.
Study WN42444 is a randomized, double-blind, placebo-controlled study. 
Eligible participants will be randomized in a 1:1 ratio to receive either gantenerumab or 
placebo. If, in the course of the study, a participant who has reached target dose
progresses to a clinical diagnosis of MCI or dementia due to AD, a ‘post-progression
dose escalation’ period (Table 3 and Table 6) will commence. During the 
post-progression dose escalation period, participants who were randomized to placebo
will switch to gantenerumab in a double-blinded manner. Participants who were 
randomized to gantenerumab will continue with gantenerumab (255 mg SC Q1W or 510 
mg SC Q2W). All participants who progress to a clinical diagnosis of MCI or dementia 
due to AD must comply with all aspects of the post-progression dose escalation 
schedules of activities (i.e., Table 3 and Table 6).
The study treatment duration is 211 weeks regardless of the dosing regimen 
(i.e., Q1W or Q2W) or whether a participant progresses to a clinical diagnosis of MCI or 
dementia due to AD. See Section 4 for a more detailed description of the study design.
The primary comparison for efficacy will be between the following arms:

Experimental arm: participants randomized to gantenerumab at the beginning of 
the study


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
Control arm: participants randomized to placebo at the beginning of the study, 
irrespective of whether they progressed during the study and thus, started 
gantenerumab
The primary objective of this study is to evaluate the difference between the 
experimental and control arms in the change from baseline to Year 4 in cognition, as 
measured by the PACC-5 score.
For pharmacodynamic measures, the primary comparison will be between 
gantenerumab and control. For safety measures, the primary comparison will be 
between gantenerumab and placebo.  Specific objectives and corresponding endpoints 
for the study are outlined in Table 7.
See Section 9.4.2 for a description of the elements of the primary estimand as per the 
estimand framework introduced in the International Council for Harmonisation (ICH)-E9 
(R1) addendum (ICH 2019).
Table 7
Objectives and Endpoints
Primary Objective
Corresponding Endpoint

To evaluate the efficacy of 
gantenerumab compared with control 
on cognition

Change from baseline to Year 4 in the 
PACC-5 score
Secondary Objectives
Corresponding Endpoints

To evaluate the efficacy of 
gantenerumab compared with control
on clinical progression

Time from randomization to clinical 
progression to MCI or dementia due to AD 
based on the diagnosis of the iCAC

To evaluate the efficacy of 
gantenerumab compared with control
on clinical progression

Time to onset of confirmed clinical 
progression, defined as the time from 
randomization to the first occurrence of 
two consecutive visits 
(approximately 6 months apart) with a 
CDR-GS 0

To evaluate the efficacy of 
gantenerumab compared with control
on cognition and/or function

Change from baseline to Year 4 in the 
A-IADL-Q-SV and the CFIa

Change from baseline to Year 4 in the 
CDR-SB

To evaluate the safety of 
gantenerumab compared with placebo

Nature, frequency, severity, and timing of 
adverse events, serious adverse events, and 
adverse events of special interest

Physical examinations (including neurological 
systems), vital signs, blood tests, ECGs, and 
C-SSRS

Nature, frequency, severity, and timing of 
MRI findings:  ARIA-E and ARIA-H

Nature, frequency, severity, and timing of 
ISRs


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Table 7
Objectives and Endpoints (cont.)
Secondary Objectives
Corresponding Endpoints

Presence of ADAs during the study relative to 
the presence of ADAs at baseline
Pharmacodynamic Biomarker 
Objectives
Corresponding Endpoints

To evaluate biomarkers 
of pharmacodynamics of 
gantenerumab compared with control

Change in brain amyloid load over time, as 
measured by amyloid PET in a subset of 
participants

Change in brain tau load over time, as 
measured by tau PET in a subset of 
participants

Change in CSF biomarkers, including, but not 
limited to, A1-42, A1-40, NfL, pTau, and tTau 
in a subset of participants

Change in blood-based biomarkers, 
including, but not limited to, A1-42, A1-40, 
NfL, and pTau in all participants

Change in MRI-derived measurements over 
time, including, but not limited to, volumetric 
changes in whole-brain, ventricles, 
hippocampus, or other structures in all 
participants
Exploratory Objectives
Corresponding Endpoints

To evaluate the efficacy of 
gantenerumab compared with control
on (1) depressive symptoms, 
(2) clinician-rated, participant-rated, 
and study partner-rated global 
impression of overall disease severity, 
and (3) health-related quality of life

(1) Change from baseline to Year 4 in the 
GDS-30

(2) Change from baseline to Year 4 in the 
AD-CGI-S, AD-PGI-S, and AD-SPGI-S scales

(3) Change from baseline to Year 4 in the 
EQ-5D-5L index-based and VAS scores

To evaluate the efficacy of 
gantenerumab compared with control
on clinical progression

Time from randomization to clinical 
progression to MCI or dementia based on the 
site clinician’s diagnostic classification

To characterize the PK profile of 
gantenerumab

Trough plasma concentrations of 
gantenerumab at specified timepoints

PK parameters estimated with population 
PK modeling

To evaluate the potential relationships
between drug exposure and the 
efficacy and safety of gantenerumab

Relationship between plasma concentration 
or PK parameters of gantenerumab and PD 
as well as efficacy endpoints

Relationship between CSF concentration or 
PK parameters of gantenerumab and safety 
endpoints


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Table 7
Objectives and Endpoints (cont.)
Exploratory Objectives
Corresponding Endpoints

To evaluate the effect of ADAs

Relationship between ADA status and 
efficacy, safety, PD, as well as PK endpoints

To identify biomarkers that are:
(1) predictive of response to 
gantenerumab (i.e., predictive 
biomarkers),
(2) early surrogates of efficacy,
(3) associated with progression to a 
more severe disease state 
(i.e., prognostic biomarkers),
(4) associated with acquired 
resistance to gantenerumab,
(5) associated with susceptibility to 
developing adverse events or can lead 
to improved adverse event monitoring
or investigation (i.e., safety 
biomarkers)
(6) able to increase the knowledge and 
understanding of disease biology and 
drug safety

Relationship between biomarkers in blood 
(Section 8.5.1) and CSF (Section 8.11.4) and 
efficacy, safety, PK, immunogenicity, or other 
biomarker endpoints

Relationship between biomarkers (such as 
MRI, PET, CSF and blood mentioned in 
secondary objectives) and efficacy, safety, 
PK, immunogenicity, or other biomarker 
endpoints
ADAlzheimer’s disease; ADAanti-drug antibody; AD-CGI-SAlzheimer’s disease Clinician 
Global Impression of Cognitive Function; AD-PGI-SAlzheimer’s disease Participant Global 
Impression of Cognitive Function; AD-SPGI-SAlzheimer’s disease Study Partner Global 
Impression of Cognitive Function; A-IADL-Q-SVAmsterdam Instrumental Activities of Daily 
Living Questionnaire Short Version; ARIA-Eamyloid-related imaging 
abnormalitiesedema/effusion; ARIA-Hamyloid-related imaging abnormalitieshemosiderin 
deposition; C-SSRSColumbia-Suicide Severity Rating Scale; CDR-SBClinical Dementia 
Rating Sum of Boxes; CDR-GSClinical Dementia Rating Global Score; CFIaCognitive 
Function Instrument acute; EQ-5D-5LEuroQol 5-Dimension, 5-Level Questionnaire; 
GDS-30Geriatric Depression Scale 30-items; CSFcerebrospinal fluid; iCACindependent 
Clinical Adjudication Committee; ISR injection-site reaction; MCImild cognitive impairment; 
MRImagnetic resonance imaging; NfLneurofilament light; PACC-5Preclinical Alzheimer’s 
Cognitive Composite-5; PD pharmacodynamic; PET positron emission tomography; 
PKpharmacokinetic; VAS visual analogue scale.
4.
STUDY DESIGN
4.1
OVERALL DESIGN
Study WN42444 is a 4-year and 9-month, Phase III, multicenter, randomized, 
double-blind, placebo-controlled, parallel-group study designed to evaluate the efficacy 
and safety of gantenerumab in amyloid-positive, cognitively unimpaired participants at 
risk for or at the earliest stages of AD.
The planned number of participants for the study is approximately 1200 participants 
randomized in a 1:1 ratio to receive either gantenerumab or placebo (600 participants 
randomized to gantenerumab and 600 participants randomized to placebo).


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Participants will be selected based on (1) evidence of underlying cerebral Apathology 
as indicated by amyloid PET or by the pTau181/A1-42 ratio in the CSF, and (2) having 
both unimpaired cognitive and functional status as evidenced by a CDR-GS0
(Morris 1993; 1997), and the Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS) Delayed Memory Index (DMI; 80 ; 
Randolph et al. 1998; Karantzoulis et al. 2013).  Eligible participants will be 6080 years 
of age, inclusive, must not meet the clinical diagnostic criteria for MCI due to AD 
(Albert et al. 2011) or dementia due to AD (McKhann et al. 2011), and must meet all the 
eligibility criteria outlined in Section 5.
If, in the course of the study, participants who have reached target dose progress to a 
clinical diagnosis of MCI or dementia due to AD (as determined by the independent 
clinical adjudication committee [iCAC]), a post-progression dose escalation period will 
commence. During the post-progression dose escalation period, participants who were 
randomized to placebo will switch to gantenerumab in a double-blinded manner, unless 
the ongoing Phase III studies of gantenerumab in early AD do not demonstrate efficacy
(see Section 4.1.2). For study purposes, clinical progression to MCI or dementia due to 
AD is determined by the iCAC. In order to conclude on clinical progression, the 
diagnostic classification change must be confirmed on the next cognitive assessment 
visit, approximately 6 months later.  Evaluation by the iCAC will be triggered by 
pre-specified criteria.  Details of the trigger and diagnostic criteria for MCI and dementia 
due to AD will be provided in the iCAC Charter.
The study treatment period for each participant is 211 weeks (i.e., baseline to Week 211,
inclusive) which constitutes the primary efficacy analysis dataset.
A schematic of the study design is provided in Section 1.2 (see Figure 1).  A schedule of 
activities is provided in Section 1.3 (see Table 1, Table 2, and Table 3 for the 
Q1W dosing regimen and Table 4, Table 5, and Table 6 for the Q2W dosing regimen).
4.1.1
Screening Period
4.1.1.1
Optional Blood-Based Biomarker Prescreening
The overall screening period of Study WN42444 is 17 weeks. Within this 17-week 
period, participating sites will have the option to prescreen individuals aged 6080 years, 
who do not have a known history of cognitive impairment or dementia, with the use of an
optional blood-based biomarker (BBBM) test. This exploratory BBBM test will assess 
whether an individual is more likely or less likely to have sufficiently elevated cerebral
amyloid levels to be eligible for Study WN42444. The prescreening period for BBBM
testing may last up to 4 weeks for each eligible participant. Sites are encouraged to 
complete the optional BBBM prescreening process expeditiously to allow participants to 
complete the overall screening process within the protocol-defined 17-week period.
Participants must sign a separate Blood-Based Biomarker Prescreening 
Informed Consent Form (ICF) to participate in the BBBM prescreening. Participation in 
the BBBM prescreening is, while encouraged where available, optional, and not a 


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prerequisite to screen for Study WN42444.  However, for participants of the BBBM 
prescreening, main screening activities, including signing of the main study participant or 
study partner ICFs, may not be initiated until it is determined whether the participant may 
or may not move on to the main screening.
Based on information from epidemiological studies, it is estimated that only 
approximately 1 of 6 study candidates will meet the CSF or PET imaging amyloid-based 
inclusion criteria for Study WN42444. The optional BBBM prescreening estimates how 
likely (i.e., more or less likely) an individual is to meet the amyloid-based inclusion 
criteria. Therefore, the optional BBBM prescreening may reduce the probability of 
undergoing the extensive screening process unnecessarily for those who are considered 
unlikely to meet the CSF or PET imaging amyloid inclusion criteria.  It is an exploratory 
test and should not be considered as a definitive test for cerebral amyloid. Only the 
subsequent CSF or PET results will be used to determine study eligibility.
Due to the experimental nature of the assay, results the BBBM prescreening test will not 
be returned to the participants or the sites. To further mask the results of the 
experimental BBBM prescreening test, approximately 10% of participants who are 
identified to be less likely to meet the amyloid-based inclusion criteria for 
Study WN42444, will also be invited to continue with the main study screening 
procedures.
Collection and submission of the prescreening blood samples for biomarker testing is 
contingent upon the review and approval by each site's Institutional Review Board (IRB) 
or Ethics Committee (EC) and, if applicable, an appropriate regulatory body. If a site has 
not been granted approval to use the BBBM prescreening, this part of the protocol will 
not be applicable at that site.
4.1.1.2
Main Screening
The overall study screening period, including the optional BBBM prescreening period, 
may last up to 17 weeks. Participants and their study partners must sign the main study
ICF before the initiation of the main study screening procedures. Details of the inclusion 
and exclusion criteria are provided in Section 5. Participants who do not meet the 
cognition- or amyloid-based inclusion criteria for participation in this study (i.e., screen 
failure) cannot be rescreened.  The investigator will record reasons for screen failure in 
the screening log and interactive voice or Web-based response system (IxRS).
Screening biomarker samples, including those collected from individuals who do not 
enroll in the study, may be used for future research and/or development of 
disease-related tests or tools as detailed in Section 8.11.5.
At the end of the screening period, but no later than 7 days prior to the scheduled 
randomization visit, results from the brain amyloid test (i.e., whether or not brain amyloid 
eligibility criteria are met) and apolipoprotein E (APOE) genotyping will be returned to 


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participants by the investigator or their qualified designee if allowed by local regulations 
and it is safe to do so. Participant’s readiness to receive these results will be determined 
by the investigator or their qualified designee based on their clinical judgment. Sites will 
follow-up with every participant within approximately 1 week after the return of results 
conversation.
Amyloid-related imaging abnormalities are known to occur in an 
APOE4 genotype-dependent fashion.  Therefore, APOE4 genotyping results are 
returned so that participants may make an optimally informed decision on further study 
participation.  By default, APOE genotyping results are shared with individuals who 
qualify to participate in Study WN42444. However, these individuals may opt out from 
learning their APOE genotyping results.  Participants who do not fulfill inclusion criteria
will have their results returned upon request. The discussion between the investigator or 
their qualified designee and the participant pertinent to the return of results must be 
documented in the site’s source documents.
Participants may be rescreened if recruitment for the study is still ongoing. In this 
case, all screening assessments must be repeated with the exception of lumbar puncture 
and PET scan, if they were performed within the previous 12 months for this study and 
were within eligible ranges. In case participant amyloid-based eligibility was 
established by an off-protocol PET scan, the same scan can be used as long as it has 
been performed within 12 months of starting rescreening. Given that APOE status will 
not change over time, there is no need to repeat clinical genotyping in case of 
rescreening.
4.1.2
Maintenance Treatment Period
After screening, participants who meet all eligibility criteria will be randomly assigned to 
one of two treatment arms in a 1:1 ratio.  The duration of the double-blind treatment 
period will last 211 weeks for each enrolled participant.
Participants in the experimental arm will be administered active gantenerumab for the 
entire duration of the study.  Participants randomized to receive placebo constitute the 
control arm. If, in the course of the study, participants who have reached target dose
progress to a clinical diagnosis of MCI or dementia due to AD (as determined by the 
iCAC), a post-progression dose escalation period will commence. During the 
post-progression dose escalation period, participants who were randomized to receive 
placebo will switch to gantenerumab in a double-blinded manner, unless the ongoing 
Phase III studies with gantenerumab in early AD do not demonstrate efficacy.  As a 
result, the control arm will contain both: (1) participants who do not meet the clinical 
progression criteria and remain on placebo throughout the duration of the study, and 
(2) participants who meet the clinical progression criteria and thus, initiate active 
gantenerumab treatment during the double-blind treatment period.  Once the 
post-progression dose escalation is initiated, neither the participant, the investigators,
nor the Sponsor will be blinded to current treatment (i.e., gantenerumab).  They will,


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however, remain blinded to the original treatment assigned at randomization
(i.e., gantenerumab vs placebo).
During the double-blind treatment period, all participants will undergo assessments for 
cognition, function, and quality-of-life (QoL) status as detailed in Section 1.3
(see Table 1, Table 2, and Table 3 for the Q1W dosing regimen and Table 4, Table 5, 
and Table 6 for the Q2W dosing regimen), as well as standard tests to monitor safety 
(e.g., blood tests and ECGs), and potential suicidality (Columbia-Suicide Severity Rating 
scale [C-SSRS]) as detailed in in Section 1.3 (see Table 1, Table 2, and Table 3 for the 
Q1W dosing regimen and Table 4, Table 5, and Table 6 for the Q2W dosing regimen).
All participants will undergo longitudinal brain magnetic resonance imaging 
(MRI) examinations to monitor safety as well as structural and functional
(where available) changes.  A central MRI reader will evaluate MRI scans in addition to 
the local safety readings that will be performed in accordance with local standards and 
procedures.
The incidence, severity, and nature of adverse events, serious adverse events, ARIA-E
and ARIA-H, ISRs, adverse events of special interest, ECGs, laboratory abnormalities, 
and the MMSE will be assessed on a regular basis by an unblinded iDMC.
Blood samples for the assessment of pharmacokinetic (PK), pharmacodynamic (PD)
biomarkers, biomarker discovery, and anti-drug antibodies (ADAs) will also be obtained 
from all participants as detailed in Section 1.3 (see Table 1, Table 2, and Table 3 for the 
Q1W dosing regimen and Table 4, Table 5, and Table 6 for the Q2W dosing regimen).
4.1.3
Dosing in the Double-Blind Treatment Period
Participants will be given the opportunity to choose one of the following two dosing 
frequency options:

1 SC injection Q1W (Table 1, Table 2, Table 3) or

2 SC injections Q2W (Table 4, Table 5, Table 6)
Participants must decide between the two dosing regimen options by Week 25.  
Participants who do not make a decision by Week 25 will continue with the Q2W dosing 
regimen. The Q2W dosing regimen is the default dosing regimen for the study.
Following the baseline assessments, participants will undergo a 9-month 
‘initial dose escalation’ period (Table 1 and Table 4) until the target dose 
(1020 mg monthly) is reached. Following the initial dose escalation period, participants 
will enter the maintenance dosing period (Table 2 and Table 5).
Participants who are randomized to placebo, but meet the clinical progression criteria
(according to the iCAC’s determination) during the double-blind treatment period, will be 
switched to gantenerumab.  A 9-month, ‘post-progression dose escalation’ period will 


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follow as detailed in Table 3 (for the Q1W dosing frequency) or Table 6 (for the Q2W 
dosing regimen) followed by maintenance dosing at target dose.  In order to keep the 
blind to the original treatment assignment, the ‘post-progression dose escalation’ will 
follow the respective Q1W or Q2W dosing regimen for all participants who have met 
clinical progression criteria (Table 3 or Table 6).  Additionally, during the 
‘post-progression dose escalation’ period, all participants will be asked to comply with all 
aspects of the post-progression dose escalation schedule of activities (Table 3 and 
Table 6), including increased frequency of in-clinic visits, increased number of 
SC injections at select visits, and safety MRI monitoring.
4.1.4
Follow-Up Period
When participants have completed the 211-week, double-blind treatment period, all 
participants who do not continue gantenerumab treatment via a post-trial access 
mechanism or another study, will be asked to return for a final safety follow-up visit at 
Week 227.
Participants, who prematurely discontinue treatment with the study drug in the 
double-blind treatment period but remain in the study, will be asked to follow the 
schedule of activities to the extent possible, unless their consent is withdrawn.
Participants who discontinue from Study WN42444 early will also be asked to return for 
a final safety follow-up visit 17 weeks after the last dose unless their consent is 
withdrawn.
4.2
RATIONALE FOR STUDY DESIGN
4.2.1
Rationale for Study Population
There is evidence from observational cohorts and clinicopathological correlation studies, 
indicating that neuropathological and in vivo biomarker changes typical of AD begin 
many years before the emergence of clinical symptoms. Moreover, changes in 
AD biomarkers have been suggested to occur in a temporally ordered manner 
(Ingelsson et al. 2004; Mormino et al. 2009, Jack et al. 2013) with Aabnormalities 
(measured by CSF A1-42 or amyloid PET) among the first to appear (see Figure 2).
Recently, emerging biomarkers like plasma neurofilament light (NfL) and plasma pTau 
have also been found to become abnormal in the course of AD (Mattsson et al. 2019; 
Barthélemy et al. 2020).


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Figure 2
Biomarker Abnormalities Detected Over Time
Source:  Jack et al. 2013.
A42amyloid beta 42; CSF cerebrospinal fluid; FDG fluorodeoxyglucose; MCI mild cognitive 
impairment; Minminimum; Max maximum; MRImagnetic resonance imaging; PET positron 
emission tomography.
Amyloid is identified by CSF A42 (purple) or PET amyloid imaging (red). Changes in tau are 
demonstrated by elevation in CSF tau (blue). Neurodegeneration is measured by FDG PET and 
structural MRI, respectively, which are drawn concordantly (orange). By definition, all curves 
converge at the top right-hand corner of the plot, the point of maximum abnormality. 
The horizontal axis of disease progression is expressed as time. Cognitive response is 
illustrated as a zone (green filled area) with low- and high-risk borders.
The early emergence of biomarker changes allows the identification of participants at 
risk for or at the earliest stages of AD. During this stage, individuals can be
characterized by the presence of abnormal biomarkers and the absence of overt clinical
signs or symptoms of AD. Accordingly, eligibility to participate in Study WN42444 
requires evidence of elevated cerebral Apathology as indicated by either amyloid PET
visual readings or the pTau181/A1-42 ratio in the CSF. The PET and CSF-based amyloid 
thresholds used to establish eligibility for Study WN42444 may be beyond what would be 
required to determine amyloid positivity in standard clinical settings and may differ from 
other gantenerumab studies. These threshold values were chosen in an effort to enable 
the detection of gantenerumab’s efficacy within the planned study duration.
Consensus is forming that AD represents a disease continuum spanning from 
asymptomatic stages to stages of overt dementia. The nomenclature that reflects the 
growing understanding of the overall disease span, has also evolved over time as 
detailed in Figure 3.


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Figure 3
Evolution of the Nomenclature of Alzheimer’s Disease Staging 
Since 2010
Source:  Dubois et al. 2010; Albert et al. 2011; McKhann et al. 2011; Sperling et al. 2011; 
Dubois et al. 2014; FDA 2018a; Jack et al. 2018.
ADAlzheimer’s disease; FDAU.S. Food and Drug Administration; IWGInternational Working 
Group; NIA-AANational Institute of Aging and the Alzheimer’s Association.
As eligible participants will exhibit abnormal biomarkers but only very subtle or no 
cognitive impairment, they are considered to be either at the earliest stages of AD 
(i.e., Stage 1 and Stage 2 of AD as per the 2018 guidance by the FDA [FDA 2018a]) or 
preclinical AD in accordance with NIAA-AA criteria, or asymptomatic and at risk for AD in 
accordance with the 2014 IWG classification (Figure 3).  However, overt cognitive 
difficulties (FDA Stage 3 and beyond) and subtle (FDA Stage 3) or overt (FDA Stage 4 
and beyond) impairment in functional activities of daily living due to cognitive difficulties
will be exclusionary, as participants with such impairments would meet the diagnostic 
criteria for MCI (Petersen et al. 1997), MCI due to AD/prodromal AD (Dubois et al. 2010; 
Albert et al. 2011), or dementia due to AD (McKhann et al. 2011) at screening.
It is expected that among cognitively unimpaired adults aged 6080 years, 
approximately 15%30% will have evidence of cerebral Adeposition based on amyloid 
PET imaging or CSF A42 concentrations (Jansen et al. 2015). 
Moreover, amyloid-positive, cognitively unimpaired participants have been shown to 
exhibit subtle detectable cognitive decline on the PACC-5 (0.14 to 0.26 standard 
deviations/year; Papp et al. 2020).
4.2.2
Rationale for Control Group
There are currently no approved disease-modifying compounds for participants who are 
at risk for or at the earliest stages of AD that could serve as an active control.


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In order to assess the efficacy and safety of gantenerumab in the target population, 
eligible participants in Study WN42444 are randomized 1:1 to either gantenerumab or 
placebo.
Participants who are randomized to placebo but are diagnosed with early AD 
(i.e., MCI or dementia due to AD) during the double-blind treatment period, will switch to 
treatment with gantenerumab. The intent of this approach is provide access to active 
treatment for study participants who would benefit from gantenerumab treatment, in the 
event that it has proven to be efficacious in the ongoing Studies WN29922 and 
WN39658 in early AD.
4.2.3
Rationale for Biomarker Assessments
Alzheimer’s disease is a heterogeneous disease, and the abundance of amyloid and 
tau pathology has been shown to vary among patients (Blennow et al. 2006). 
Given expected differences in baseline amyloid and tau burden, it is hypothesized 
that participants may not be equally likely to benefit from treatment with gantenerumab. 
Biomarker data will be collected prior to dosing in an effort to identify which participants 
are most likely to benefit. Pharmacodynamic biomarkers will be assessed to 
demonstrate evidence of biological activity of gantenerumab and the impact on 
Alzheimer's pathologies, to support the selection of a recommended dose and dosing 
regimen. As these biomarkers may also have prognostic value, their potential 
association with disease progression will also be explored.
4.2.3.1
Rationale for PET-, CSF- and Blood-Based Biomarker 
Assessments
Amyloid PET, tau PET and CSF, will be assessed at several longitudinal timepoints in a 
subset of participants who provide additional consent.
Amyloid PET imaging is of particular interest as it may provide evidence of a decrease in 
brain amyloid burden and; therefore, prove target engagement of the investigational 
treatment (Vandenberghe et al. 2013; Sevigny et al. 2016; Vandenberghe et al. 2016).  
The results of the amyloid PET assessments are expected to help in understanding the
pharmacodynamic effect of gantenerumab on brain amyloid load, as well as the 
relationship between changes in amyloid load and changes in other endpoints of the
study.
Tau PET imaging is a promising tool for monitoring the spatial and temporal changes of 
tau load, and has been reported to be a good predictor of short-term cognitive decline 
(Ossenkoppele et al. 2021).  The results of the tau PET assessments are expected to 
help in understanding the relationship between treatment with gantenerumab and 
changes in tau load.
Decreased CSF A1−42 and elevated CSF tTau and pTau are considered a biochemical 
signature of AD and may be observed in individuals who are at risk for or at the earliest 


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stages of AD. Accumulating evidence suggests that low CSF A1−42 reflects underlying 
amyloid plaque pathology, whereas increased tTau and pTau levels may be reflective of 
neurodegeneration and/or tau pathology. Moreover, amyloid deposition may be the 
initiating event in the cascade of pathologic processes underlying AD, while tau 
pathology appears to be a subsequent event associated with neurodegeneration.
Therefore, tTau and pTau may be studied as downstream biomarkers of the primary 
target of anti-amyloid therapies such as gantenerumab.
Several clinical trials with anti-amyloid antibodies, including gantenerumab, have shown 
treatment-related changes in both amyloid and tau biomarkers (Farlow et al. 2012; 
Salloway et al. 2014; Ostrowitzki et al. 2017).  On the basis of these data and on the 
proposed mechanism of action of gantenerumab, levels of CSF tTau and pTau, and 
additional exploratory biomarkers reflecting other pathologies, neurodegeneration and 
neuroinflammation will be assessed at baseline and at several longitudinal timepoints. 
Because gantenerumab is also expected to clear amyloid from the brain, levels of 
CSF A1−42 and other Aisoforms will also be measured.
More recently, technical advances have made it possible to also measure brain-derived 
proteins like amyloid, tau, and NfL in the blood (Mielke et al. 2017; Ovod et al. 2017).  
Interestingly, plasma NfL and plasma pTau have been shown to become abnormal in 
individuals that are cognitively normal but amyloid-positive (Mattsson et al. 2019; 
Grothe et al. 2021). Therefore, BBBMs for amyloid and tau, as well as additional 
exploratory biomarkers reflecting other pathologies, neurodegeneration, and 
neuroinflammation, will be assessed at baseline and several longitudinal timepoints.
4.2.3.2
Rationale for MRI-Based Biomarker Assessments
Several MRI techniques have demonstrated sensitivity to detect structural and functional 
cerebral abnormalities in individuals with AD, including preclinical AD. Previous studies 
reported changes in, among others, whole-brain and hippocampal and ventricular 
volumes (Fox et al. 2000; Fox et al. 2005; Jack et al. 2010). It was also found that the 
rate of volumetric changes correlated closely with changes in cognitive performance 
(Li and Wahlund 2011). Additionally, others reported measurable volumetric change and 
brain atrophy even in the preclinical stage of AD (Zhang et al. 2016;
Ossenkoppele et al. 2019; Younes et al. 2019).  To quantify the effects of gantenerumab 
on neurodegeneration, whole-brain, regional brain, hippocampal and ventricular 
volumes, changes will be assessed at screening and during study treatment.
Advanced anatomical and functional MRI measures, including diffusion MRI (dMRI), 
resting-state functional MRI (rs-fMRI) and arterial spin-labeling MRI (ASL-MRI) will be 
acquired and analyzed in all participants who are at sites where the required software 
and hardware are available.
Resting-state functional MRI studies generated evidence for the association between 
elevated cerebral amyloid load and functional connectivity alterations, reduced 


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resting-state functional connectivity of various brain networks, as well as impairment in
clinical and cognitive measures in individuals with AD (Sheline et al. 2010; 
Binnewijzend et al. 2012; Brier et al. 2012; Sheline and Raichle 2013). In addition, 
therapeutic interventions, such as memantine (Lorenzi et al. 2011) or donepezil 
(Goveas et al. 2011; Solé-Padullés et al. 2013), were found to have an impact on the 
decreased brain functional connectivity of individuals with AD. Lastly, compromised 
resting-state functional connectivity in persons with preclinical AD was shown to 
foreshadow neurodegeneration and predict tau accumulation (Franzmeier et al. 2020; 
Hampton et al. 2020).
Diffusion-tensor imaging (DTI) MRI provides imaging metrics of the cellular organization 
by measuring water diffusion properties under the influence or restriction of biological 
barriers. Widespread group differences in the degree of fractional anisotropy were
reported between participants with AD and healthy volunteers (Jack et al. 2013; 
Nir et al. 2013). White matter degeneration can be measured via DTI years before 
symptom onset (Ly et al. 2014; Hoy et al. 2017).
Potential changes in cerebral blood flow (CBF) due to gantenerumab treatment will be 
measured with use of MRI-based ASL.  Persons with AD were shown to have regionally 
reduced CBF compared with age-matched healthy volunteers as measured by ASL-MRI, 
especially in the temporal-parietal and posterior cingulate cortices (Schuff et al. 2009; 
Mattson et al. 2014). As with the previously described MRI techniques, ASL-MR can 
detect CBF changes in the preclinical AD population, and is predictive of future decline 
(Zhang et al. 2017; Fazlollai et al. 2020).
The acquisition parameters of each sequence, structure, and length of each MRI session 
and image processing algorithms will be outlined in a separate MRI manual. The central 
reader will conduct all study-related MRI assessments and readings, including 
volumetric measurements.
4.3
JUSTIFICATION FOR DOSE AND SCHEDULE
The putative efficacy of gantenerumab in this population is hypothesized to be driven by 
its ability to reduce brain Aburden according to the amyloid hypothesis of AD 
(Selkoe 1991; Hardy and Selkoe 2002; Selkoe and Hardy 2016).
Gantenerumab treatment reduced mean amyloid burden to a mean near the amyloid 
positivity threshold (approximately 24 centiloids [Navitsky et al. 2018]) after 2 years of 
treatment, and to zero centiloids after 3 years of treatment in the OLEs of 
Studies WN25203 (Scarlet RoAD) and WN28745 (Marguerite RoAD; Klein et al. 2021).
It is anticipated that similar rates of amyloid reduction will be obtained in both of the 
ongoing pivotal studies (i.e., Studies WN29922 and WN39658) and in this study 
(i.e., Study WN42444). The baseline amyloid burden of the population to be enrolled in 
the study is expected to be similar in the range of centiloids (interquartile range:


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71.6105.0) to that observed in the population of Studies WN29922 and WN39658 at 
baseline.
The proposed target dose in Study WN42444 is 1020 mg of gantenerumab per month
(i.e., 28 days) administered at 255 mg Q1W or 510 mg Q2W. This target dose was 
selected based on available clinical data collected through the clinical development 
program of gantenerumab in early AD, and is supported by PK/PD modeling. The target
dose will be administered following the initial dose escalation period of 9 months.
The low starting doses and gradual increase in dosing (i.e., slow dose escalation) are 
expected to reduce the risk of ARIA-E for both APOE 4 carriers and non-carriers based 
on the ARIA-E hazard model.
The ARIA-E hazard model was first developed using bapineuzumab data 
(Hutmacher et al. 2013). This model, which includes drug concentrations, time since 
first dose, and APOE 4 allele status, was applied to the double-blind results in
Study WN25203.  The model was then tested on publicly available aducanumab data
from Study NCT01677572 to predict the incidence of ARIA-E events with a high degree 
of accuracy, including the observed ARIA-E rate differences across APOE 4 allele 
groups. The ARIA-E hazard model has been updated with observations from the OLEs
of Studies WN25203 and WN28745 with the use of higher doses of gantenerumab.
An overall ARIA-E rate of approximately 26% is predicted based on the current ARIA-E 
hazard model.
An exploratory PK/PD (amyloid PET) model was developed based on PK and 
amyloid PET data from double-blind Studies WN25203 and WN28745 and their OLEs
with use of nonlinear mixed-effects modeling. The model represents the current 
knowledge of the effects of gantenerumab on amyloid plaque removal.
Simulations generated with use of this model, showed amyloid plaque reduction to the 
targeted amyloid positivity threshold (24 centiloids) as shown in the Figure 4. 
In addition, the magnitude and time course of amyloid plaque removal are predicted to 
be comparable for both proposed maintenance dosing regimens, i.e., 1020 mg per 
month (i.e., 28 days) administered as 510 mg Q2W or 255 mg Q1W.


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Figure 4
Median Amyloid PET Over Time Comparing Different Dosing 
Regimens (Q1W vs. Q2W)
PET positron emission tomography; Q1W every 1 week, Q2W every second week, 
Q4W every 4 weeks; UTdose escalation.
Colored solid lines: median (p50).
Black dotted line: amyloid−positivity threshold at 24 centiloids.
Number of individuals per regimen: 200 participants.
Q2W UT regimen (mg): 120 Q4W (3) 255 Q4W (3) 510 Q4W (3) 510 Q2W (up to 
Week 209).
Q1W UT regimen (mg): 120 Q4W (3) 255 Q4W (3) 255 Q2W (6) 255 Q1W (up to 
Week 210).
Note: The predictions of plaque removal in the low centiloid range may have a higher uncertainty 
due to the paucity of observed data in this range, lack of long-term information (with high 
gantenerumab doses) and the fact that individual centiloid values can become negative.
Participants may choose 1 of 2 dosing regimens for maintenance dosing; either 255 mg 
Q1W or 510 mg Q2W. If a participant chooses not to make a selection by Week 25, 
then they will continue on the 510 mg Q2W dosing regimen by default. Participants will 
use the selected dosing regimen throughout the study duration following the initial, 
9-month dose escalation period. The regimen may differ between participants in dosing 
frequency from Week 25 on, but the total dose of gantenerumab will remain the same at 
1020 mg per month (i.e., 28 days). The option to choose between 2 dosing regimens 
(Q1W or Q2W) allows for factoring in the participant’s preference. The Q1W 
administration schedule will enable some participants to simplify their treatment 
administration by decreasing the number of abdominal SC injections per administration, 
from 2 to 1 at the target dose. Alternatively, the Q2W administration schedule will 
enable other participants to increase the time between SC injections should that be their 
preference, or better accommodate their activities and/or life events.
Switching between the different dosing regimens is not permitted.


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Gantenerumab exerts its mechanism of action primarily via microgliamediated 
clearance of amyloid plaques. A change in the dosing frequency, while maintaining 
average exposure to gantenerumab, is expected to have no impact on the extent of 
amyloid plaque removal and thus, a dose of 1020 mg per month administered either as 
510 mg Q2W, or 255 mg SC Q1W is expected to result in a similar treatment effect.
When evaluating the efficacy and pharmacodynamics of gantenerumab compared with 
the control arm, the comparison will be made irrespective of the dosing frequency.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he or she has completed all 
phases of the study, including the safety follow-up visit shown in the schedule of 
activities (see Section 1.3).
The end of this study is defined as the date of the last visit of the last participant in the 
study or the date at which the last data point required for safety analyses or safety 
follow-up is received from the last participant, whichever occurs later.  The end of the 
study is expected to occur 227 weeks after the last participant is randomized.
In addition, the Sponsor may decide to terminate the study at any time.
4.5
DURATION OF PARTICIPATION
The total duration of study participation for each participant is expected to be 244 weeks, 
which includes the screening period (up to 17 weeks), the double-blind treatment period 
(211 weeks), and the subsequent safety follow-up visit 16 weeks after the final safety 
and efficacy assessment at Week 211.
5.
STUDY POPULATION
Study WN42444 will enroll approximately 1200 participants aged 6080, who are 
cognitively unimpaired and at risk for or are at the earliest stages of AD during the global 
enrollment phase of this study. Additional criteria for the study population are detailed in 
Sections 5.1, 5.2, and 5.3.  Prospective approval of protocol deviations to recruitment 
and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
5.1.1
Optional Blood-Based Biomarker Prescreening Procedure
Potential participants are eligible to participate in the optional BBBM prescreening 
procedure only if all of the following criteria apply:

Capable of giving signed informed consent as described in Appendix 1

Aged 6080 years (inclusive) at the time of signing the Blood-Based Biomarker 
Prescreening ICF


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
Participants who do not have a known clinical diagnosis of cognitive impairment, 
MCI, prodromal AD, or any form of dementia
5.1.2
Main Study
Potential participants are eligible to be included in the study only if all of the following 
criteria apply, irrespective of participation in the optional BBBM prescreening procedure:

Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol

Age 6080 years (inclusive) at the time of signing the ICF

Willing and able to comply with the study protocol and complete all aspects of the 
study (including cognitive and functional assessments, physical and neurological 
examinations, MRI, CSF collection, genotyping, and PET imaging)

Cognitively unimpaired with a screening CDRGS of 0, and RBANS DMI 80

Evidence of cerebral amyloid accumulation: amyloid-based eligibility can be 
established by any one of the following 3 methods:
–
CSF pTau181/A1-42 ratio 0.04 measured in CSF collected at screening with 
use of Elecsys immunoassays.
–
Qualitative visual read of the amyloid PET scan performed during screening by 
the core/central PET laboratory
–
Qualitative visual read of prior, off-protocol amyloid PET scan with either 
[18F]-Florbetapir, [18F]-Florbetaben, or [18F]-Flutemetamol obtained up to 
12 months prior to Study WN42444 screening period. Off-protocol PET scans 
will be centrally read, which will determine if the participant meets the 
amyloid-based eligibility criteria for Study WN42444.

Participants who have an available person (referred to as a “study partner” 
throughout the protocol) who:
–
Has frequent and sufficient contact (e.g., minimum twice a week in-person, via 
telephone, video calls, by e-mail or other electronic means) with the participant, 
and is willing and able to provide accurate information regarding the 
participant’s cognitive and functional abilities, signs the necessary ICF(s), and 
has sufficient cognitive capacity to accurately report on the participant’s 
cognitive and functional abilities
–
Is in 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
–
Is fluent in the language of the tests used at the study site
–
Every effort should be made to have same study partner participate throughout 
the duration of the study

Fluent in the language of the tests used at the study site


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
Adequate visual and auditory acuity, sufficient to perform neuropsychological testing 
(eye glasses and hearing aids are permitted)

Agreed not to donate blood or blood products for transfusion for the duration of the 
study and for 1 year after the final dose of study drug

Agreed not to participate in other interventional research studies for the duration of 
this trial

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 17 weeks after the final 
dose of study treatment
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.
The following are examples of contraceptive methods with a failure rate of
1% per year: 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 ICF.
5.2
EXCLUSION CRITERIA
5.2.1
Exclusions Related to CNS Disorders
Potential participants are excluded from the study if any of the following criteria apply:

Any evidence of an underlying neurological or neurodegenerative condition that may 
lead to cognitive impairment other than AD, including, but not limited to, 
frontotemporal dementia, dementia with Lewy bodies, vascular dementia, 
Parkinson’s disease, corticobasal syndrome, Creutzfeldt-Jakob disease, progressive 
supranuclear palsy, frontotemporal lobar degeneration, Huntington disease, normal 
pressure hydrocephalus, seizure disorder, delirium, hypoxia, or encephalopathy 
related to prior COVID-19 infection

Clinical diagnosis of MCI, prodromal AD, or any form of dementia


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
History or presence of intracranial or intracerebral vascular malformations, 
aneurysm, subarachnoid hemorrhage, or intracerebral macrohemorrhage

History or presence of posterior reversible encephalopathy syndrome

History of ischemic stroke with clinical symptoms or an acute event that is consistent 
with a transient ischemic attack within 12 months of screening

History of severe, clinically significant (i.e., resulting in persistent neurologic deficit 
or structural brain damage) CNS trauma (e.g., cerebral contusion)

History or presence of intracranial mass lesion (e.g., glioma, meningioma) that could 
potentially impair cognition or lead to progressive neurological deficits

Infections that may affect brain function or a history of infections that resulted in 
neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, and viral or bacterial 
meningitis and encephalitis)

History of major depression, schizophrenia, schizoaffective disorder, or bipolar 
disorder
History or presence of major depression is acceptable if the participant is 
considered to be in remission or depression is controlled by treatment and the 
participant has had no episode of major depression within 12 months of 
screening.

At risk for suicide

History of alcohol and/or substance abuse or dependence (according to the criteria 
specified in the Diagnostic and Statistical Manual of Mental Disorders, Version 5) 
within 2 years of screening
5.2.2
Exclusions Related to Imaging Findings
Potential participants are excluded from the study if any of the following criteria apply:

According to the MRI central reader, show MRI evidence of any of the following:
–
1 lacunar infarcts
–
Any territorial infarct 1 cm3
–
Any white matter lesion that corresponds to an overall Fazekas score of 3,
i.e., one or more confluent hyperintense lesion on the fluid-attenuated inversion 
recovery (FLAIR) sequence, which is 20 mm in any dimension

A combined number of microbleeds and areas of leptomeningeal hemosiderosis 
(i.e., cumulative ARIA-H) on the MRI of 5 (and should not include any 
disseminated leptomeningeal hemosiderosis) based on the review of the screening 
MRI performed by the central reader prior to randomization

Presence of any other significant cerebral abnormalities, including ARIA-E, as 
assessed in the screening MRI scan

Inability to tolerate MRI procedures or who have a contraindication to MRI, 
including, but not limited to, presence of pacemakers not compatible with MRI, 
aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the 


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eyes, skin, or body that would contraindicate an MRI scan, or any other clinical 
history or examination finding that would pose a potential hazard in combination with 
MRI
5.2.3
Exclusions Related to Cardiovascular Disease
Potential participants are excluded from the study if any of the following criteria apply:

History or presence of clinically significant systemic vascular disease 
(e.g., 70% stenosis of the carotid or vertebral arteries, symptomatic aortic 
aneurysm)

History or presence of atrial fibrillation

Within the last year, experienced unstable or clinically significant cardiovascular 
disease (e.g., myocardial infarction)

History or presence of heart failure, even if the heart failure is clinically 
asymptomatic

Uncontrolled hypertension (e.g., blood pressure 160 mmHg systolic or 95 mmHg 
diastolic)
5.2.4
Exclusions Related to Hepatic and Renal Disorders
Potential participants are excluded from the study if any of the following criteria apply:

Chronic kidney disease, indicated by creatinine clearance 30 mL/min to be 
calculated by the central laboratory with use of the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) formula (Levey et al. 2009) at screening, 
which remains 30 mL/min if retested

Confirmed and unexplained impaired hepatic function as indicated by screening 
AST or ALT 3the upper limit of normal (ULN) or total bilirubin 2ULN
5.2.5
Exclusions Related to Infections and Immune Disorders
Potential participants are excluded from the study if any of the following criteria apply:

History of, or are known to currently have an HIV infection, or hepatitis B or hepatitis 
C virus infection that has not been adequately treated, or history of spirochete 
infection of the CNS (e.g., syphilis, Lyme disease, or borreliosis)

History or presence of systemic autoimmune disorders that may lead to progressive 
neurological impairment with associated cognitive deficits (e.g., multiple sclerosis, 
lupus erythematosus, anti-phospholipid antibody syndrome, and Behçet disease)

Systemic immunosuppression or immunomodulation due to the continuing effects of 
immunosuppressant or immunomodulating medications

Current COVID-19 infection
5.2.6
Exclusions Related to Metabolic and Endocrine Disorders
Potential participants are excluded from the study if any of the following criteria apply:

Abnormal thyroid function as indicated by abnormal screening tests, or abnormal 
thyroid function that requires a new treatment or an adjustment of current treatment


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A participant may be rescreened after 3 months of adequate treatment for 
abnormal thyroid function.

Evidence of folic acid deficiency (as indicated by folic acid level below the lower limit 
of normal by the central laboratory’s measurement) or vitamin B-12 deficiency 
(as indicated by vitamin B-12 level below the lower limit of normal and/or 
methylmalonic acid levels above the ULN by the central laboratory’s measurements)
Participants may be rescreened after 3 months of adequate treatment for folic 
acid or vitamin B-12 deficiency.

Screening hemoglobin A1c (HbA1c) 8% (retesting is permitted if HbA1c 8.4%) or 
poorly controlled insulin-dependent diabetes with hypoglycemic episodes
Participants may be rescreened after 3 months to allow optimization of diabetic 
control.
5.2.7
Exclusions Related to Medications
The following medications are prohibited at screening and during the study. 
Potential participants who start any of the exclusionary medications during the study 
could be withdrawn from study treatment.

Any previous administration of gantenerumab is exclusionary at screening

Any previous administration of active immunotherapy (vaccine) that is being 
evaluated to prevent or postpone cognitive decline is exclusionary at screening and 
prohibited during the entire period of study participation

Any passive immunotherapy (Ig) or other long-acting biologic agent to prevent or 
postpone cognitive decline within 1 year of screening are exclusionary.  Use of 
passive immunotherapy (Ig) or other long-acting biologic agents agent to prevent or 
postpone cognitive decline is also prohibited during the entire period of study 
participation.

Any other investigational treatment within 5 half-lives or 6 months (whichever is 
longer) prior to screening is exclusionary and prohibited during the entire period of 
study participation

Any previous administration of sodium oligomannate (GV-971) is exclusionary at 
screening. The use of GV-971 is prohibited during the entire period of study 
participation.

Any previous treatment with medications specifically intended to treat symptoms 
related to Parkinson’s disease or any other neurodegenerative disorder is 
exclusionary at screening and the use of these medications is prohibited during the 
study. Certain medications are acceptable, if the participant is taking the medication
for a non-neurodegenerative disorder (e.g., pramipexole for restless leg syndrome).

Anticonvulsant medications are exclusionary at screening and throughout the study, 
except as treatment for an approved pain indication or an adverse event after study 
start


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
Typical anti-psychotic or neuroleptic medications are exclusionary at screening and 
throughout the study, except as brief treatment for a non-psychiatric indication 
(e.g., emesis)

Atypical anti-psychotic medications are exclusionary at screening and during the 
study except for intermittent short-term use

Anticoagulation medications within 3 months of screening with no plans to initiate 
any prior to randomization
–
Anti-platelet treatments (e.g., aspirin, clopidogrel, dipyridamol) and low dose 
low-molecular-weight heparin for prophylaxis are permitted

Psychedelic drugs and substances (e.g., psilocybin, LSD), recreational cannabis 
and illicit use of opioids (e.g., opium, morphine, fentanyl or diacetylmorphine/heroin) 
or ketamine are exclusionary at screening and during the entire study

Medical marijuana (licensed and/or standardized marijuana or its derivatives, as 
prescribed or recommended by a healthcare professional in the treatment of a 
medical condition) is allowed if on a stable dose for at least 1 month prior to 
screening. Medical marijuana does not have to be discontinued prior to cognitive 
testing if on a stable dose for at least 1 month prior to cognitive testing.

Chronic use of prescribed opiates or opioids for pain management is allowed if on a 
stable dose for at least 1 month prior to screening. Chronically used, prescribed 
opioids do not have to be discontinued prior to cognitive testing if on a stable dose 
for at least 1 month prior to cognitive testing.

Chronic use of prescribed benzodiazepines, barbiturates and hypnotic medications 
are allowed if on a stable dose for at least 1 month prior to screening.
Chronically used, prescribed benzodiazepines, barbiturates and hypnotic 
medications do not have to be discontinued prior to cognitive testing if on a stable 
dose for at least 1 month prior to cognitive testing.

Nootropics and stimulant medications (e.g., piracetam, amphetamine, 
methylphenidate preparations, or modafinil) are exclusionary within 1 month of 
screening and throughout the study

Medical food supplements (e.g., Axona®, Souvenaid®) are allowed if on a stable 
dose for at least 1 month prior to screening

Any previous treatment with cholinesterase inhibitors (e.g., donepezil, galantamine, 
rivastigmine) and N-methyl-D-aspartate receptor antagonists (e.g., memantine) are 
exclusionary at screening. Cholinesterase inhibitors (e.g., donepezil, galantamine, 
rivastigmine) and N-methyl-D-aspartate receptor antagonists (e.g., memantine) are
prohibited during the study until the participant is determined to have progressed 
dementia due to AD as determine by the iCAC.
5.2.8
Additional Exclusions
Potential participants are excluded from the study if any of the following criteria apply:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 17 weeks after the final dose of gantenerumab


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Women of childbearing potential must have a negative serum pregnancy test 
result within 14 days prior to initiation of study treatment.

Deformity of the lumbosacral region of the spine that would contraindicate lumbar 
puncture (LP) in participants who will receive a LP

Clinically significant abnormal screening blood, CSF (with the exception of CSF A
and tau levels) or urine results that remain abnormal at retest

Impaired coagulation (screening PT 1.2the ULN that remains abnormal on 
retest)

History of cancer, with the following exceptions:
–
If considered to be cured
–
If not being actively treated with anti-cancer therapy or radiotherapy and is not 
likely to require treatment in the ensuing 5 years
–
For prostate cancer or basal cell carcinoma, no significant progression over the 
previous 2 years

Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins, including 
gantenerumab

Hypersensitivity to any gantenerumab excipients

Any other severe or unstable medical conditions that could be expected to progress, 
recur, or change to such an extent that it could put the participant at special risk, 
interfere with the participant’s ability to complete the study assessments, or would 
require the equivalent of institutional or hospital care

Reside in a skilled nursing facility such as a convalescent home or long-term care 
facility

Require residence in such facilities during the study may continue in the study and 
be followed for efficacy and safety, provided that they have a study partner who 
meets the study partner requirements

Planned or recent (within 12 months prior to screening) exposure to ionizing 
radiation that in combination with the planned administrations of the radioligand 
would result in a cumulative exposure that exceeds recommended local guidelines
5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and Dietary Restrictions
This study has no meal or dietary restrictions.
5.3.2
Caffeine, Alcohol, and Tobacco
This study has no caffeine, alcohol, or tobacco restrictions.
5.3.3
Activity
This study has no activity restrictions.


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5.3.4
Contraception Requirements
During the study, female participants of childbearing potential must use contraception or 
take other precautions as described in Section 5.1.
5.4
SCREEN FAILURES
Individuals who do not meet the cognition or amyloid-based inclusion criteria for 
participation in this study (screen failure) cannot be rescreened. Rescreening on other 
criteria may be allowed as detailed in Section 5.2. The investigator will maintain a
record of reasons for screen failure (see Section 8).
6.
STUDY TREATMENT(S) AND CONCOMITANT THERAPY
Study treatment is defined as any investigational treatment, marketed product, placebo, 
or medical device intended to be administered to a study participant according to the 
study protocol.
The term ‘study drug’ in Study WN42444 refers to gantenerumab or placebo.  
Gantenerumab and placebo are also designated as investigational medicinal products 
(IMPs). According to E.U. guidance, the PET tracers, as used in the context of this 
study, are designated as non-IMPs.  In some regions, according to local regulations, 
these PET tracers may be considered to be IMPs (see Section 6.1.3).


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6.1
STUDY TREATMENTS ADMINISTERED
Table 8 provides a description of assigned study treatments for this study.
Table 8
Study Treatment Description
Gantenerumab
Placebo
[18F]-Florbetaben
[18F]-Flutemetamol
[18F]-MK-6240
Use
Experimental
Placebo 
comparator
Amyloid PET tracer
Tau PET tracer
Type of 
medicinal 
product
IMP
IMP
According to E.U. guidance, the PET tracers, as used in the 
context of this study, are designated as non-IMPs.  In some 
regions, according to local regulations, these PET tracers may 
be considered to be IMPs.
Drug form
Solution for SC
injection
Solution for 
SC injection
Solution for IV
injection
Solution for IV
injection
Solution for IV
injection
Unit dose 
strength(s)
120 mg/0.8 mL
255 mg/1.7 mL
Not 
applicable
Approximately 
20 mL of sterile 
solution for 
approximately 
300 MBq 
(see Investigator’s 
Brochure)
Approximately 
20 mL of sterile 
solution for 
approximately 
185 MBq 
(see Investigator’s 
Brochure)
Approximately 
20 mL of sterile 
solution for 
approximately 
185 MBq 
(see Investigator’
s Brochure)
Dosage 
level(s)
See 
Section 6.1.1
See 
Section 6.1.2
300 10% MBq
185 10% MBq
185 10% MBq
Formulation(s)
Refer to 
Investigator’s 
Brochure
Not 
applicable
Refer to 
Investigator’s 
Brochure
Refer to 
Investigator’s 
Brochure
Refer to 
Investigator’s 
Brochure
Packaging
Refer to 
Investigator’s 
Brochure
Refer to 
Investigator’s 
Brochure
Syringe
or glass vial 
sealed with a 
synthetic rubber 
closure and 
aluminum
overseal
Syringe
or glass vial sealed 
with a synthetic 
rubber closure and 
aluminum overseal
Syringe
or glass vial 
sealed with a 
synthetic rubber 
closure and 
aluminum
overseal
Labeling
Per local requirements
Route of 
administration
SC injection
SC injection
IV injection
IV injection
IV injection
Source
Sponsor
Sponsor
Life Molecular 
Imaging
GE Healthcare
Cerveau 
Technologies, Inc
IMPinvestigational medicinal product; PETpositron emission tomography.
At applicable sites, study treatment may be administered by a trained nursing 
professional at the participant’s home or another suitable location, if the patient has 
given written informed consent to participate in mobile nursing (MN) visits.


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Guidelines for dose modification and treatment interruption or discontinuation 
for participants who experience adverse events are provided in Appendix 3.
6.1.1
Gantenerumab
The active treatment under investigation for this study is gantenerumab.  
Gantenerumab will be administered by SC injections to all participants.
Participants who choose the Q1W dosing regimen at the target dose, and are 
randomized to the active treatment arm will receive a dose of gantenerumab 120 mg SC 
every 4 weeks (Q4W) three times, 255 mg SC Q4W three times, and 255 mg SC Q2W 
six times, regardless of APOE 4 status, prior to reaching the target dose of 255 mg 
Q1W (i.e., 1020 mg per month) as detailed in Table 1.
Participants who choose the Q2W dosing regimen at the target dose, and are 
randomized to the active treatment arm will receive a dose of gantenerumab 120 mg SC 
Q4W three times, 255 mg SC Q4W three times, and 510 mg SC Q4W three times, 
regardless of APOE 4 status, prior to reaching the target dose of 510 mg Q2W
(i.e., 1020 mg per month) as detailed in Table 4.
Note:  the minimum number of study drug doses, as outlined above, must be 
administered during each titration step prior to dose escalation.
Following the initial dose escalation period, study drug will be administered at a Q1W 
(Table 2) or Q2W (Table 5) dosing regimen. Participants will use their selected dosing 
regimen throughout the maintenance dosing phase of the study.
For Q4W injections, a visit window of 7 days is allowed for dosing visits.  Once study 
drug is administered Q1W or Q2W, the visit window for dosing visits is 3 days.  
It is recommended not to administer more than 1020 mg (i.e., 4255 mg Q1W or 
2510 mg for Q2W) within 28 days.  Always return to the initial planned dosing regimen
for subsequent visits.  If administration is not possible on the scheduled dosing day, the 
study drug should be administered as soon as possible within the time window from the 
scheduled dosing date. If the study drug cannot be administered within the time window, 
the dose should be skipped, and the participant should receive the next dose at the next 
scheduled time with the study drug dosing resumed in accordance with the original 
dosing schedule.
During the initial dose escalation, the maintenance dosing periods, and the
post-progression dose escalation period (if applicable), injections will be administered 
SC into the abdomen as a single injection, 2 or 3 injections as any combination of the
following:

0.8 mL injection for the 120 mg dose or placebo

1.7 mL injection for the 255 mg dose or placebo


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Participants on the Q1W dosing regimen will receive 1 SC study drug injection per 
dosing visit during the initial dose escalation and maintenance dosing periods 
(Table 1 and Table 2). However, participants on the Q1W dosing regimen will receive 
2 SC study drug injections per dosing visit at Week 1P, Week 5P, and Week 9P, and 
1 SC study drug injection per dosing visit at all other dosing visits during the 
post-progression dose escalation period (Table 3).
Participants on the Q2W dosing regimen will receive 1 SC study drug injection per 
dosing visit until Week 25 during the initial dose escalation period (Table 4). Starting at 
Week 25, participants will receive 2 SC study drug injections per dosing visit during the 
initial dose escalation, maintenance dosing, and post-progression dose escalation 
periods with the exception of dosing at Week 1P, Week 5P, and Week 9P 
(Table 4, Table 5, and Table 6) when they will receive 3 SC study drug injections per 
dosing visit (Table 6).
During pre-specified visits, the study drug may be administered by the participant or their
study partner (non-professional caregiver) at the participant’s home or another suitable 
location depending on the individual participant’s/study partner’s preference, if 
appropriately trained and certified by the investigator or delegate, and allowed by local 
regulations.
During the initial dose escalation period, participants will receive SC injections of study 
drug by the investigator or an appointed qualified study staff for the first 3 doses at the 
clinic. If the participant or their study partner is willing and determined capable of 
administering SC injections by the investigator or delegate, this participant or study 
partner will receive observer and dose administration training at the first 3 dosing visits 
(i.e., Weeks 1, 5, 9). At the next 4 visits (i.e., Weeks 13, 17, 21, and 25) the injections 
will be administered by the participant or study partner under the site staff’s supervision. 
Following the supervised dosing visits at the clinic, subsequent dosing may be 
administered by the participant or study partner at home except for doses that coincide 
with a clinic visit, in which case the participant or study partner should administer the 
injection in the clinic, under investigator/study staff supervision. Study staff will 
document the outcome of the supervised administrations. Training and supportive 
materials will be provided to the site and the participant and/or their study partner. 
Following the in-person instructional training and supervised administrations at the site, 
adequate supply of study drug will be provided. Participants should be observed for at 
least 2 hours after dosing for the first 4 administrations of study drug (corresponding to 
the injections at Week 1, Week 5, Week 9 and Week 13); the observation time may be 
reduced to at least 1 hour following all other administrations. However, participants must 
be observed for a minimum of 1 hour after each injection by their study partner or 
another suitably trained individual (i.e., “postdose observer”) even if they are 
self-administering the study drug.  Study partners and postdose observers will be trained 
by the site staff to recognize signs and symptoms of allergic reactions and the 
appropriate actions to be taken if the participant were to develop those signs and 


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symptoms. Postdose observers must also sign the Postdose Observer ICF prior to the 
initiation of the training.
At subsequent visits as specified in the schedule of activities (see Section 1.3), the 
investigator or appointed qualified study staff will determine if the participant or study 
partner continues to be qualified to perform home administrations. If at any time the 
investigator, participant, or study partner determines that home administration by the 
participant or study partner is unqualified, then the study drug must be administered at 
home or in the clinic by an alternative trained study drug administrator.
Starting from the fifth dose, at applicable sites, study drug may also be administered by 
a trained healthcare professional (mobile nurse) at the participant’s home or another 
suitable location, if the participant has given written informed consent.
During the post-progression dose escalation period (Section 1.3 [Table 3 and Table 6]), 
participants must be observed for at least 2 hours after the first 4 ‘definitely active doses’ 
(i.e., dosing at Week 1P, Week 5P, Week 9P and Week 13P).  The observation time 
may be reduced to at least 1 hour following all other administrations. Participant or 
study partner administration is prohibited during the post-progression dose escalation
period. The study drug administration by the participant or their study partner may 
resume after Week 37P following assessment and adequate training, if necessary, by 
the site. Sites must verify participant/study partner readiness for study drug
administration.
A vial adapter will be available in countries where it has been approved to withdraw the 
medication from the vial into a disposable syringe (this device will be optional for health 
care professionals and for participants and study partners [non-professional caregivers]).
For study drug administration days that include efficacy assessments, study drug must 
be administered at the clinical site by the site staff or the participants/study partner.  
Study personnel preparing and administering study drug must not be involved with any 
efficacy or safety assessments.
Any cases of overdose, medication error, drug abuse, or drug misuse of study treatment
should be noted on the Study Drug Administration electronic Case Report Form (eCRF).  
Adverse events associated with an overdose, medication error, drug abuse, or drug 
misuse of study treatment should be recorded on the Adverse Event eCRF
(see Section A27.13).
Refer to the Pharmacy Manual and/or the Home Administration Manual and the 
Gantenerumab Investigator's Brochure for information on study drug handling, including 
preparation and storage, and accountability.


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6.1.2
Placebo
A placebo of identical composition (except gantenerumab) and volume to gantenerumab
will be administered by SC injection to the abdomen. The dosing schedule of the 
placebo and gantenerumab will also be identical throughout the duration of the study as 
detailed in Section 1.3.
Additional details on dosing in Study WN42444 are provided in Section 4.1.3.
6.1.3
Positron Emission Tomography Tracers
For screening, the possible amyloid PET ligands will be [18F]-Florbetaben and 
[18F]-Flutemetamol. [18F]-Flutemetamol is only allowed for screening if access to 
[18F]-Florbetaben at the imaging site is not possible. If during screening, the 
amyloid-based eligibility is established based on an off-protocol (i.e., historical) amyloid 
PET scan, the participant will not be allowed to participate in the optional longitudinal 
amyloid PET assessments, unless a repeat [18F]-Florbetaben amyloid PET scan is 
obtained at baseline. Such participants may still participate in the optional longitudinal 
tau PET assessments.
For the optional longitudinal amyloid PET assessments only [18F]-Florbetaben will be 
used, except that, the use of [18F]-Flutemetamol will be allowed in Japan due to
insufficient availability of [18F]-Florbetaben. Participants who will be assessed with 
[18F]-Flutemetamol will not be accounted for in the 200 participant target sample size for 
the longitudinal amyloid PET assessments.
For the longitudinal tau PET assessment, [18F]-MK-6240 will be used.
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.
Additional requirements for all participants receiving an amyloid or tau PET scan include:

Females of childbearing potential will undergo additional pregnancy tests and must 
have a negative pregnancy test result prior to the tracer injection

Planned or recent (within 12 months prior to screening) exposure to ionizing 
radiation that in combination with the planned administrations of the radioligand 
would result in a cumulative exposure equal to or less than recommended local 
guidelines
For the safety reporting requirements dealing with the PET tracers used in this study,
please see Section 8.3.4).


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6.2
PREPARATION, HANDLING, STORAGE, AND 
ACCOUNTABILITY
Investigational medicinal products required for completion of this study will be provided 
by the Sponsor. The study site (i.e., investigator or other authorized personnel such as
pharmacist or mobile nurse) is responsible for maintaining records of IMP delivery to the 
site, IMP inventory at the site, IMP use by each participant, and disposition or return of 
unused IMP, thus enabling reconciliation of all IMP received, and for ensuring that 
participants are provided with doses specified by the protocol.
The study site should follow all instructions included with each shipment of IMP. 
The study site will acknowledge receipt of IMPs supplied by the Sponsor, with use of an 
IxRS to confirm the shipment condition and content. Any damaged shipments will be 
replaced. The investigator or designee must confirm that appropriate temperature 
conditions have been maintained during transit, either by time monitoring 
(shipment arrival date and time) or temperature monitoring, for all IMPs received and 
that any discrepancies have been reported and resolved before use of the IMPs. 
All IMPs must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, with 
access limited to the investigator and authorized staff.
Only participants enrolled in the study may be administered the IMP, only authorized 
staff may dispense the IMP, and only authorized healthcare professionals or trained 
participants/study partners may administer the IMP.
Investigational medicinal products 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 accountability log.
If applicable, participants or study partners will confirm completed administration in the 
home (nonclinical) setting with use of a diary. Further details will be described in the 
Home Administration Manual.
Refer to the Pharmacy Manual and/or the Home Administration Manual and the 
Gantenerumab Investigator's Brochure for information on IMP handling, including 
preparation and storage, and accountability.


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6.3
TREATMENT ASSIGNMENT AND BLINDING
6.3.1
Treatment Assignment
This is a randomized, double-blind study. After the main study written informed consent 
has been obtained, all screening procedures and assessments have been completed, 
and eligibility has been established for a participant, the study site will obtain the 
participant's identification number and treatment kit assignment from an IxRS.
Participants will be randomly assigned to 1 of 2 treatment arms. The ratio will be 1:1, 
1 experimental to 1 control. The randomization method will be stratified 
block-randomization. Randomization to treatment allocation will be stratified by the 
following criteria:  geographic region (Western Europe, Australia, and New Zealand), the 
participant’s APOE 4 carrier status (non-carrier vs. heterozygote carrier vs. homozygote 
carrier), the method used to determine amyloid positivity (PET vs. CSF), and 
participation in the optional longitudinal amyloid PET and tau PET assessments.
6.3.2
Blinding
The study is to be conducted in a double-blinded manner to minimize potential bias from 
investigators and participants. The Sponsor, participants and their study partners, and
the site staff will remain blinded to treatment assigned at randomization, even after a 
participant progresses to MCI or dementia due to AD and starts active treatment.
In order to protect study blinding, no one administering or with the potential to administer 
drug to participants will be permitted to conduct any efficacy assessments.
Study partners will only be permitted to support 1 participant in the trial and may not be 
enrolled as study participants at the same time.
The Master Randomization or Master Medication List will not be available at the study 
center to Roche monitors, Roche project statisticians, or to the project team at Roche. 
Unblinding should not occur except in the case of emergency situations where 
knowledge of the study drug assigned would affect participant care. The investigator 
should make every effort to contact the Medical Monitor before unblinding a participant. 
If unblinding is necessary for participant management, the investigator will be able to 
break the treatment code by contacting the IxRS.  The investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event). Any request from the investigator for
information about the treatment administered to study participants for another purpose 
must be discussed with the Medical Monitor.
While PK and immunogenicity samples must be collected from participants not exposed 
to gantenerumab to maintain the blinding of treatment assignment, PK and ADA assay 
results for such participants are generally not needed for the safe conduct or proper 
interpretation of the study data. Laboratories responsible for performing study drug PK 
and ADA assays will be unblinded to participant treatment assignments to identify 
appropriate samples for analysis. Pharmacokinetic and ADA samples from participants 


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not exposed to gantenerumab will not be analyzed for study drug PK concentration or 
ADAs except by request (e.g., to evaluate a possible error in dosing).
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 8.3.4) that are considered by the investigator or Sponsor to be related to an 
IMP (defined in Section 6). 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.
6.4
STUDY TREATMENT COMPLIANCE
When participants are dosed at the site, they will receive study treatment directly from 
the investigator, their designee or via self/study partner administration under medical 
supervision. The date and time of each dose administered in the clinic will be recorded 
in the source documents and recorded on the eCRF. The dose of study treatment and 
study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study treatment.
When participants self-administer study treatment at home, compliance with study 
treatment will be assessed via regular phone calls per Section 6.1.1 and the dosing diary 
per Section 6.2.
Details on treatment administration (e.g., dose and timing) should be noted in the source 
documents and on the Study Drug Administration eCRF. Cases of overdose, medication 
error, drug abuse, or drug misuse, along with any associated adverse events, should be 
reported as described in Appendix 2.
6.5
DOSE MODIFICATION
Rules regarding dose interruptions or modifications in participants who develop 
ARIA events are provided in Section A31.  Discontinuation from study treatment is 
detailed in Section 7.1. Participant non-compliance and other potential reasons to 
discontinue a participant from the study are detailed under Section 7.2.
6.6
CONTINUED ACCESS TO STUDY TREATMENT AFTER THE 
END OF THE STUDY
The Sponsor will offer continued access to gantenerumab free of charge to eligible 
participants in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.


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A participant will be eligible to receive 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 gantenerumab 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
A participant will not be eligible to receive gantenerumab after completing the study if 
any of the following conditions are met:

The gantenerumab 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 gantenerumab or data suggest 
that the gantenerumab is not effective for the prevention of symptomatic AD and/or 
the treatment of prodromal to mild AD

The Sponsor has reasonable safety concerns regarding the gantenerumab as a 
treatment for AD

Provision of the gantenerumab 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:
https://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
6.7
TREATMENT OF OVERDOSE
An overdose is the administration of a drug in a quantity that is higher than the assigned 
dose. There is no known antidote for treating gantenerumab. Cases of medication 
error, including overdoses, along with any associated adverse events, should be 
reported as described in Appendix 2.
In the event of an overdose, the investigator should take the following steps:

Contact the Medical Monitor immediately

Closely monitor the participant for any adverse event or serious adverse event and
laboratory abnormalities. The investigator may choose to perform additional 
MRI monitoring for ARIA at any time (see Section A31).
Supportive treatment, in line with local regulations and guidelines, for any noted 
symptoms is recommended.


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6.8
CONCOMITANT THERAPY
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, herbal and homeopathic remedies, and nutritional supplements) used by a 
participant in addition to protocol-mandated treatment from 3 months prior to the 
screening visit until the study completion or discontinuation visit must be recorded on the 
Concomitant Medications eCRF along with the following information:

Reason for use

Dates of administration, including start and end dates

Dosage information, including dose and frequency
The Medical Monitor may be consulted if there are any questions related to concomitant 
or prior therapy.
6.8.1
Permitted Therapy
The following medications are permitted if the dose and dosing regimen have been 
stable for at least 3 months (unless otherwise specified below) prior to the screening 
visit, and are expected to remain stable after screening or if required for treatment of an 
adverse event after study start:

Anticonvulsant medications for an approved pain indication

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin Norepinephrine 
Reuptake Inhibitors (SNRIs) for the treatment of depressive symptoms

Chronic use of prescribed opiates or opioids for pain management is allowed if on a 
stable dose for at least 1 month prior to screening.  Chronically used, prescribed 
opioids do not have to be discontinued prior to cognitive testing if on a stable dose 
for at least 1 month prior to cognitive testing.

Chronic use of prescribed benzodiazepines, barbiturates and hypnotic medications 
are allowed if on a stable dose for at least 1 month prior to screening.  
Chronically used, prescribed benzodiazepines, barbiturates and hypnotic 
medications do not have to be discontinued prior to cognitive testing if on a stable 
dose for at least 1 month prior to cognitive testing.

Intermittent, short-term use of prescribed opiates or opioids for pain, as well as 
benzodiazepines, buspirone, and short-acting hypnotic medication for sleep or 
anxiety are allowed, except within 2 days or 5 half-lives (whichever is longer) prior to 
any neurocognitive assessment

Medical marijuana (licensed and/or standardized marijuana or its derivatives, as 
prescribed or recommended by a healthcare professional in the treatment of a 
medical condition) is allowed if on a stable dose for at least 1 month prior to 
screening.  Medical marijuana does not have to be discontinued prior to cognitive 
testing if on a stable dose for at least 1 month prior to cognitive testing.

Intermittent use of centrally acting antihistamine medications except within 2 days or
5 half-lives (whichever is the longer) prior to any cognitive assessment


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
Anti-platelet treatments (e.g., aspirin, clopidogrel, dipyridamol) and low dose low-
molecular-weight heparin for prophylaxis are permitted

Participants who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use

Medical food supplements (e.g., Axona®, Souvenaid®) are allowed if on a stable 
dose for at least 1 month prior to cognitive testing including at screening
Whenever possible, one of the medications listed below should be used if appropriate.
Concomitant and excluded therapies for determination of participant eligibility are 
described in Section 5.2.7.
6.8.1.1
COVID-19 Vaccination
Based on the available information, no interactions between gantenerumab 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 Alzheimer’s disease.
However, the published safety data show that overlapping adverse events between 
gantenerumab/placebo and the vaccines 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.
Just as with other vaccinations (e.g., influenza), the administration of COVID-19 
vaccines will be considered as a concomitant medication in these studies.
In the situation that vaccination of a study participant with a COVID-19 vaccine is
considered:

COVID-19 vaccines that have been approved or authorized for temporary use can 
be administered to study participants according to the national and local guidance, 
and their use should be documented on the “Concomitant Medication” eCRF. 
Only those administered during the time of the protocol specified reporting window 
for concomitant medications should be collected. Sites should collect as much 
information as is available regarding the vaccine received on the concomitant 
medication page of the eCRF. The following should be included where available:
–
Manufacturer or proprietary name
–
Vaccine type
–
Date of administration (if 2 or more doses are received, sites should record 
each administration as a separate entry)
–
If different COVID-19 vaccines are administered (e.g., Pfizer-BioNTech 
COVID-19 Vaccine at first dose and the Oxford University/AstraZeneca 
COVID-19 Vaccine at second dose) this should be clearly captured

To facilitate the correct clinical assessment of any adverse events and to continue 
correct attribution of adverse events related to study drug (gantenerumab/placebo) 


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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.

Any adverse events observed in association with the use of vaccines should be 
documented on the adverse event page in the eCRF and clinically managed, as it is 
medical practice for any other concomitant vaccination

On the same adverse event page, assign the adverse event causality in the 
"Other suspected causes" field to "Concomitant medication". The Injection Site 
Reaction eCRF should not be completed for local injections reactions due to the 
vaccine.
6.8.2
Cautionary Therapies
6.8.2.1
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential druginteractions are generally 
unknown.
6.8.3
Prohibited Therapy
The following medications are prohibited for a pre-specified duration prior to study start, 
as indicated, and during the entire period of study participation (participants who start 
these medications during the study may be withdrawn from study treatment):

Any previous administration of gantenerumab is exclusionary at screening

Any previous administration of active immunotherapy (vaccine) that is being 
evaluated to prevent or postpone cognitive decline is exclusionary at screening and 
prohibited during the entire period of study participation

Any passive immunotherapy (Ig) or other long-acting biologic agent to prevent or 
postpone cognitive decline within 1 year of screening are exclusionary.  Use of 
passive immunotherapy (Ig) or other long-acting biologic agents to prevent or 
postpone cognitive decline is also prohibited during the entire period of study 
participation.

Any other investigational treatment within 5 half-lives or 6 months (whichever is 
longer) prior to screening is exclusionary and prohibited during the entire period of 
study participation

Any previous administration of GV-971 is exclusionary at screening.  The use of 
GV-971 is prohibited during the entire period of study participation.

Any previous treatment with medications specifically intended to treat symptoms 
related to Parkinson’s disease or any other neurodegenerative disorder is 
exclusionary at screening and the use of these medications is prohibited during the 
study. Certain medications are acceptable, if the participant is taking the medication
for a non-neurodegenerative disorder (e.g., pramipexole for restless leg syndrome).


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
Anticonvulsant medications are exclusionary at screening and throughout the study, 
except as treatment for an approved pain indication or an adverse event after study 
start

Typical anti-psychotic or neuroleptic medications are exclusionary at screening and 
throughout the study, except as brief treatment for a non-psychiatric indication 
(e.g., emesis)

Atypical anti-psychotic medications are exclusionary at screening and during the 
stud except for intermittent short-term use

Anticoagulation medications within 3 months of screening with no plans to initiate 
any prior to randomization
–
During the study, short-term use of anti-coagulant medications may not result 
in permanent discontinuation from the study; however, will require temporary 
interruption of the study drug.

Psychedelic drugs and substances (e.g., psilocybin, LSD), recreational cannabis 
and illicit use of opioids (e.g., opium, morphine, fentanyl or diacetylmorphine/heroin) 
or ketamine are exclusionary at screening and during the entire study

Nootropics and stimulant medications (e.g., piracetam, amphetamine, 
methylphenidate preparations, or modafinil) are exclusionary within 1 month of 
screening and throughout the study

Any previous treatment with cholinesterase inhibitors (e.g., donepezil, galantamine, 
rivastigmine) and N-methyl-D-aspartate receptor antagonists (e.g., memantine) are 
exclusionary at screening. Cholinesterase inhibitors (e.g., donepezil, galantamine, 
rivastigmine) and N-methyl-D-aspartate receptor antagonists (e.g., memantine) are
prohibited during the study unless the participant has progressed to dementia as 
determined by the iCAC
7.
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION OR WITHDRAWAL
Study and site closure is described in Appendix 1.
7.1
DISCONTINUATION OF STUDY TREATMENT
It may be necessary for a participant to permanently discontinue 
(definitive discontinuation) study treatment. If study treatment is definitively 
discontinued, the participant will remain in the study for additional assessments. See the 
schedule of activities (see Section 1.3) for data to be collected at the time of 
discontinuation of study treatment and for any further follow-up evaluations that need to 
be completed.


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Participants must permanently discontinue study treatment if any of the following criteria 
are met:

Any medical condition that the investigator determines (including upon the 
Sponsor’s recommendation) may jeopardize the participant's safety if he or she 
continues to receive study treatment

Investigator determination (including upon the Sponsor’s recommendation) that 
treatment discontinuation is in the best interest of the participant

Pregnancy

Upon evidence of disseminated leptomeningeal hemosiderosis

Upon evidence of intracerebral macrobleed
If study treatment is discontinued permanently for participants dosed at home, any 
remaining study drug doses should be returned to the study site (if applicable).
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
Participants who discontinue from the study treatment for any reason should be 
encouraged to continue with all remaining assessments until the end of the study. 
However, participants who are unwilling to return to the clinic will be asked to complete 
the Early Termination and safety follow-up visits within 2 weeks and 17 weeks,
respectively from the final dose of study drug.
7.2
PARTICIPANT DISCONTINUATION OR WITHDRAWAL FROM 
THE STUDY
A participant may withdraw from the study at any time at his or her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. The participant will then be permanently 
discontinued both from the study treatment and from the study at that time.
Participants who withdraw from the study will not be replaced.
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.
If a participant withdraws consent from the study, the Sponsor may retain and continue 
to use any data collected before withdrawal of consent.  Samples collected prior to 
withdrawal may be analyzed, unless the participant specifically requests that the 
samples be destroyed (as documented in the source documents) 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.
All participants who discontinue from the study early will be asked to return 2 weeks 
after the final dose of study drug to complete the early termination visit and 17 weeks 


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after the final dose of study drug for the safety follow-up visit.  If participants dosed at
home discontinue the study early, any remaining study drug doses should be returned to 
the study site (if applicable).
Every effort should be made 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. However, participants will not be followed for any reason after
consent has been withdrawn. If a participant requests to be withdrawn from the study,
this request must be documented in the source documents and signed by the
investigator.
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

Any medical condition that the investigator or Sponsor determines may jeopardize
the participant’s safety if he or she continues in the study

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 3 consecutive dose administrations (with Q4W dosing regimen), more than 
6 consecutive dose administrations (with Q2W dosing regimen), or 12 consecutive 
dose administrations (with Q1W dosing regimen) because of non-safety related reasons 
or more than half of the dosing visits in a calendar year. See the schedule of activities in 
Section 1.3 for details on Early Termination and Safety Follow-up visits to be performed 
for participants who permanently discontinue study treatment.  If a participant requests 
to be withdrawn from treatment or follow-up assessments, this request must be 
documented in the source documents and signed by the investigator.
7.3
PARTICIPANTS LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule. If the participant is unable or unwilling to comply with study 
visits, site personnel should assess reasons the participant is unable or unwilling to 
return to the clinic, and determine if there are ways to support participant 
participation.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 


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calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.

Should the participant continue to be unreachable, he or she will be considered lost 
to follow-up and will be withdrawn from the study
8.
STUDY ASSESSMENTS AND PROCEDURES
Written informed consent for participation in the study must be obtained from all 
participants and their study partners (non-professional caregivers) before performing any
study-related procedures. Informed Consent Forms for enrolled participants, their study 
partners, and postdose observers, as well as for those who are not subsequently 
enrolled, will be maintained at the study site.  Written informed consent for participation 
in the study must be obtained from:

All participants before performing any study-related procedures (including optional 
prescreening evaluations)

All study partners (non-professional caregivers) before performing any study-related 
screening procedures excluding the optional prescreen

Each postdose observer before they undertake any study-related procedure, 
including any training
Informed Consent Forms for enrolled participants, their study partners, and postdose
observers, as well as for those who are not subsequently enrolled, will be maintained at 
the study site.
Study procedures and their timing are summarized in the schedule of activities
(see Section 1.3). Prospective approval of protocol deviations, also known as protocol 
waivers or exemptions, is not permitted.
Urgent safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment. Adherence to the study design requirements, including those specified 
in the schedule of activities, is essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before enrollment.  The investigator will maintain a 
detailed record of all participants screened, to document eligibility or record reasons for 
screening failure, as applicable.
Medical history and baseline conditions, including clinically significant diseases, 
surgeries, cancer history (including prior cancer therapies and procedures), reproductive 
status, and use of alcohol and drugs of abuse will be recorded at baseline. 
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, herbal and homeopathic remedies, and nutritional supplements) used by the 


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participant within 3 months prior to the screening visit will be recorded at baseline. 
Demographic data, including age, sex, and self-reported race or ethnicity, relationship 
status of participants and their study partner, living situation and length of acquaintance 
will also be recorded and updated upon changes. At the time of each follow-up physical 
examination, an interval medical history should be obtained and any changes in 
medications, demographic data and allergies should be recorded.
As 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).
Participants will be closely monitored for safety throughout the study. 
Participants should be assessed for toxicity prior to each dose; treatment will be 
administered only if the clinical assessment and local laboratory test values are 
acceptable. Urgent safety concerns should be discussed with the Sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.
At applicable sites, certain study assessments may be performed by a MN professional
at the participant's home or another suitable location 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 home 
administration at 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. Mobile nursing visits will be scheduled on specified visit days, to allow for relevant 
assessments to be performed by the MN professional. The MN Manual will specify the 
assessments that may be performed by a MN professional.
8.1
EFFICACY ASSESSMENTS
8.1.1
Clinical Outcome Assessments
Clinical outcome assessments (COAs) will be completed to assess the treatment benefit 
of gantenerumab as outlined in the schedule of activities (see Section 1.3) and in the 
order specified in Section 8.10. Cognitive, functional, neuropsychiatric and quality of life 
assessments (i.e., PACC-5, CDR, CFIa, Amsterdam Instrumental Activities of Daily 
Living Questionnaire Short Version [A-IADL-Q-SV], AD-CGI-S, AD-PGI-S, AD-SPGI-S,


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GDS-30, and the EQ-5D-5L) will be administered. Detailed descriptions of COAs
included in Study WN42444 are provided in Section 8.10.2.
8.1.2
Pharmacodynamic Assessments
Biomarker efficacy assessments are detailed in Section 8.5.
8.2
SAFETY ASSESSMENTS
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the head, 
eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary (optional), and neurological systems. 
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF.
A limited physical examination will be symptom-directed. Investigators should pay 
special attention to clinical signs related to previous serious illnesses. 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.
The schedule of activities (see Section 1.3) indicates when complete and limited 
physical examinations are to be recorded. During unscheduled visits, the investigator or 
designee may choose the appropriate scope of physical examination (complete vs.
limited physical examination) depending on the reason for the unscheduled visit.
8.2.2
Vital Signs
Vital signs will consist of pulse rate and systolic and diastolic blood pressure 
measurements.
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
If obtained manually, the pulse rate will be determined by radial pulse and should be 
counted for a minimum of 20 seconds.
Blood pressure and pulse measurements should be taken before blood collection for 
laboratory tests and preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions (e.g., television, cell phones). The same arm should be used 
for all blood pressure measurements.
Record abnormalities observed at baseline on the General Medical History and Baseline 
Conditions eCRF. At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.


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The schedule of activities (see Section 1.3) indicates when vital signs (pulse and blood 
pressure measurements) are to be recorded.
8.2.3
Electrocardiograms
Single 12-lead ECGs will be obtained as outlined in the schedule of activities 
(see Section 1.3).
All ECG recordings must be performed a standard high-quality, high fidelity digital 
electrocardiograph machine.  Lead placement should be as consistent as possible. 
Electrocardiogram 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, 
LPs). 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 reports. Paper copies of ECG tracings will be kept as part of the participant's 
permanent study file at the site.
The centrally-provided electrocardiograph machine should record the heart rate, 
QRS interval, RR interval, PR interval, QT interval, QTcB and QTcF (i.e., the QT interval 
corrected through use the Bazett formula and Fridericia's formula, respectively).
8.2.4
Clinical Safety Laboratory Tests
See Appendix 24 for the list of clinical laboratory tests to be performed and to the 
schedule of activities (see Section 1.3) for the timing and frequency.  Clinical laboratory 
tests conducted by a central laboratory must be conducted in accordance with the 
laboratory manual.
The investigator must review the laboratory report, document this review, and record any 
clinically-relevant changes occurring during the study in the Adverse Event Case Report 
Form (CRF) (see Appendix 24).
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 17 weeks of the final dose of study treatment should 
be repeated until the values return to normal or baseline or are considered to be stable 
and no longer considered clinically significant by the investigator. If such values do not 
return to normal or baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the Sponsor notified.
If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g., serious adverse event or 
adverse event or dose modification), the results must be recorded on the eCRF.


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Samples collected for safety laboratory tests will be destroyed no later than the time of 
completion of the final Clinical Study Report.
8.2.5
Pregnancy Testing
The schedule for pregnancy testing for enrolled female participants is outlined in 
Section 1.3 and will be conducted as outlined in Appendix 4.
8.2.6
Monitoring for Suicidal Ideation and Behavior
Participants should be monitored appropriately and observed closely for suicidal ideation 
and behavior or any other unusual changes in behavior, especially at the beginning and 
end of the course of study drug treatment, or at the time of dose changes.
Consideration should be given to discontinuing study drug in participants who 
experience signs of suicidal ideation or behavior, following a risk assessment.
Study partners, families, and caregivers of participants should be alerted about the need 
to monitor participants for the emergence of unusual changes in behavior, as well as the 
emergence of suicidal ideation and behavior and to report such symptoms immediately 
to the study investigator.  Assessment of suicidal ideation and behavior or
treatment-emergent suicidal ideation and behavior will be monitored during
Study WN42444 with use of the C-SSRS (Posner et al. 2011).
The C-SSRS (https://www.cssrs.columbia.edu) is an assessment tool used to assess the 
lifetime suicidality of a participant (C-SSRS assessment at baseline) as well as any new 
instances of suicidality (C-SSRS assessments after baseline). 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 assessments will be 
performed as indicated in the schedule of activities (see Section 1.3, Table 1, Table 2, 
and Table 3 for the QW1 dosing regimen and Table 4, Table 5, and Table 6 for the Q2W 
dosing regimen).
The assessment will be completed by a certified C-SSRS rater after he or she interviews 
the participant and their study partner during the study visit.
8.2.7
Brain Magnetic Resonance Imaging
In this study brain MRIs will be performed as outlined in the schedule of activities 
(see Section 1.3) for screening purposes, to support safety assessments, and to provide 
baseline information for the PET assessments. A detailed description is provided in 
Section 8.5.4.
During the initial dose escalation period (Table 1 and Table 4), MRIs must be performed 
after the third dose of current dose level while on the Q4W schedule, or after the 
sixth dose of the current dose level while on the Q2W schedule. Magnetic resonance 
imaging scans should be performed at least 7 days prior to dose escalation to the next 
dose level and the results must be available for review by the investigator or their 


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qualified designee before the dosing can proceed. It is not recommended that the MRI is 
performed on the same day as the study drug administration.
During the maintenance dosing period (Table 2 and Table 5), MRIs should be
performed at least 7 days but no more than 13 days before the dosing visit that requires 
a safety MRI result. Results must be available for review by the investigator or their 
qualified designee before dosing at the visit that requires a safety MRI result can 
proceed. Magnetic resonance imaging scans should be performed before or at least 3 
days following CSF sampling.
During the post-progression dose escalation period of the Q1W dosing schedule
(Table 3), a minimum of 3 ‘definitely active doses’ during the first 2 dosing levels and 
minimum of 6 ‘definitely active doses’ during the third dosing level must be 
administered before the participant is eligible for the next dose escalation. If required 
by the schedule of activities, MRIs should be performed at least 7 days prior to dose 
escalation to the next dose level, and results must be available for review by the 
investigator or their qualified designee before the dosing can proceed.
Magnetic resonance imaging scans should be performed before or at least 3 days 
following CSF sampling.
During the post-progression dose escalation period of the Q2W dosing schedule
(Table 6), a minimum of 3 ‘definitely active doses’ at each dosing level must be 
administered before the participant is eligible for the next dose escalation. If required 
by the schedule of activities, MRIs should be performed at least 7 days prior to dose 
escalation to the next dose level, and results must be available for review by the 
investigator or their qualified designee before the dosing can proceed.  
Magnetic resonance imaging scans should be performed before or at least 3 days 
following CSF sampling.
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, including participant eligibility as well as for analysis, 
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 8.5.2).
See Section A35 for instructions in the event of new MRI findings (ARIA-E and 
ARIA-H).
8.3
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, AND OTHER 
SAFETY REPORTING
The definitions of adverse event and serious adverse event can be found in Appendix 2.


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Adverse events will be reported by the participant and their study partner (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an adverse event or serious adverse 
event and remain responsible for following up adverse events that are serious, are
considered related to the study treatment or study procedures, or caused the participant 
to discontinue the study treatment/study (see Section 7).
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
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 e-mailing the form using the fax number or 
e-mail address provided to investigators. All other medical occurrences that begin 
before the start of study treatment but after obtaining informed consent will be recorded 
on the General Medical History and Baseline Conditions eCRF, not the Adverse Event 
eCRF.
All adverse events will be reported from the start of treatment until 17 weeks after the 
final dose of study treatment at the timepoints specified in the schedule of activities 
(see Section 1.3).
All serious adverse events will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 2.  The investigator will submit any updated serious adverse event data to the 
Sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek adverse event or serious adverse event 
information after conclusion of study participation.  However, if the investigator learns of 
any serious adverse event, including a death, at any time after a participant has been 
discharged from the study, and he or she considers the event to be reasonably related to 
the study treatment or study participation, the investigator must promptly notify the 
Sponsor.
Adverse events that occur during the participant’s participation in imaging procedures at 
the imaging center or that are reported at the time of the participant’s visit to the imaging 
center will be communicated to the referring clinical site.  Conversely, any clinically 
significant adverse events reported to the clinical site that may affect the participation of 


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any one participant or all participants enrolled in this study will be communicated to the 
imaging center within 24 hours of learning of the event.
Clinical observations by the responsible physician or designee at the imaging center, as 
well as vital sign measurements performed at the imaging center, will be recorded in the 
source data only and will not be part of the clinical study database unless any of these 
clinical observations/vital signs are clinically significant and constitute adverse events as 
assessed by the responsible physician or designee at the imaging site.
All adverse events that occur or are reported during the participant’s visit at the imaging 
center will be retrospectively entered into the clinical database by the clinical site without 
the need to complete an Adverse Event Worksheet.
Additional measures for at-home administration:  Every 4 weeks, except when there 
is an in-person clinic visit, the investigator or an appointed qualified study staff will have 
a telephone conversation with the participant and study partner to elicit, in a non-leading 
way, information on medication errors, adverse events, and changes to concomitant 
medications that may have occurred in the home setting.  Therefore, there will be 
contact between the study staff and the participant/study partner at least every 4 weeks.  
The study staff is encouraged to have more frequent calls with a particular 
participant/study partner if considered appropriate by the investigator.  Following the first 
2 years of study treatment, the frequency of this telephone surveillance may be reduced 
to occur at least once, at midtime, between the 6-month in-person clinic visits.
However, for participants who enter the post-progression dose escalation period, there 
will be contact between the study staff and the participant/study partner at least every 
4 weeks for 2 years after entering the post-progression dose escalation period (Table 3
and Table 6). Following this 2-year period, the frequency of this telephone surveillance 
can be reduced again as outlined above. In addition, the participant and study partner 
must be instructed to contact the investigator and seek approval for continued study 
drug dosing in the home setting in case of onset of any new symptoms or symptom 
worsening, new or changed concomitant medications, or medication errors.
In addition, after administration of a PET ligand, but prior to initiation of study drug, the 
following adverse events should be reported:

All adverse events (serious or non-serious) believed to be related to a PET ligand

All serious adverse events occurring within 48 hours of PET ligand administration 
regardless of relatedness to the PET ligand
For reporting of serious adverse events, the above-outlined principles apply.
For non-serious PET ligand-related adverse events, a PET ligand-specific non-serious 
adverse event reporting paper form should be completed and submitted to the Sponsor 
or its designee, either by faxing or by scanning and e-mailing the form using the fax 
number or e-mail address provided to investigators.


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8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
The method of recording, evaluating, and assessing causality of adverse events and 
serious adverse events and the procedures for completing and transmitting serious 
adverse event reports are provided in Appendix 2.
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events. Open-ended and non-leading verbal questioning of the participant is 
the preferred method to inquire about adverse event occurrences.
8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
After the initial adverse event or serious adverse event report, the investigator is 
required to proactively follow each participant at subsequent visits or contacts. 
All adverse events will be followed 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 (as defined in Section 7.3), or the participant withdraws consent. 
Further information on follow-up procedures is provided in Appendix 2.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification (i.e., within 24 hours of awareness) by the investigator to the Sponsor 
of a serious adverse event is essential so that legal obligations and ethical 
responsibilities towards the safety of participants and the safety of a study treatment
under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory authorities about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/EC, and investigators.
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local 
regulatory requirements and Sponsor policy and forwarded to investigators as 
necessary.


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To determine reporting requirements for serious adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below:
Drug
Document
Gantenerumab
Gantenerumab Investigator's Brochure
[18F]-Florbetaben 
(Neuraceq)
[18F]-Florbetaben Investigator’s Brochure
[18F]-Flutemetamol 
(Vizamyl)
[18F]-Flutemetamol Investigator’s Brochure
[18F]-MK-6240
[18F]-MK-6240 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.
An investigator who receives an investigator safety report describing a serious adverse 
event or other specific safety information (e.g., summary or listing of serious adverse 
events) from the Sponsor will review and then file it along with the 
Investigator’s Brochure and will notify the IRB/EC, if appropriate according to local 
requirements.
8.3.5
Pregnancy
Female participants of childbearing potential will be instructed through the ICF to 
immediately inform the investigator if they become pregnant during the study or within 
17 weeks after the final dose of gantenerumab.
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
All pregnancies reported during the study should be followed until pregnancy outcome, 
with follow-up information on the infant collected according to procedures outlined in 
Appendix 4. The Sponsor or a designee may follow-up by telephone, fax, e-mail, 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 medical assessment of the reported case.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered serious adverse events.


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8.3.6
Death Events
Information on reporting deaths is provided in Appendix 2.
8.3.7
Anticipated Events Not Qualifying for Expedited Reporting
Events not qualifying for expedited reporting will not be defined for this study.
8.3.8
Adverse Events of Special Interest and Selected Adverse 
Events
8.3.8.1
Adverse Events of Special Interest
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 the investigator becomes aware 
of the event; see Section A25 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 A27.8)

Suspected transmission of an infectious agent by a study treatment, 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 treatment is suspected.
Descriptions of risks and management of the above-listed adverse events are provided 
in Appendix 2.
8.3.8.2
Selected Adverse Events
Data on associated symptoms and safety MRI scans will be collected for the following 
selected adverse events:

ARIA-E: ARIAs suggestive of vasogenic edema and sulcal effusions

ARIA-H: ARIAs suggestive of microhemorrhages and/or hemosiderin deposits
Please see Section A27.1 for further details on how to report ARIA events.
8.3.9
Reporting Requirements for Medical Device Complaints
In this study, the vial adapter may be provided to the participant or study partner
(non-professional caregiver) in countries where it has been approved to aid study 
drug administration in the home setting is considered a medical device. The investigator 
must report all medical device complaints and any associated adverse events to the 
Sponsor, as described in Appendix 5.


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8.3.10
Medical Monitors and Emergency Medical Contacts
Contact Information for All Sites
Medical Monitor/Emergency Medical Contact:
, MD
Mobile Telephone No.:
Medical Monitor/Emergency Medical Contact:
, MD (Secondary)
Mobile Telephone No.:
To ensure the safety of study participants, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached. The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls. Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.
8.4
PHARMACOKINETICS
Blood samples will be collected for measurement of plasma concentrations of 
gantenerumab as specified in the schedule of activities (see Section 1.3).
Samples may be collected at additional timepoints during the study if warranted and 
agreed upon between the investigator and the Sponsor. The timing of sampling may be 
altered during the course of the study on the basis of newly available data (e.g., to obtain 
data closer to the time of peak plasma concentrations) to ensure appropriate monitoring.
An additional plasma PK sample will be obtained as soon as is feasible
(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).
Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded. Accurate recording of the date and time of study drug administration and 
PK sampling is critical.
Samples will be used to evaluate the pharmacokinetics of gantenerumab. 
Samples collected for analyses of gantenerumab plasma concentration may also be 
used to evaluate safety or efficacy aspects related to concerns arising during or after the 
study. Gantenerumab concentrations will be also measured in CSF in a subset of 
participants (see Section 8.11.4).
Genetic analyses will not be performed on these plasma samples. 
Participant confidentiality will be maintained.


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Pharmacokinetic samples will be destroyed no later than 5 years after the final 
Clinical Study Report has been completed to allow for assay development and validation 
(if needed).
Information on unblinding of personnel responsible for performing PK assays is provided 
in Section 6.3.
8.5
PHARMACODYNAMICS
The following pharmacodynamics biomarker samples will be collected, as applicable, 
from participants at all sites. For information on the optional pharmacodynamics 
biomarker assessments (i.e., blood-based biomarker prescreening, longitudinal amyloid 
and tau PET scans and longitudinal CSF sampling) please see Section 8.11.
8.5.1
Plasma Biomarker Samples
Plasma samples for the assessment of biomarkers, including but not limited to, A1-42, 
A1-40, NfL, and pTau, will be collected as specified in the schedule of activities 
(see Section 1.3), to provide evidence of gantenerumab activity (i.e., pharmacodynamic 
biomarkers, safety biomarkers) and further the understanding of AD biology based on 
change from baseline to the end of the study in longitudinal biomarker samples.  
These samples will also be used for exploratory research on biomarkers and biomarker 
assay development.
An additional plasma biomarker sample for the assessment of exploratory biomarkers 
will be obtained as soon as practical (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) or ARIA-H that meets the 
discontinuation criteria.
8.5.2
Clinical Genotyping Sample
During screening, whole blood samples for DNA extraction will be collected from all 
participants for evaluation of their APOE genotype for risk assessment and stratification 
purposes.
Eligible participants will be informed about their APOE 4 genotype at the end of the 
screening period, unless they opt out. For more details regarding the return of APOE
genotyping results, please see Section 4.1.1.
8.5.3
CSF Sample (only for Participants who are Enrolled by CSF 
Amyloid Assessment)
Cerebrospinal fluid will be obtained from participants who choose to provide CSF 
samples during screening (CSF-enrolled participants) for confirmation of Aand tau 
levels for eligibility purposes.


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Cerebrospinal fluid will be collected via LP by an individual who meets all local 
requirements and is proficient in the procedure.  Cerebrospinal fluid sampling and 
post-LP care will be performed in accordance with local practice.  All CSF sampling 
should be performed in the morning (between 8:00 a.m. and noon) to minimize potential 
diurnal variability of CSF biomarkers.
Approximately 12 mL of CSF will be collected at screening.  The sample will be divided 
into aliquots onsite and used for the following:

Biomarker analysis, including, but not limited to:  A1-42, A1-40, tTau, pTau, and NfL

Measurement of gantenerumab levels in the CSF

Samples may also be used to support the development of biomarker assays for 
diagnostic use
8.5.4
Brain Magnetic Resonance Imaging
Magnetic resonance imaging should be performed with use of 1.5-T or 3.0-T scanners. 
Whenever possible, the same scanner should be used for an individual participant for 
the entire duration of the study. Magnetic resonance imaging will be conducted at 
screening to (1) determine whether the exclusion criteria are met (e.g., number of 
microhemorrhages or presence of mass lesions), (2) serve as a baseline measure of 
(regional) brain volumes and (3) serve as baseline information for the PET assessments
(where applicable). In addition, structural MRI (to assess whole-brain and regional brain 
atrophy), and optional imaging, including functional resting-state MRI (rs-fMRI), dMRI, 
and ASL-MRI, will be performed at multiple timepoints to determine potential treatment 
effects on MRI outcome measures (for the schedule of activities, see Section 1.3).
Magnetic resonance imaging will also be used during the entire study to monitor safety 
(e.g., occurrence of ARIA-E or ARIA-H). Additional unscheduled MRI scans may be 
performed to better understand relevant CNS adverse events (such as increased 
confusion) 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 
clinically indicated and administration of contrast agent is considered safe for the 
participant according to local standards.  If a contrast agent is used, the participant’s
renal function must be checked according to the local standards to ensure that contrast 
administration is safe.
Magnetic resonance imaging should be performed before or at least 3 days after CSF 
sampling (i.e., LP), unless and earlier MRI scan is clinically warranted.
Magnetic resonance imaging scans may include all or some of the following sequences:
Core Sequences:

3D T1weighted

T2*weighted


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
T2weighted

T2FLAIR

DWI
Optional Sequences (subset of sites/subjects depends on the scanner 
specification):

BOLD rs-fMRI and related fieldmap: optional and if available (to assess 
resting-state functional connectivity at investigative sites having the required 
software and sequences)

dMRI and related fieldmap: optional and if available (to assess fiber tract integrity)

ASL-MRI and related fieldmap: optional and if available (to assess CBF)
All sequences (except rs-fMRI, dMRI and ASL-MRI) will be used to assess MRI safety 
and inclusion/exclusion criteria. Additional sequences may be obtained if clinically 
warranted.
Magnetic resonance imaging scans will be reviewed by a central MRI core laboratory, 
which will perform both, the clinical reads and assessment of MRI outcome measures. 
Magnetic resonance imaging scans should preferably be transferred to the central 
MRI core laboratory electronically. Magnetic resonance imaging results must be made 
available to investigators before dosing can proceed (see Section 8.2.7 for additional 
details on MRI safety management).
Magnetic resonance imaging facility qualification and scan quality control will be 
performed by the central MRI core laboratory.
Additional MRI instructions regarding the specific imaging sequences, acquisition times, 
procedures for MRI scan acquisition and transmittal to the central reading facility can be 
found in the MRI Manual and Imaging Review Charter.
8.6
GENETICS
See Section 8.5.2 for information on clinical genotyping.
8.7
BIOMARKER ASSESSMENTS
See Section 8.5 for more information on plasma biomarker, clinical genotyping, and CSF
assessments.
The following biomarker samples will be collected, as applicable, from participants at all 
sites:

Clinical Genotyping Samples

CSF Sample – only for participants who are enrolled by CSF amyloid assessment

Plasma Biomarker Samples


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Biomarker samples collected at participating sites and biomarker samples 
requiring separate consent are described in Section 8.11.
Plasma biomarker samples and CSF samples collected at screening, including those 
collected from individuals who do not enroll in the study, may be used for exploratory
research and/or development of disease-related tests or tools.
Biomarker samples will be collected according to the schedule of assessment outlined in 
Section 1.3. Biomarker samples will be sent to one or several central laboratories or to 
the Sponsor or a designee. Instructions for the collection and handling of biomarker 
samples, including sampling procedures, storage conditions, and shipment instructions, 
are provided in the laboratory manual.
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 8.11.5) biomarker samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed.
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.  Results of biomarker analyses may be reported outside of the CSR.
8.8
IMMUNOGENICITY ASSESSMENTS
Antibodies to gantenerumab will be evaluated in plasma samples collected from all 
participants according to the schedule of activities (see Section 1.3). 
Additionally, plasma samples should also be collected at the final visit from participants 
who discontinued study treatment or were withdrawn from the study. These samples will 
be tested by the Sponsor or Sponsor's designee.
Plasma samples will be screened for antibodies binding to gantenerumab and the titer of 
confirmed positive samples will be reported.
All samples collected for detection of antibodies to study treatment will also be evaluated 
for gantenerumab plasma concentration to enable interpretation of the antibody data. 
Samples may be stored for a maximum of 5 years (or according to local regulations) 
after the final Clinical Study report has been completed at a facility selected by the 
Sponsor to enable further analysis of immune responses to gantenerumab.
Remaining volumes from these samples may also be used for further characterization of 
potential immune responses and for any gantenerumab-related exploratory analyses or 
assay development/validation experiments.


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8.9
HEALTH STATUS UTILITY
For all participants throughout the study, the investigator and study site personnel will 
collect data about health care resource utilization associated with medical encounters.
The data collected will include the reasons and duration of hospitalizations and 
emergency room visits and exclude procedures, tests, and encounters mandated by the 
protocol.
The Sponsor may use the collected data to conduct economic analyses.
Exploratory analyses with use of the EQ-5D-5L health states will be defined for each 
participant at each measurement timepoint according to EuroQol instructions. For more 
details on the EQ-5D-5L health status evaluation please see Section 8.10.2.9.
The health states will then be converted into a single index value. The index values, 
presented in country-specific value sets, are a major feature of the EQ-5D instrument, 
facilitating the calculation of quality-adjusted life-years that are used to inform economic 
evaluations of healthcare interventions. Note that these exploratory analyses will not be 
included in the CSR.
8.10
CLINICAL OUTCOME ASSESSMENTS
Performance outcome (PerfO), clinicianreported outcome (ClinRO), 
Participant-reported outcome (PRO), and observer-reported outcome (ObsRO)
measures will be completed to assess the treatment effect of gantenerumab. 
In addition, PRO measures will enable the capture of each participant's direct experience 
with gantenerumab.

PerfO data will be collected through use of the following measures:
–
RBANS
–
PACC-5, including the following 5 subtests:
1.
Logical Memory ImmediateDelayed Recall subtest from the 
Wechsler Memory Scale (WMS LM III)
2.
Free and Cued Selective Reminding Test Immediate RecallDelayed 
Recall (FCSRTIRDR)
3.
Coding from the Wechsler Adult Intelligence Scale IV (WAISIV Coding)
4.
MMSE
5.
Category Fluency Test (CFT) - 3 categories

ClinRO data will be collected through use of the following measures:
–
CDR
–
AD-CGI-S scale
–
DCF


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
PRO data will be collected through use of the following measures:
–
CFIa, participant version
–
A-IADL-Q-SV, self-report version
–
GDS30
–
AD-PGI-S scale
–
EQ-5D-5L

ObsRO data will be collected through use of the following measures:
–
CFIa, study partner version
–
A-IADL-Q-SV study partner version
–
AD-SPGI-S scale
–
EQ-5D-5L Proxy Version 1 (EQ-5D-5L Proxy 1) 
8.10.1
Data Collection Methods for Clinical Outcome Assessments
Clinician-reported outcome, PerfO, PRO, and ObsRO measures, translated into the local 
language as appropriate, will be completed through use of an electronic device provided 
by the Sponsor via the electronic clinical outcome assessment (eCOA) vendor.
No paper PRO, ObsRO, PerfO nor ClinRO back-up option is allowed in this study.
Potential raters will receive training and be approved by the eCOA vendor prior to being 
allowed to administer any COAs in the study. These trained raters will administer the 
measures using the electronic device, which will be distributed to each site.
The electronic device will be pre-programmed to enable the appropriate COAs to be 
administered in the recommended order and to capture audio recordings of the 
measures where applicable (e.g., PACC-5 and CDR) at each specified timepoint within 
the correct time window. According to the endpoint hierarchy, the PACC-5 
(primary endpoint) will be prioritized in order to mitigate participant’s fatigue.  The data 
will be transmitted to a centralized database maintained by the electronic device vendor
and will be subject to an Endpoint Quality Program performed by the eCOA vendor.
Audio eCOA recordings will be used for quality assurance purposes. The data will be 
available for access by appropriate study personnel.  Two distinct study rater roles at 
every site have been created in order to have an independent clinician dedicated to the 
ClinROs administration (CDR and AD-CGI-S) as defined in Table 9.
The Principal Investigator or a qualified, clinically experienced designee will complete 
the DCF training at the beginning of the study, and will then be responsible to complete 
the form at every study visit for each participant at their site. This function should not be 
delegated to Rater Role 1 (Cognitive/Functional) or Rater Role 2 (Independent) as 
defined in Table 9.




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During clinic visits, PRO and ObsRO measures should be administered as outlined 
below:

Participants' health status should not be discussed prior to administration of the 
instruments

Sites must administer the official version of each instrument using the study 
electronic device, as provided by the Sponsor. Instruments must not be copied from 
the protocol.

Sites should allow sufficient time for participants and study partners to complete the 
instruments

Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions

Participants and study partners should be instructed to answer questions to the best 
of their ability; there are no right or wrong answers

Site staff should not interpret or explain questions

Participants and study partners should not obtain advice or help from others 
(e.g., family members or friends) when completing the instruments
All cognitive and functional assessments should be performed in the clinic at the visit 
timepoints indicated in the schedule of activities (Section 1.3). However, in exceptional 
circumstances for post-randomization visits, if the participant, their study partner or the 
primary rater cannot perform these assessments as per the schedule of activities, they 
may be performed within a 28 days’ time window (i.e., 28 days).
8.10.2
Description of Clinical Outcome Assessment Instruments
8.10.2.1
Preclinical Alzheimer’s Cognitive Compositive-5
The PACC-5 (Papp et al. 2017) is a rater-administered PerfO composite measure to 
assess cognitive decline in individuals at risk for or at the earliest stages of AD.  It 
includes the following five components:  the Logical Memory ImmediateDelayed Recall 
subtest from the Wechsler Memory Scale (WMS LM III), the Free and Cued Selective 
Reminding Test Immediate RecallDelayed Recall (FCSRTIRDR), the MMSE, the 
Coding from the Wechsler Adult Intelligence ScaleIV (WAISIV Coding), and the CFT.  
The selected set of tests provide for a thorough assessment of cognitive domains that 
are known to likely be affected early in the disease:  (1) episodic memory, thereby using 
2 different tests for that purpose (a story recall; Logical Memory IIa, as well as a list 
recall test; FCSRT), (2) attention/speed processing (Coding), and (3) executive function 
(MMSE and CFT; Papp et al. 2020).  The PACC-5 is computed based on z-scores from 
the five components. More details will be given in the Statistical Analysis Plan (SAP).  
The components of the PACC-5 are described in more detail as follows.
Mini Mental State Examination
The MMSE is a rater-administered PerfO measure that includes a set of standardized 
items to assess a participant’s cognitive impairment across six domains: orientation, 


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registration, attention and calculation, short-term recall, language, and constructional 
praxis/visuospatial abilities (Folstein et al. 1975; Appendix 6). The total score ranges 
from 030, with lower scores indicating greater impairment. The MMSE takes 
approximately 1015 minutes to complete.
Free and Cued Selective Reminding Test Immediate RecallDelayed Recall
The FCSRTIRDR is a PerfO measure of verbal episodic memory with use of
controlled learning and semantic cueing to assess memory impairment associated with 
AD (Grober and Buschke 1987; Grober et al. 2018; Appendix 7). The FCSRTIRDR 
begins with a study phase designed to enhance learning and retrieval, enabling a more 
specific measurement of the characteristic memory impairment of AD 
(Grober et al. 2010; 2018). The study phase consists of 16 stimulus items from different 
semantic categories; these are either pictures or words depending on the version used 
(Grober et al. 2009).  Words stimuli will be used in this study. Items are presented in 
groups of 4 on a card. The participant is given a verbal category cue (e.g., fruit) and the 
participant selects and names the item on the card that correspond to the cued category 
(e.g., grape). Once all 4 cued items have been identified, immediate verbal cued recall 
of the items is tested. This is repeated for the other 3 sets. The study phase is followed 
by the test phase which consists of 3 recall trials. In each trial the participant must first 
freely recall as many items as possible. For any items not freely recalled, the participant 
is tested through cued recall.  Free and cued delayed recall is tested after a 30-minute 
delay, following the same procedure of free and cued immediate recall.  The following 
scores can be derived: free recall (the cumulative sum of free recall from the 3 trials; 
range: 048), total recall (the cumulative sum of free recallcued recall from the 3 trials, 
range:  048), and Cueing Index (total recall-free recall)/(48-free recall, range:  0.01.0), 
delayed free recall (number of words at the delayed free recall, range: 016), and the 
delayed total recall (sum of delayed free recalldelayed cued recall, range: 016).
Higher scores indicate better cognitive performance.  The FCSRTIRDR takes 
approximately 4550 minutes to be administered.
Logical Memory Immediate RecallDelayed Recall
The Logical Memory Immediate RecallDelayed Recall (WMS LM III) subtest from the 
Wechsler Memory Scale (Wechsler 2008) is an individually administered assessment 
that measures verbal episodic memory (Appendix 8).  The LM consists of 3 parts:  
Logical Memory Immediate Recall (LM I), Logical Memory Delayed Recall (LM II), and 
Logical Memory Delayed Recognition.  The participant reads through two passages.  
The LM I requires participants to immediately recall as many details from the passages 
as they can.  The LM II is the same but is administered after a 2030 minute delay.  
In LM Recognition, the participant is asked 15 yes/no recognition memory questions 
about the passages.  The number of free recalls and thematic units are recorded for LM I 
and II. A total raw score for the LM I and LM II is obtained by the sum of the item 
scores, ranging from 025. The score for LM Recognition is determined by how many 
questions were answered correctly ranging from 015. Higher scores indicate less 
cognitive impairment. The total raw scores can be converted into subtest scaled scores 


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with mean of 10 and standard deviation of 3 with use of the conversion table. The LM 
takes approximately 30 minutes to complete.
Coding
Coding is a performance-based outcome measure used to assess associative learning, 
motor speed, attention and visuoperceptual functions and is a subtest of the 
Wechsler Adult Intelligence Scale IV (WAISIV; Wechsler 1939; 2008; Jaeger 2018;
Appendix 9). The test requires the participant to match certain symbols to numbers 
based on a given key. They must correctly match as many as they can within the time 
limit of 120 seconds. The number of correct symbols within the allowed time constitutes 
the score, with higher scores indicating better performance. It takes approximately 
5 minutes to complete the test.
Category Fluency
Verbal fluency is the ability to generate words under certain stimulus constraints 
(e.g., letter, category). The category verbal fluency (e.g., animals) is a PerfO measure 
assessing speed and flexibility of verbal thought (Appendix 10). Verbal fluency tests are 
sensitive tools for detecting dementia (Pasquier et al. 1995; Lezak et al. 2004) and for 
monitoring cognitive decline over time (Clark et al. 2009). They imply to give a category 
to the subject (e.g. animals, fruits, vegetables). The principle of the verbal fluency task 
is always the same: the participant is given 60 seconds to generate as many words 
starting with the given letter (letter/phonemic fluency) or pertaining to the given category 
(category/semantic fluency). Total score is determined by how many words are correctly 
given and higher scores indicate better cognitive performance.
8.10.2.2
Clinical Dementia Rating Scale
The CDR (Morris 1993) is a ClinRO measure used to stage the severity of AD dementia 
based on a semi-structured interview with the participant and a reliable informant 
(e.g., caregiver/study partner; Appendix 11).  The CDR characterizes the participant’s 
level of cognitive and functional impairment across six domains (memory, orientation, 
judgment and problem solving, community affairs, home and hobbies, and personal 
care) on a 5-point rating scale in which 0 “None”, 0.5 “questionable”, 1 “mild”, 
2 “moderate”, 3 “severe” (with the exception of personal care, which is rated on a 
4-point rating scale and excludes the questionable impairment level).
Two scores can be generated; the CDR-GS and the CDR Sum of Boxes (CDR-SB).  
The CDR-GS is calculated based on the Washington University CDR-assignment 
algorithm and characterizes a participant’s level of global impairment/stage of dementia 
according to the following categories:  0 (normal), 0.5 (very mild dementia), 
1 (mild dementia), 2 (moderate dementia), and 3 (severe dementia).  The CDR-SB is 
calculated by summing the ratings across each of the six domains (total score:  018), 
with higher scores indicating greater impairment.  The CDR-SB 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).


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Administration of the CDR should be undertaken by a trained clinician and takes 
approximately 60 minutes to complete (approximate 20-minute interview with the 
participant and approximate 40-minute interview with the study partner).
8.10.2.3
Amsterdam Instrumental Activity of Daily Living Questionnaire 
Short Version
The A-IADL-Q-SV (Jutten et al. 2017) is an ObsRO measure designed to assess a 
participant’s ability to perform instrumental activities of daily living 
(including household/leisure activities, use of household appliances, management of
finances, etc.) in early stages of AD (Appendix 12 [participant] and Appendix 13
[study partner]). The A-IADL-Q-SV includes 30 items rated by the study 
partner/caregiver, with each item divided into 2 questions; the initial question asks 
whether the activity was performed by the participant during the past 4 weeks 
(“Yes”, “No”, “Don’t know”). If the activity was performed, the second question captures 
the level of difficulty experienced while performing the activity on a 5-point Likert scale 
(“no difficulty” to “no longer able to perform the activity”). If the activity was not 
performed, the second question captures why the activity was not performed 
(“never done before”, “no longer able to do so due to physical problems'', “no longer able 
to do so due to difficulties with memory, planning, or thinking”, or “other”, including a free 
text response). If the response option “Don’t know” is selected for the initial question, no 
follow-up question is administered and the item is scored as missing. The total score for 
the A-IADL-Q-SV is calculated as a weighted average or with use of item response 
theory methods, with higher scores indicating better functioning. The A-IADL-Q-SV 
takes approximately 15 minutes to complete.  The self-report (PRO) version of the 
A-IADL-Q-SV will also be used in this study and will be completed by the study 
participant.
8.10.2.4
Cognitive Function Instrument acute
The CFIa (Walsh et al. 2006; Amariglio et al. 2015; Li et al. 2017), is an outcome 
measure developed to assess memory-related cognitive and functional decline in 
non-demented elderly individuals (Appendix 14 [participant] and Appendix 15
[study partner). The CFIa is a modified version of the original CFI (Walsh et al. 2006), 
and differs in terms of recall period and item response options. The CFIa consists of 
14 items, rated on a 5-point Likert scale ranging from “Never” to “Always'' and referring 
to the participant’s current ability (most recent experience). The CFIa takes 
approximately 10 minutes to complete. A total sum score is calculated with higher 
scores indicating greater cognitive impairment. The participant (PRO) and study partner 
(ObsRO) versions of the CFIa will be used in this study. The CFIa participant version
will be completed by the study participant, while the CFIa study partner version will be 
completed by the study partner.
8.10.2.5
Geriatric Depression Scale-30
The GDS-30 is a PRO measure, developed by Yesavage et al. (1983; Appendix 16) as a 
screening instrument to measure depression in older adults. The GDS includes 30 items 


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relating to sad mood, lack of energy, positive mood, agitation, and social withdrawal 
(Sheik et al. 1991). Items are rated on a dichotomous scale (“yes”/”no”) with a recall 
period “over the past week”. The total score ranges from 030, with higher scores 
indicating greater depression. A score between 0 and 9 is considered normal, a score 
between 10 and 19 indicates mild depression, and a score between 20 and 30 indicates 
severe depression. The GDS-30 takes approximately 10 minutes to complete.
8.10.2.6
Clinician Global Impression of Cognitive Function
The AD-CGI-S is a ClinRO global impression of severity measure designed to assess 
the impact of cognitive impairment on daily function (Appendix 17). This study-specific 
AD-CGI-S was developed in house by the Sponsor for use in clinical trials assessing 
those at risk for or at the earliest stages of AD (Guy 1976). The AD-CGI-S consist of a 
single item, asking the clinician to rate the severity of their cognitive problems and their 
impact on the participant’s ability to perform daily activities at this time (current status).
The item includes six response categories ranging from “no problems” to “severe 
cognitive problems and functionally dependent in daily activities inside and outside 
home”. The item is scored from 05 with higher scores indicating more severe cognitive 
and functional problems. This AD-CGI-S takes approximately 5 minutes to complete.
8.10.2.7
Participant Global Impression of Cognitive Function
The AD-PGI-S is a self-reported (PRO) global impression of severity measure designed 
to assess the impact of cognitive impairment on daily function (Appendix 18). 
This study-specific AD-PGI-S was developed in house by the Sponsor for use in clinical 
trials assessing those at risk for or at the earliest stages of AD (FDA 2018b). 
The AD-PGI-S consist of a single item, asking the participant to rate the severity of their 
cognitive problems and their impact on the participant’s ability to perform daily activities 
over the past 7 days (recall period). The item includes six response categories ranging 
from “no problems” to “severe thinking problems that mean I rely on someone for daily 
activities inside and outside of my home”. The item is scored from 05 with higher 
scores indicating more severe cognitive and functional problems. This AD-PGI-S takes 
approximately 5 minutes to complete.
8.10.2.8
Study Partner Global Impression of Cognitive Function
The AD-SPGI-S is a study partner-reported (ObsRO) global impression of severity 
measure designed to assess the impact of cognitive impairment on daily function
(Appendix 19). This study-specific AD-SPGI-S was developed in house by the Sponsor 
for use in clinical trials assessing those at risk for or at the earliest stages of AD
(FDA 2018b). The AD-SPGI-S consists of a single item, asking the study partner to rate 
the severity of their cognitive problems and their impact on the participant’s ability to 
perform daily activities over the past 7 days (recall period). The item includes six
response categories ranging from “no problems” to “severe thinking problems that mean 
he/she relies on someone for daily activities inside and outside of his/her home”. 
The item is scored from 05 with higher scores indicating more severe cognitive and 
functional problems. This AD-SPGI-S takes approximately 5 minutes to complete.


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8.10.2.9
EuroQol EQ-5D-5L
The EQ-5D-5L is a widely used measure to assess health status (EuroQol Group 1990;
Appendix 20). There are 2 parts to the EQ-5D-5L which asks the individual to select a 
response that best describes their health ‘today’.  The first part consists of a 5-item 
health state profile used to assess mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  Items are rated on a 5-point Likert scale ranging from 
1 (no problems) to 5 (extreme problems/unable to do).  The second part consists of a 
visual analogue scale (VAS) that measures health state ranging from 0 (worth health 
imaginable) to 100 (best health imaginable).  A total index value can be calculated with 
use of published weighting (EuroQoL website) typically ranging from 0 (equivalent to 
dead; negative values representing worse than dead) to 1 (full health). The EQ-5D-5L 
takes approximately 5 minutes to complete and will be used in this study for informing 
pharmacoeconomic evaluations.  The EQ-5D is a family of instruments to describe and 
value health.
The following 2 versions are used in this study:

EQ-5D-5L interview-administered proxy version 1 (ObsRO):  the study partner 
(the proxy) is asked to rate the participant’s health-related QoL in his/her 
(the proxy’s) opinion (Appendix 21)

EQ-5D-5L, interview-administered version (PRO):  the participant is asked to rate 
his or her own health-related QoL
8.10.2.10
Repeatable Battery for the Assessment of Neuropsychological 
Status
The RBANS (Randolph 1998) is a rater-administered PerfO measure (Appendix 22).  
It is a standardized brief neurocognitive battery that has undergone population-based 
norming in North America for individuals aged 1289 years.  There are twelve subtests 
across five domains: immediate memory (list learning and story memory), 
visuospatial/constructional (figure copy and line orientation), language (picture naming 
and semantic fluency), attention (digit span and coding), delayed memory 
(list recall, list recognition, story memory, and figure recall).  A total scale index score is 
calculated.  These index scores are age-based, with a normal mean of 100 and standard 
deviation of 15 (which corresponds to one standard deviation) based on the scale 
normative data.  Lower scores indicate higher cognitive decline. It takes approximately 
30 minutes to complete.
8.10.2.11
Diagnostic Classification Form
The DCF (Appendix 23) is a ClinRo that is designed to capture the study participant’s 
diagnostic status at each clinic visit within the study by the Principal Investigator
(or designee) at the site. If there is a change in diagnosis from the previous visit 
(e.g., change from “cognitively unimpaired” to “MCI due to AD”), supporting information 
for the change in diagnosis will need to be captured in the body of the form.


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8.11
ADDITIONAL ASSESSMENTS AND PROCEDURES 
REQUIRING SEPARATE CONSENT AT PARTICIPATING SITES
8.11.1
Optional Blood-Based Biomarker Prescreening
Evidence of abnormal cerebral amyloid deposition is expected to be present in 
approximately 15%30% cognitively unimpaired individuals aged 6080 years
(Jansen et al. 2015). Therefore, the screen failure rate based on the amyloid inclusion 
criterion is expected to be around 85% in Study WN42444.
In order to enable a more efficient and less burdensome screening process, sites, where 
approved, and participants will have the opportunity to participate in BBBM 
prescreening. For more details on the optional blood-based biomarker prescreening 
process please see Section 4.1.1.
Collection and submission of the prescreening blood samples for biomarker testing is 
contingent upon the review and approval by each site's IRB or EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval to use the BBBM 
prescreening, this part of the protocol will not be applicable at that site.
Approximately 20 mL (equivalent to 11.5 tablespoons) of blood will be collected during 
prescreening, processed and sent to a central laboratory to test for biomarkers that may 
help to indicate levels of amyloid the participant’s brain and to evaluate the likelihood of 
a participant to meet the amyloid-based inclusion criteria for Study WN42444.  The blood 
samples collected at prescreening, along with the associated information provided 
(date of birth, sex, and whether the participant has ever been diagnosed with cognitive 
impairment) may also be used for future research related to Alzheimer’s disease, 
common pathways among diseases and/or the development of tests or tools that help 
with detecting or understanding Alzheimer’s disease, even if the participant is not eligible 
for or decides not to take part in Study WN42444, unless the participant specifically asks
for the samples to be destroyed.
Instructions for the collection and handling of biomarker samples, including sampling 
procedures, storage conditions, and shipment instructions, are provided in the laboratory 
manual.
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 8.11.5) biomarker samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed.
Due to the experimental nature of the assay, results for the BBBM prescreening test will 
not be returned to participants or sites.  To further mask the results of the experimental 
BBBM prescreening test, approximately 10% of participants who are identified to be less 
likely to meet the amyloid-based inclusion criteria for Study WN42444, will also be 
invited to continue with the main study screening procedures.


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See Section 8.7 for information on availability of data from biomarker analyses.
8.11.2
Optional Longitudinal Amyloid PET Imaging (Only for 
Participants Who Enrolled via Amyloid PET at Screening)
8.11.2.1
Participants
Participants will be eligible for this assessment if they are eligible for the main study and 
have had an amyloid PET scan assessment at screening with use of [18F]-Florbetaben 
([18F]-Flutemetamol is permitted in Japan only) during screening.  Participation in both 
the optional amyloid and tau PET longitudinal assessments is encouraged but subject to 
local radiation limits.
Participants that enrolled in the study by providing an off-protocol PET scan are not 
eligible for the optional longitudinal amyloid PET assessments.
The planned number of participants for the longitudinal amyloid PET assessment is 
approximately 400 participants.
8.11.2.2
Design
For the longitudinal amyloid PET assessments, only florbetaben will be used in all 
countries except Japan, where use of [18F]-Flutemetamol will also be permitted at sites 
without access to [18F]-Florbetaben.  Participants who will be assessed with 
[18F]-Flutemetamol will not be accounted for in the 400-participant target sample size.  
Moreover, the same PET tracer ([18F]-Florbetaben or [18F]-Flutemetamol) has to be used 
for the same participant throughout all longitudinal amyloid PET assessments.
Each participant will receive up to 5 injections of amyloid radioligands 
(including 1 injection at screening) and will undergo an amyloid PET scan after each 
injection. Participants will undergo an amyloid PET scan (see Section 1.3).
A minimum of 10 half-lives is required between the 2 tracer injections (i.e., a minimum of 
18 hours must elapse between injections) for those who are participating in both, 
longitudinal amyloid PET and tau PET assessments. Therefore, it is not possible to 
perform the amyloid and tau PET scans on the same day.
8.11.2.3
Preparation and Administration of the Radioligand
8.11.2.3.1
[18F]-Florbetaben Injection and Administration
The recommended dose of florbetaben is 300 MBq (8.1 mCi, effective radiation dose 
5.8 mSv), with a maximum 30 g mass dose, administered to participants as a single 
slow IV bolus within 40 seconds in a total volume of up to 10 mL. Injection into a large 
vein is recommended, followed by a flush with approximately 10 mL of 0.9% sterile 
sodium chloride. In countries where [18F]-Florbetaben PET radioligand is approved for 
marketing, see the approved local product information for more information. In countries 
where the [18F]-Florbetaben PET radioligand is not approved for marketing, the 
[18F]-Florbetaben Investigator’s Brochure will be provided.


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8.11.2.3.2
Flutemetamol Injection and Administration
The recommended dose of [18F]-Flutemetamol is 185 MBq (5.0 mCi, effective radiation 
dose 5.9 mSv), with a maximum of 20 g mass dose, administered to participants as a 
single slow IV bolus at 6 seconds/mL in a total volume of up to 10 mL. Injection into a
large vein is recommended, followed by a flush with approximately 515 mL of 
0.9% sterile sodium chloride.  In countries where [18F]-Flutemetamol PET radioligand is 
approved for marketing, for more information see the approved local product information.  
In countries where the [18F]-Flutemetamol PET radioligand is not approved for 
marketing, the Investigator’s Brochure will be provided.
[18F]-Florbetaben or [18F]-Flutemetamol will be provided in accordance with approved 
national and/or local standards. For additional information on amyloid radioligands, refer 
to their respective Investigator Brochures and to the Technical Operations Manual.
8.11.2.4
Amyloid PET-Specific Assessments
Detailed procedures for participant preparations and amyloid PET data collection are 
specified in the amyloid PET Technical Operations Manual.  Key aspects of the amyloid 
PET examination include:

The PET scan should not be performed if the participant has an ongoing ARIA-E

For women of childbearing potential (including those who have had a tubal ligation), 
a urine pregnancy test will be conducted within 24 hours before the PET scan
The result must be negative for the participant to receive the amyloid tracer.

At selected sites that can support dynamic imaging and imaging starting at the time 
of tracer injection, an early-frame PET scan of up to 60 minutes in length will be 
acquired as soon as the injection is completed to allow assessment of cerebral 
perfusion. The initial scan will be followed by another 20-minute scan (as described 
below) with a short break in between.

A 20-minute amyloid brain PET scan will be acquired after an uptake period 
targeting 90 minutes for florbetaben and flutemetamol

Further acquisition details, including allowable deviation from target uptake time, 
participant preparation, required computed tomography (CT), transmission or MRI 
scans used for attenuation correction are described in the PET Technical 
Operations Manual
8.11.2.5
Imaging Processing and Analysis
The Sponsor in conjunction with the imaging Contract Research Organization (CRO) will 
prepare and distribute a detailed scanning manual for image acquisition and 
reconstruction procedures and parameters for each center prior to the start of the study. 
All imaging data will be transferred to the imaging CRO for quality control, qualitative 
image assessment, and quantitative image analysis as documented in the amyloid PET 
Technical Operations Manual.


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8.11.3
Tau PET Imaging
8.11.3.1
Participants
Participants will be eligible for optional longitudinal tau PET assessments if they are 
eligible for the main study. The planned number of participants for the optional 
longitudinal tau PET is 600 participants. Participation in both the amyloid and tau PET 
longitudinal assessments is encouraged but subject to local radiation limits.
8.11.3.2
Design
Each participant will receive up to 5 injections of [18F]MK-6240 in this optional 
longitudinal PET assessment and will undergo a PET scan after each injection. 
Participants will undergo an [18F]MK-6240 PET scan (see Section 1.3).
Enrollment in the longitudinal tau PET assessment does not preclude enrollment in other 
longitudinal assessments. Given that participants enrolled in this study may also 
participate in the longitudinal amyloid PET assessment, a minimum of 10 half-lives is 
required between 2 tracer injections (i.e., 18 hours must elapse between injections) for 
those who are participating in both longitudinal amyloid and tau PET assessment.
Therefore, it is not possible to perform the amyloid and tau PET scans on the same day.
8.11.3.3
Preparation and Administration of [18F]MK-6240
According to E.U. guidance, [18F]MK-6240 as used in the context of this study is 
considered a non-IMP in the E.U. In some regions, according to local regulations, 
[18F]MK-6240 may be considered an IMP.
[18F]MK-6240 Injection and Administration
The recommended dose of [18F]MK-6240 is 185 MBq (5 mCi, effective radiation dose 
5.4 mSv), with a maximum 20 g dose, administered to participants as a single IV bolus.
Injection into a large vein is recommended, followed by a flush with approximately 10 mL 
of sterile saline flush.
The [18F]MK-6240 injection will be provided in accordance with approved national 
and/or local standards. For additional information, refer to the respective Investigator 
Brochures and to the Technical Operations Manual.
8.11.3.4
Tau PET-Specific Assessments
Detailed procedures for participant preparations and [18F]MK-6240 tau PET data 
collection are specified in the Tau PET Technical Operations Manual. Key aspects of 
the tau PET examination include:

The PET scan should not be performed if the participant has an ongoing ARIA-E


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
For women of childbearing potential (including those who have had a tubal ligation), 
a urine pregnancy test will be conducted within 24 hours before the PET scan
The result must be negative for the participant to receive the amyloid tracer.

A 20-minute tau brain PET scan will be acquired after an uptake period targeting 
90 minutes

Further acquisition details, including allowable deviation from target uptake time, 
participant preparation, required CT, transmission or MRI scans used for attenuation 
correction are described in the PET Technical Operations Manual
8.11.3.5
Imaging Processing and Analysis
The Sponsor in conjunction with the imaging CRO will prepare and distribute a detailed 
scanning manual for image acquisition and reconstruction procedures and parameters 
for each center prior to the start of the study. All imaging data will be transferred to the 
imaging CRO for quality control, qualitative image assessment, and quantitative image 
analysis as documented in the Tau PET Technical Operations Manual.
8.11.4
Optional Longitudinal Cerebrospinal Fluid Sampling (Only for 
Participants Enrolled via CSF at Screening)
Participants who provide a CSF sample during screening (i.e., CSF-enrolled 
participants) can participate in optional longitudinal CSF sampling for monitoring Aand 
tau levels, PK measurements as well as other CSF biomarkers.
Each participant will undergo a total of up to 4 CSF sample collections (see Section 1.3).  
The planned number of participants for the optional longitudinal CSF sampling is 
approximately 400 participants.
Cerebrospinal fluid will be collected via LP by an individual who meets all local 
requirements and is proficient in the procedure.  Cerebrospinal fluid sampling and 
post-LP care will be performed in accordance with local practice.  All CSF sampling
should be performed in the morning (between 8:00 a.m. and noon) to minimize potential 
diurnal variability of CSF biomarkers.
Approximately 12 mL of CSF will be collected at each timepoint.  The sample will be 
divided into aliquots onsite and used for the following:

Biomarker analysis, including, but not limited to:  A1-42, A1-40, tTau, pTau, and NfL

Measurement of gantenerumab levels in the CSF

Samples may also be used to support the development of biomarker assays for 
diagnostic use
Cerebrospinal fluid samples will be sent to one or several central laboratories or to the 
Sponsor or a designee. Instructions for the collection and handling of biomarker 
samples, including sampling procedures, storage conditions, and shipment instructions, 
are provided in the laboratory manual.


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Cerebrospinal fluid samples, including those collected from individuals who do not enroll 
in the study, may be used for future research and/or development of disease-related 
tests or tools.
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 8.11.5), biomarker samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed.
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.
8.11.5
Overview of the Research Biosample Repository and External 
Research Entities
The Research Biosample Repository (RBR) is a centrally administered group of facilities
managed by Roche and 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 patients in the future.
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional research. Roche is planning to also collaborate with external 
research entities (e.g., the National Centralized Repository for Alzheimer’s Disease and 
Related Dementias [NCRAD] and the Alzheimer’s Therapeutic Research Institute 
[ATRI]). Some of the RBR samples will be shared with these external research entities 
that will store and use them for the same type of research activities.
Alongside samples, the information collected from the participants during the trial may 
also be shared with the external research entities, but only after personal information 
that can identify the participant has been removed.  Participants of the optional BBBM
prescreening may give a separate consent to participate in this optional long-term 
storage, regardless of whether they enroll in Study WN42444 or not.
The 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

To study drug response, including drug effects and the processes of drug absorption 
and disposition


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
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
8.11.5.1
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 ICF 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 8.11.5) will not be 
applicable at that site.
8.11.5.2
Sample Collection
The following samples will be stored in the RBR and external research entities 
(e.g., NCRAD, ATRI) and used for research purposes, including, but not limited to, 
research on biomarkers related to gantenerumab, diseases, or drug safety:

Leftover blood from the clinical genotyping sample, BBBM prescreening sample, 
plasma biomarker sample, CSF samples 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, whole-exome sequencing (WES), or 
other genomic analysis methods. Genomics is increasingly informing researcher's 
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.
The RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the storage period will be in accordance with the 
IRB/ECapproved ICF and applicable laws (e.g., health authority requirements).
8.11.5.3
Data Protection, Use, and Sharing
The RBR samples, as well as their associated data will be labeled with a unique 
participant identification number.


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Participant’s information associated with RBR samples is confidential and may only be 
disclosed to third parties as permitted by the ICF (or separate authorization for use and 
disclosure of personal health information) signed by the participant, unless permitted or 
required by law.
Data generated from RBR samples will be analyzed in aggregate rather than on an 
individual participant basis.  Thus, there will be no identification and reporting of 
incidental findings to investigators or participants.  In addition, 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, with the exception of data generated from blood samples collected for WGS or WES 
as described below.
If permitted by local law, a patient may request access to uninterpreted WGS or WES 
data derived from analysis of his or her blood sample.  If a participant wishes to access 
these data, the investigator must inform the Sponsor, using the following e-mail address:  
global.return-genomics-results@roche.com.  The Sponsor will provide available data to 
the investigator in the form of a raw genomic sequencing data file, but will not provide 
any interpretation of the data.  The investigator should not include the data file in the 
participant’s medical record.  Samples may be stored and analyzed in the future, and 
some samples may never be analyzed.  Thus, data may not be available at the time of 
the request or may never be available.
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 and external research entities (e.g., NCRAD, ATRI) data will become 
and remain the exclusive and unburdened property of the Sponsor or the external 
research entities (e.g., NCRAD, ATRI), except where agreed otherwise.
8.11.5.4
Consent to Participate in the Research Biosample Repository
The ICFs for the main study and the optional prescreening will contain a separate 
section that addresses participation in the RBR with the samples collected during 
prescreening and the main study screening regardless of whether they enroll in the main 
study or not.  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 choose not to provide optional RBR samples 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 


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provide optional RBR samples.  Participants who choose not to provide optional RBR
samples will not provide a separate signature.  The investigator should document 
whether or not the participant has given consent to provide optional RBR samples and 
(if applicable) the date of consent, by completing the Sample Informed 
Consent/Withdrawal 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 and external research 
entities (e.g., NCRAD, ATRI) research.
8.11.5.5
Withdrawal from the Research Biosample Repository
Participants who give consent to provide RBR samples have the right to withdraw their
consent for their prescreening samples and/or their main study samples at any time for 
any reason. After withdrawal of consent, any remaining prescreening samples and/or 
main study samples will be destroyed.  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 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 Participant 
Withdrawal Form and must enter the date of withdrawal on the Sample Informed 
Consent/Withdrawal 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 e-mailing the study number and participant number to the following e-mail 
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.
8.11.5.6
Monitoring and Oversight
The RBR samples will be tracked in a manner consistent with Good Clinical Practice 
(GCP) 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 ICF.  
Sponsor monitors and auditors will have direct access to appropriate parts of records 
relating to an individual's 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.


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9.
STATISTICAL CONSIDERATIONS
Statistical analysis will follow the estimand framework. More details on the statistical 
analyses will be provided in the SAP. In the event of any discrepancy between this 
protocol and the SAP, the SAP prevails.
9.1
STATISTICAL HYPOTHESES
The  change from baseline to Year 4 in cognition, as measured by the PACC-5 score will 
be the primary endpoint as defined in Section 3.
The primary efficacy analysis will compare the change from baseline to Year 4 in the 
PACC-5 between the experimental and control arms.
The null and alternative hypotheses for the primary endpoint are as follows:

H0 (null hypothesis):  there is no difference in the change from baseline to Year 4 in 
the PACC-5 between the experimental and control arms

H1 (alternative hypothesis):  there is a difference in the change from baseline to 
Year 4 in the PACC-5 between the experimental and control arms
9.2
SAMPLE SIZE DETERMINATION
In this study, approximately 1200 participants will be enrolled and randomized in a 
1:1 ratio to each study arm.  The study is powered to compare the change from baseline 
to Year 4 in the PACC-5 between the experimental and control arms. Assuming a 35% 
dropout rate at Year 4, two-sided testing at the overall 0.05 level, a control arm
coefficient of variation (CV) of 1.99 for the Year 4 change scores (standard deviation of 
control participant change scores/mean of control participant change scores) and 
600 participants per arm, the study will have at least 80% power to detect a true effect of 
40% reduction of the mean PACC-5 decline in the control arm.
The assumption for the control arm CV is based on data from a population with similar 
inclusion and exclusion criteria in 4 observational cohorts (ADNI, AIBL; Biomarkers for
Identifying Neurodegenerative Disorders Early and Reliably Study [BioFINDER], HABS).
An increase in sample size and/or duration of the study may be considered if factors 
external to the study or blinded study data analysis warrant a change to the sample size 
assumption.  As a result, the sample size may be increased from 1200 up to 
1800 participants (900 participants per arm). Further details will be described in the 
SAP.  The assessment will be performed by the Sponsor at a specified timepoint.  
The Sponsor will remain blinded and the sample size will not be reduced on the basis of 
this assessment.
The planned number of participants who take part in the optional longitudinal amyloid 
PET assessment is approximately 400 participants (200 participants per study arm).
The planned number of participants was selected primarily based on practical feasibility.


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The planned number of participants who take part in the optional longitudinal tau PET 
assessment is approximately 600 participants (300 participants per study arm).  
The planned number of participants was selected primarily based on practical feasibility.
Subject to operational feasibility, this number may be increased to a maximum of 
800 participants (400 participants per study arm).
The planned number of participants who take part in the optional longitudinal CSF 
assessment is approximately 400 participants (200 participants per study arm). 
The planned number of participants was selected primarily based on practical feasibility 
and not based on power calculations.
9.3
ANALYSIS SETS
The analysis sets are defined in Table 10.
Table 10 Analysis Sets and Description
Participant Analysis Set
Description
All Randomized 
Participants
All participants randomly assigned to study treatment
Safety
All participants randomly assigned to study treatment and who 
receive at least 1 dose of study drug
All analyses will be performed on the all randomized participant population, unless 
specified otherwise.
All safety analyses will be performed on the safety population and participants will be 
grouped according to the treatment they actually received.  For all efficacy analyses, 
participants will be grouped according to the treatment assigned at randomization.
9.4
STATISTICAL ANALYSES
The SAP will be finalized prior to the locking and unblinding of the study database, and it 
will include a more technical and detailed description of the statistical analyses 
described in this section.
In particular, supplementary estimands and details concerning the estimand strategy will 
be defined in the SAP, as well as any sensitivity analyses to the estimands of study
endpoints, and any pre-specified subgroup analyses.
The following sections present the planned statistical analyses of the most important 
endpoints, including the primary endpoint.


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9.4.1
General Considerations
In addition to the analyses detailed in the following sections, study results will be 
presented by study arm (with total when appropriate) and summarized according to the 
type of the variables:

For continuous variables, using descriptive statistics such as the mean, standard 
deviation, median, and range, as appropriate, including the number of participants 
contributing to these statistics

For categorical variables, using the frequency and proportion of participants falling 
into each category, grouped by study arm (and total). The percentages reported in 
these tables will be rounded; therefore, may not always sum to 100%.
The type I error will be controlled at a 2-sided 0.05 level for multiplicity across the 
primary and confirmatory secondary endpoints. The confirmatory secondary endpoints, 
a subset of the secondary endpoints described in Section 3, will be specified in the SAP.
9.4.2
Primary Endpoint
9.4.2.1
Primary Estimand
The change from baseline to Year 4 in cognition, as measured by the PACC-5 score is 
the primary endpoint.
If a participant withdraws from study treatment, the reason for withdrawal will be 
classified as either study drug or condition-related (SDCR) or not study drug or 
condition-related (NSDCR). More details of this classification will be given in the SAP.
The primary comparison of interest is the difference between the experimental and 
control arms in the change from baseline to Year 4 in cognition, as measured by the 
PACC-5 score. The primary comparison will be made regardless of whether:

A participant initiates a symptomatic treatment for AD (e.g., acetylcholinesterase 
inhibitors and memantine) after progression to dementia due to AD as determined 
by the iCAC

A participant has a treatment interruption due to ARIA-E or safety reasons
(e.g., short-term anticoagulation)

A participant withdraws from the study treatment due to a SDCR reason
Further, the primary comparison will be made in the hypothetical scenario that a NSDCR 
withdrawal from the study treatment would not have occurred.
Note that the control arm will contain both participants who do not meet the clinical 
progression criteria and remain on placebo throughout the duration of the study and 
participants who meet the clinical progression criteria and initiate active gantenerumab 
at the time of the clinical progression.


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The elements of the primary estimand as per the estimand framework introduced in the 
ICH-E9 (R1) addendum (ICH 2019) as well as the intercurrent events and the handling 
strategies are defined in Table 11.  A full list of intercurrent events will be specified in the 
SAP.
Table 11 Primary Estimand and Estimand Framework
Primary Estimand
Estimand Framework
Population
Participants at risk for or at the earliest stages of AD as defined 
by the study inclusion and exclusion criteria
Primary efficacy variable
Change from baseline to Year 4 in the PACC-5
Treatment
Gantenerumab treatment with a target dose of 255 mg Q1W or 
510 mg Q2W versus placebo followed by gantenerumab upon 
the diagnosis of MCI or dementia due to AD by the iCAC
Summary measure
The difference in variable means between study arms
Intercurrent events

SDCR withdrawal from study treatment: a treatment policy 
strategy will be applied

NSDCR withdrawal from study treatment: a hypothetical 
strategy will be applied

Treatment interruption due to ARIA-E or safety reasons: a 
treatment policy strategy will be applied

Initiation of symptomatic treatment for AD 
(e.g., acetylcholinesterase inhibitors and memantine) after 
progression to dementia due to AD as determined by the 
iCAC: a treatment policy strategy will be applied
A full list of intercurrent events will be specified in the SAP.
ADAlzheimer’s disease; ARIA-Eamyloid-related imaging abnormalitiesedema/effusion; 
iCACindependent Clinical Adjudication Committee; MCI mild cognitive impairment; 
NSDCRnot study drug or condition-related;; PACC-5 Preclinical Alzheimer’s Cognitive 
Composite-5; Q1W every 1 week; Q2W every 2 weeks; SAPStatistical Analysis Plan; 
SDCRstudy drug or condition-related.
9.4.2.2
Primary Estimator
The difference in mean change from baseline to Year 4 in the PACC-5 will be estimated 
with use of a longitudinal data model adjusting for the randomization stratification 
factors.  Formal statistical testing of the difference between the two arms will be 
performed for the Year 4 visit.  When applying the treatment policy strategy, all the 
available data will be included in the analysis. When applying the hypothetical strategy, 
data will be censored at the time of the intercurrent events (i.e., NSDCR withdrawal from 
study treatment) and data after the intercurrent events will be imputed.  The imputation 
rules will be described in the SAP.


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9.4.3
Secondary Endpoints
The secondary endpoints are described in Section 3. The confirmatory secondary 
endpoints, a subset of the secondary endpoints described in Section 3, will be specified 
in the SAP.
A multiple testing procedure will be applied to adjust for multiple statistical testing of the 
confirmatory secondary endpoints. The overall type I error rate will thereby be 
controlled. Details about the multiple statistical testing procedure will be given in the 
SAP.
The remaining secondary endpoints will not be adjusted for multiple testing.
The following continuous secondary efficacy endpoints will be analyzed in the same way 
as the primary efficacy endpoint:

Change from baseline to Year 4 in cognitive functional activities of daily living, as 
measured by the CFIa and the A-IADL-Q-SV

Change from baseline to Year 4 in cognition and function, as measured by the 
CDR-SB
The following time to event secondary efficacy endpoints will be analyzed with use of an 
estimand whose elements, as per the estimand framework introduced in the ICH-E9 
(R1) addendum (ICH 2019), will be described in the SAP:

Time to onset of confirmed clinical progression, defined as the time from 
randomization to the first occurrence of 2 consecutive visits 
(approximately 6 months apart) with a CDRGS0

Time from randomization to clinical progression to MCI or dementia due to AD 
based on the diagnosis of the independent Clinical Adjudication Committee (iCAC)
The comparison of interest is between the experimental and control arms.
The appropriate statistical methods for time to event secondary efficacy endpoints will be 
described in the SAP and could include, for example, Cox proportional hazards 
regression.
9.4.4
Safety Endpoints
Safety will be assessed through descriptive summaries of the endpoints listed in Table 7.
9.4.5
Other Analyses
9.4.5.1
Summaries of Conduct of Study
The number of participants who enroll, discontinue, or complete the study will be
summarized by study arm. Reasons for premature study withdrawal and study 
treatment discontinuation will be listed and summarized. Intercurrent events will be 
listed and summarized. Enrollment and major protocol deviations will be listed and 
evaluated for their potential effects on the interpretation of study results.


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9.4.5.2
Summaries of Demographics and Baseline Characteristics
Demographics and baseline characteristics (including age, sex, race, APOE 4 status) 
will be summarized by study arm. The baseline value will be defined as the last 
available value recorded prior to the initiation of study treatment. Descriptive statistics 
(mean, standard deviation, median, and range) will be presented for continuous 
variables and counts and percentages will be presented for categorical variables.
9.4.5.3
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 CV, as appropriate. Because a sparse PK sampling design is being used, 
population (nonlinear 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 
(AUC), Cmax, and trough concentration, will depend on the final PK model used for this 
analysis. The results of this modeling analysis may be reported separately in the 
Clinical Study Report.
Cerebrospinal fluid concentrations of gantenerumab will be tabulated and summarized 
as appropriate.
The influence of background medication on the pharmacokinetics of gantenerumab will 
be explored and, if appropriate, concentration-effect relationships may be assessed 
post-hoc for PD, efficacy, immunogenicity or safety measures.
Additional PK analyses will be conducted as appropriate and may be reported separately 
in the CSR.
9.4.5.4
Immunogenicity Analyses
The numbers and proportions of ADA-positive participants and ADA-negative 
participants at baseline (baseline prevalence) and after drug administration 
(post-baseline incidence) will be summarized for participants exposed to gantenerumab.
When determining post-baseline incidence, participants are considered to be 
ADA-positive if they are ADA-negative or have missing data at baseline but develop an 
ADA response following study drug exposure (treatment-induced ADA response), or if 
they are ADA-positive at baseline and the titer of 1 or more post-baseline samples is at 
least 4fold higher in comparison to the titer at the baseline (treatment-enhanced 
ADA response). Participants are considered to be ADA-negative if they are 
ADA-negative or have missing data at baseline and all post-baseline samples are 
negative, or if they are ADA-positive at baseline but do not have any post-baseline 
samples with a titer that is at least 4fold greater than the titer of the baseline sample
(treatment-unaffected ADA response).


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The relationship between ADA status and safety, efficacy, pharmacokinetics, and
biomarker endpoints may be analyzed and reported via descriptive statistics.
9.5
INTERIM ANALYSIS
9.5.1
Optional Interim Analysis
Based on availability of information pertaining to gantenerumab or other compounds with 
a similar mode of action that may emerge during the course of this study, the Sponsor
may choose to conduct an interim analysis once participants have completed at least 
2 years of treatment.
An independent data coordinating center will be responsible for the interim analysis and 
study results will only be reviewed by the iDMC.  The Sponsor will remain blinded. 
Interactions between the iDMC and Sponsor will be carried out as specified in the 
iDMC Charter.  Details of the interim analysis, including the decision to conduct the 
optional interim analysis, the rationale, timing, and statistical details for the analysis
(such as the data that would be reviewed by the iDMC and futility or efficacy thresholds) 
will be documented in the SAP, and the SAP will be submitted to relevant health 
authorities as required at least 2 months prior to conducting the interim analysis.
9.6
INDEPENDENT DATA MONITORING COMMITTEE
A formal iDMC will be used for this study. The iDMC will be unblinded and evaluate 
participant safety and select efficacy on a regular basis. In addition to the data defined 
in the iDMC Charter (e.g., the incidence, severity, and nature of adverse events, serious
adverse events, ARIA-E and ARIA-H, ISRs, adverse events of special interest, and the 
MMSE), the iDMC will review all necessary cumulative data at regular intervals during 
the study, including further efficacy data when needed.
The frequency of these assessments is specified in the iDMC Charter. At the time of
each review, the iDMC will make appropriate recommendations (e.g., the study should 
continue as planned, enrollment in a specific arm should be discontinued, the treatment 
regimen should be modified, the protocol should be amended, and enrollment should be 
held pending further safety evaluations). The iDMC will also evaluate planned or 
unplanned interim analyses for efficacy or futility.
Decisions will be made in consideration of 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.


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Appendix 1 Regulatory, Ethical, and Study Oversight 
Considerations
TABLE OF CONTENTS
A11.
Regulatory and Ethical Considerations
A12.
Financial Disclosure
A13.
Informed Consent Process
A14.
Data Protection
A15.
Administrative Structure
A16.
Dissemination of Clinical Study Data
A17.
Data Quality Assurance
A18.
Source Documents
A19.
Study and Site Closure
A110. Publication Policy
A111. Protocol Deviations


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A11.
REGULATORY AND ETHICAL CONSIDERATIONS
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines

Applicable International Council for Harmonisation (ICH) Guideline for Good Clinical 
Practice (GCP)

Applicable laws and regulations
The protocol, Informed Consent Form (ICF), Investigator's Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an Institutional Review Board 
(IRB) or Ethics Committee (EC) by the investigator and reviewed and approved by the 
IRB/EC before the study is initiated.
Any substantial amendments to the protocol will require IRB/EC and health authority 
approval (as locally required) before implementation of changes, with the exception of 
administrative changes or changes necessary to eliminate an immediate hazard to study 
participants.
The investigator will be responsible for the following:

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

Notifying the IRB/EC of serious adverse events or other significant safety findings, 
as required by IRB/EC procedures

Providing oversight of the conduct of the study at the site and ensuring adherence to 
requirements of 21 Code of Federal Regulations (CFR; U.S. sites only), 
the ICH Guideline for GCP, the IRB/EC, Regulation (E.U.) No. 536/2014 (E.U. sites 
only), and all other applicable local regulations
A12.
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 
study and for 1 year after completion of the study (see definition of end of study in 
Section 4.4).


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A13.
INFORMED CONSENT PROCESS
This section relates to the informed consent process for the optional blood-based 
biomarker (BBBM) prescreening and the main study.
Participation in the optional BBBM prescreening requires signing of a separate BBBM 
prescreening ICF. The investigator or authorized designee will explain the nature of the 
optional BBBM prescreening to the participant and answer all questions regarding the 
optional BBBM prescreening.
For participation in the main study, the investigator or authorized designee will explain 
the nature of the study to the participant, to the participant’s study partner, and to the 
participant’s postdose observer(s) (if applicable). The investigator or authorized 
designee will also answer all questions regarding study participation during the informed 
consent process for the Main Participant, Study Partner, Postdose Observer, and 
Mobile Nursing ICFs.
Participants, the participant’s study partner, and the participant’s postdose observer(s)
must be informed that their participation is voluntary. The participant, the participant’s 
study partner, and the participant’s postdose observer(s) will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50 (U.S. sites 
only), the ICH Guideline for GCP, and the IRB/EC.
The medical record must include a statement that written informed consent was obtained 
before the participant, the participant’s study partner, and the participant’s post-dose 
observer(s) were enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.
If any of the ICFs are revised (through an amendment or an addendum) to communicate 
information that may affect a participant's, participant’s study partner’s, or the
participant’s postdose observer(s)’ willingness to continue in the study, the participant, 
the participant’s study partner, or the participant’s postdose observer(s) must re-consent 
by signing the most current version of the ICF or the addendum, in accordance with 
applicable laws and IRB/EC policy.
A copy of each ICF must be provided to the participant, the participant’s study partner 
and the participant’s postdose observer(s). A participant who is rescreened is not 
required to sign another ICF if the rescreening occurs within 90 days from the previous 
ICF signature date.
The BBBM prescreening ICF and the Main Participant ICF will each contain a separate 
section that addresses the use of remaining mandatory samples for optional exploratory 
research.  The investigator or authorized designee will explain to each participant the 


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objectives of the exploratory research.  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 signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research.  Participants who decline to participate in this optional research will not provide 
this separate signature.
A14.
DATA PROTECTION
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; 
the participant's name or any information that would make the participant identifiable will 
not be transferred.
Participants must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to participants, who will be required to give consent for their data to be 
used as described in the ICF.
Participants must be informed that their medical records may be examined by auditors or 
other authorized individuals representing the Sponsor or Sponsor collaborators and 
licensees, by appropriate IRB/EC members, and by inspectors from health authorities.
A15.
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd. The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 200 sites globally will participate to enroll approximately 
1200 participants. Enrollment will occur through an interactive voice or Web-based 
response system.
Central facilities will be used for certain assessments throughout the study 
(e.g., specified laboratory tests, biomarker and pharmacokinetic analyses), as specified 
in Section 8 and Appendix 24.
An independent Data Monitoring Committee (iDMC) will be employed to monitor and 
evaluate participant safety throughout the study. An Independent Review Facility will 
collect, store, and review imaging data.
A16.
DISSEMINATION OF CLINICAL STUDY DATA
Study data, which may include imaging data and data on genomic variants, may be
submitted to government or other health research databases or shared with researchers, 


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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. 
For more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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 Roche policy on study data publication.
A17.
DATA QUALITY ASSURANCE
All participant data relating to the study will be recorded on printed or electronic Case 
Report Forms (eCRFs) unless transmitted to the Sponsor or designee electronically 
(e.g., laboratory data). The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the Case Report Form (CRF).
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents.
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g., risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities,
and requirements, including handling of non-compliance issues and monitoring 
techniques (central, remote, or onsite monitoring), are provided prior to study initiation, in 
the various functional monitoring plans (including, but not limited to, Quality Tolerance 
Limit Management Plan and Trial Monitoring Plan).
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
The Sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).
Study monitors will perform ongoing monitoring activities as specified in the 
Trial Monitoring Plan to confirm that data entered into the CRF by authorized site 


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personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, the 
ICH Guideline for GCP, and all applicable regulatory requirements.
Records and documents pertaining to the conduct of this study, including signed ICFs,
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period.  No records may be 
destroyed during the retention period without the written approval of the Sponsor.  
No records may be transferred to another location or party without written notification to 
the Sponsor.
A18.
SOURCE DOCUMENTS
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents, or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
Definition of what constitutes source data and its origin can be found in the 
Trial Monitoring Plan.
A19.
STUDY AND SITE CLOSURE
The Sponsor or designee reserves the right to close the study site or terminate the study 
at any time for any reason at the sole discretion of the Sponsor.  Study sites will be 
closed upon study completion.  A study site is considered closed when all required 
documents and study supplies have been collected and a site closure visit has been 
performed.
The investigator may initiate site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, 
but are not limited to, the following:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor's procedures, or the ICH Guideline 
for GCP

Inadequate recruitment of participants by the investigator


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
Discontinuation of further study treatment development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform 
the investigators, the IRBs/ECs, the health authorities, and any contract research 
organizations used for the study of the reason for termination or suspension, as 
specified by the applicable regulatory requirements.  The investigator shall promptly 
inform the participants and should ensure appropriate participant therapy and/or 
follow-up.
A110. PUBLICATION POLICY
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission.  This allows the Sponsor to protect proprietary information and to 
provide comments.
The Sponsor will comply with the requirements for publication of study results.  
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of results of multicenter studies only in their entirety and not as 
individual site 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.
A111. 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 GCP 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.


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Appendix 2 Adverse Events:
Definitions and Procedures for Recording, Evaluating, Follow-
Up, and Reporting
TABLE OF CONTENTS
A21
Definition of Adverse Event
A22
Definition of Serious Adverse Event
A23.
Recording and Follow-Up of Adverse Events and/or 
Serious Adverse Events
A23.1
Adverse Event and Serious Adverse Event Recording
A23.2
assessment of Severity
A23.3
Assessment of Causality
A23.4
Follow-up of Adverse Events and Serious Adverse
Events
A23.4.1
Investigator Follow-Up
A23.4.2
Sponsor Follow-Up
A24.
Reporting of Serious Adverse Events
A24.1
Serious Adverse Event Reporting to The Sponsor via 
an Electronic Collection Tool
A24.2
Serious Adverse Event Reporting to The Sponsor via 
Paper CRF
A25.
Reporting Requirements for Serious Adverse Events 
and Adverse Events of Special Interest
A25.1
Events That Occur Prior to Study Treatment Initiation
A25.2
Events That Occur After Study Treatment Initiation
A26.
Reporting Adverse Events That Occur after the 
Adverse Event Reporting Period
A27.
Procedures for Recording Adverse Events
A27.1
ARIA Findings
A27.2
Injection Reactions
A27.3
Diagnosis Versus Signs And Symptoms
A27.4
Adverse Events that are Secondary to Other Events
A27.5
Persistent of Recurrent Adverse Events
A27.6
Abnormal Laboratory Values
A27.7
Abnormal Vital Sign Values
A27.8
Abnormal Liver Function Tests


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Follow-Up, and Reporting
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A27.9
Deaths
A27.10
Preexisting Medical Conditions
A27.11
Lack of Efficacy or Worsening of Alzheimer’s Disease
A27.12
Hospitalization or Prolonged Hospitalization
A27.13
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse
A27.14
Cases of Medication Error
A27.15
Participant-Reported or Observer-Reported Outcome 
Data
A27.16
Safety Biomarker Data


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A21
DEFINITION OF ADVERSE EVENT
Adverse Event Definition
An adverse event is any untoward medical occurrence in a patient or clinical study 
participant temporally associated with the use of a study treatment, whether or not 
considered related to the study treatment.
Note:  An adverse event can; therefore, be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the Adverse Event Definition
The following events meet the definition of adverse event:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease)

Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition

New condition detected or diagnosed after study treatment administration, even 
though it may have been present before the start of the study

Signs, symptoms, or clinical sequelae of a suspected druginteraction

Signs, symptoms, or clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication
Overdose per se will not be reported as an adverse event or serious adverse 
event unless it is an intentional overdose taken with possible suicidal or
self-harming intent.  Such overdoses should be reported regardless of sequelae.
"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an adverse event or serious adverse event.  Such instances will 
be captured in the efficacy assessments. However, the signs, symptoms, and/or 
clinical sequelae resulting from lack of efficacy will be reported as an adverse 
event or serious adverse event if they fulfill the definition of an adverse event or 
serious adverse event.


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Follow-Up, and Reporting
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Events NOT Meeting the Definition of Adverse Event
The following events do not meet the definition of adverse event:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition

The disease or disorder being studied or expected progression, signs, or symptoms 
of the disease or disorder being studied, unless more severe than expected for the 
participant’s condition

Medical or surgical procedure (e.g., endoscopy, appendectomy)
The condition that leads to the procedure is the adverse event.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of a preexisting disease or condition present or 
detected at the start of the study that do not worsen
A22
DEFINITION OF SERIOUS ADVERSE EVENT
If an event is not an adverse event per the definition in Section A21, it cannot be a 
serious adverse event even if serious conditions are met (e.g., hospitalization for signs 
or symptoms of the disease under study).
A serious adverse event is defined as any untoward medical occurrence that, at any 
dose:

Results in death

Is life-threatening
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event.  It does not refer to an 
event that hypothetically might have caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are adverse events.  If a complication prolongs hospitalization or 
fulfills any other seriousness criteria, the event is serious.  When in doubt as to 
whether "hospitalization" occurred or was necessary, the adverse event should 
be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an adverse event.


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Follow-Up, and Reporting
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
Results in persistent disability or incapacity
The term "disability" means a substantial disruption of a person’s ability to 
conduct normal life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly or birth defect

Other situations:
Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition.  These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (according to National Cancer Institute Common Terminology Criteria 
for Adverse Events [NCI CTCAE]; see Section A232); 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 electronic Case Report Form (eCRF).
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after the investigator becomes aware of the 
event; see Section A25 for reporting instructions).
A23.
RECORDING AND FOLLOW-UP OF ADVERSE EVENTS AND/OR 
SERIOUS ADVERSE EVENTS
A23.1 ADVERSE EVENT AND SERIOUS ADVERSE EVENT RECORDING
When an adverse event or serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory 
reports, and diagnostics reports) related to the event.


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The investigator will then record all relevant adverse event or serious adverse event
information on the eCRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the Adverse Event eCRF.
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor.
The investigator will attempt to establish a diagnosis of the event on the basis of signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the adverse event or serious 
adverse event.
A23.2 ASSESSMENT OF SEVERITY
The investigator will assess the severity of each adverse event reported during the study 
through use of the NCI CTCAE (v5.0) grading scale.  The investigator will use the 
grading scale in Table A21 for assessing the severity of adverse events that are not
specifically listed in the NCI CTCAE.
Table A21 Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d


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Table A21 Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE (cont.)
CTCAECommon Terminology Criteria for Adverse Events; NCINational Cancer Institute.
Note:  Based on the most recent version of NCI CTCAE (v 5.0), which can be found at:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.
a Examples of instrumental activities of daily living include preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by participants who 
are not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section A25 for reporting instructions), per the definition of serious 
adverse event in Section A22.
d Grade 4 and 5 events must be reported as serious adverse events (see Section A25 for 
reporting instructions), per the definition of serious adverse event in Section A22.
A23.3 ASSESSMENT OF CAUSALITY
The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each adverse event or serious adverse event.
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.
The investigator will use clinical judgment to determine the relationship.
Alternative causes, such as underlying diseases, concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration, will be considered and investigated.
The investigator will also consult the Investigator’s Brochure and/or prescribing 
information (for marketed products) in his or her assessment.
For each adverse event or serious adverse event, the investigator must document in the 
medical notes that he or she has reviewed the adverse event or serious adverse event 
and has provided an assessment of causality.
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report to the Sponsor.  
However, it is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the serious adverse event data 
to the Sponsor.


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The investigator may change his or her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated causality 
assessment.
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
A23.4 FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE
EVENTS
A23.4.1
Investigator Follow-Up
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the adverse event or serious adverse 
event as fully as possible.  This may include additional laboratory tests or investigations, 
histopathologic examinations, or consultation with other health care professionals.
If a participant dies during participation in the study or during a recognized follow-up
period, the investigator will provide the Sponsor with a copy of any post-mortem findings,
including histopathology.
New or updated information should be recorded on the originally-completed 
Adverse Event eCRF.  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 the investigator becomes 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
During the adverse event reporting period (defined in Section 8.3.1), 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.
For reporting of pregnancies, see Appendix 4.
A23.4.2
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, e-mail, and/or a monitoring visit 


Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
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to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
A24.
REPORTING OF SERIOUS ADVERSE EVENTS
A24.1 SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR VIA AN
ELECTRONIC COLLECTION TOOL
The primary mechanism for reporting a serious adverse event to the Sponsor will be the 
electronic data collection tool, as described in Section A25.
If the electronic system is unavailable, the site will use the paper Clinical Trial Adverse 
Event/Special Situations Form, as described in Section A25, to report the event within 
24 hours.
The site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.
After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data.
If a site receives a report of a new serious adverse event from a study participant or 
receives updated data on a previously reported serious adverse event after the 
electronic data collection tool has been taken offline, the site can report this information 
on a paper Clinical Trial Adverse Event/Special Situations Form, as described in 
Section A25.
A24.2 SERIOUS ADVERSE EVENT REPORTING TO THE SPONSOR VIA 
PAPER CRF
Under certain circumstances, serious adverse events may be reported to the Sponsor 
through use of a paper Clinical Trial Adverse Event/Special Situations Form, as 
described in Section A25.
A25.
REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS 
AND ADVERSE EVENTS OF SPECIAL INTEREST
A25.1 EVENTS THAT OCCUR PRIOR TO STUDY TREATMENT INITIATION
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention (e.g., cerebrospinal 
fluid sampling or lumbar puncture, discontinuation of medications) should be reported.


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In addition, the following serious adverse events should be reported after administration 
of a positron emission tomography (PET) ligand and prior to initiation of study drug:

All serious adverse events believed to be related to the PET ligand (non-serious 
adverse events believed to be related to the PET ligand should also be reported; 
see Section 8.3.1)

All serious adverse events occurring within 48 hours of the PET ligand 
administration, regardless of relatedness to the PET ligand
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 the investigator 
becomes aware of the event), either by faxing or by scanning and e-mailing the form, 
using the fax number or e-mail address provided to investigators.
A25.2 EVENTS THAT OCCUR AFTER STUDY TREATMENT INITIATION
After initiation of study treatment, serious adverse events and adverse events of special 
interest will be reported until 17 weeks after the final dose of study treatment
(i.e., the participant’s safety follow-up visit).  Investigators should record all case details 
that can be gathered immediately (i.e., within 24 hours after the investigator becomes 
aware of the event) on the Adverse Event eCRF and submit the report 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 the investigator becomes aware of the event), either by faxing or by 
scanning and e-mailing the form, using the fax number or e-mail 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 more than 17 weeks after the 
final dose of study treatment are provided in Section A26.
A26.
REPORTING 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 
17 weeks after the final dose of study treatment), if the event is believed to be related to 
be prior to exposure to study treatment.  These events should be reported through use 


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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 e-mailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form, using the fax number or e-mail 
address provided to investigators.
A27.
PROCEDURES FOR RECORDING ADVERSE EVENTS
When an adverse event occurs, it is the responsibility of the investigator to review all 
documentation related to the event (e.g., hospital progress notes, laboratory reports, and 
diagnostics reports).  The investigator will then record all relevant adverse event 
information on the Adverse Event eCRF.  It is not acceptable for the investigator to send 
photocopies of the participant's medical records to the Medical Monitor in lieu of 
completion of the eCRF.  Investigators should use correct medical terminology and 
concepts when recording adverse events on the Adverse Event eCRF.  
Avoid colloquialisms and abbreviations.  Only 1 adverse event term should be recorded 
in the event field of the Adverse Event eCRF.
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor.  In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor.
A27.1 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 (i.e., onset or worsening of CNS symptom[s] that is/are 
attributable to ARIA-E magnetic resonance imaging (MRI) findings in the judgment
of the investigator), and/or

ARIA findings that result in a change in study treatment (e.g., dosage modification, 
treatment interruption, or treatment discontinuation), and/or

Findings that are otherwise clinically significant in the investigator’s judgment
Any accompanying symptoms 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 A27.5 for details on recording persistent 
adverse events).


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A27.2 INJECTION REACTIONS
Injection reactions (local and systemic) are defined as adverse events that occur during 
or within 24 hours after study treatment administration and are judged to be related to 
the study treatment injection.
If a participant experiences both a local and systemic reaction to a single administration 
of study treatment, each reaction should be recorded separately on the Adverse Event 
eCRF.
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 captured as a single diagnosis on the Adverse Event 
eCRF (e.g., "anaphylactic reaction").  If possible, avoid ambiguous terms such as 
"systemic reaction".
A27.3 DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
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 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 1 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.
A27.4 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

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


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
If dizziness leads to a fall and consequent fracture, all 3 events should be reported 
separately on the eCRF

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
A27.5 PERSISTENT OF 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 the investigator becomes aware that the event became 
serious; see Section A25 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.
A27.6 ABNORMAL LABORATORY VALUES
Not every abnormal laboratory value qualifies as an adverse event.  A laboratory value
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  
A laboratory value abnormality that is not associated with the underlying disease 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., dose 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upper limit of normal (ULN) 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 A27.5 for 
details on recording persistent adverse events).
A27.7 ABNORMAL VITAL SIGN VALUES
Not every abnormal vital sign value qualifies as an adverse event.  A vital sign 
abnormality that is associated with the underlying disease should not be reported as an 
adverse event unless judged by the investigator to be more severe than expected.  
A vital sign abnormality that is not associated with the underlying disease 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., dose 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 (e.g., hypertension) should be recorded 
on the Adverse Event eCRF.


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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 A27.5 for 
details on recording persistent adverse events).
A27.8 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 
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 A27.6) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after the 
investigator becomes aware of the event), either as a serious adverse event or an 
adverse event of special interest (see Section A25).
A27.9 DEATHS
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 8.3.1), regardless of relationship to study treatment, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see Section A25).
This includes death attributed to progression of Alzheimer’s disease (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.
Autopsy reports, including cause of death, for all participants who die during the study
should be requested.


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Deaths that occur after the adverse event reporting period should be reported as 
described in Section A26.
A27.10
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
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 that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
A27.11
LACK OF EFFICACY OR WORSENING OF ALZHEIMER’S 
DISEASE
Deterioration that is judged by the investigator to have unexpectedly worsened in 
severity or frequency or changed in nature (i.e., deterioration beyond the expected 
pattern of progression of the underlying disease) should be recorded as an adverse 
event. When recording an unanticipated worsening of AD on the Adverse Event eCRF, 
it is important to convey the concept that the condition has changed by including 
applicable descriptors (e.g., "accelerated 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.
A27.12
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 A2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


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
Planned hospitalization required by the protocol

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
–
The participant was hospitalized for an elective procedure that was planned 
prior to the study, was scheduled during the study despite the fact that the 
condition had not worsened, or was scheduled during the study when treatment 
became necessary because of the expected normal progression of the 
condition
–
The participant has not experienced an adverse event

Hospitalization due solely to the expected progression of AD
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of participant requirement for outpatient 
care outside of normal outpatient clinic operating hours
A27.13
CASES OF OVERDOSE, MEDICATION ERROR, DRUG ABUSE, 
OR DRUG MISUSE
Special situations (overdoses, medication errors, drug abuse, or drug misuse) are to be 
reported for study treatment.
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
In cases where drug is to be self-administered by the participant, drug misuse 
could involve the drug being administered to someone other than the participant.
Note: Special situations are not in themselves adverse events, but may result in 
adverse events.


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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 the investigator becomes aware 
of the event; see Section A25).  For study treatment, adverse events associated with 
special situations should be recorded as described below for each situations’ 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.
As an example, an accidental overdose that resulted in a headache would require 
2 entries on the Adverse Event eCRF, 1 entry to report the accidental overdose and 
1 entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
All special situations associated with study treatment, 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.


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
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.

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 
"participant supplied drug to third party" as the event term.  Check the 
"Drug misuse" box.
A27.14
CASES OF MEDICATION ERROR
A medication error is defined as an accidental deviation in the administration of a drug 
(e.g., wrong drug dose administered, sham procedure performed in participant assigned 
to active drug, drug administered in wrong location, sham procedure performed 
incorrectly, expired drug administered).  In some cases, a medication error may be 
intercepted prior to administration of the drug.
Medication errors are not in themselves adverse events, but may result in adverse 
events.  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 the investigator becomes aware of the 
event; see Section A25).
As an example, a medication error that resulted in a headache would require 2 entries 
on the Adverse Event eCRF, 1 entry to report a medication error and 1 entry to report 
the headache.  The "Medication error" boxes would need to be checked for both entries.


Appendix 2:  Adverse Events:  Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting
Gantenerumab—F. Hoffmann-La Roche Ltd
167/Protocol WN42444, Version 2
A27.15
PARTICIPANT-REPORTED OR OBSERVER-REPORTED
OUTCOME DATA
Adverse event reports will not be derived from PRO or ObsRO data by the Sponsor
(detailed list of PROs and ObsROs included in the study is provided in Section 8.10). 
Sites are not expected to review the PRO or ObsRO data for adverse events.
A27.16
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.


Gantenerumab—F. Hoffmann-La Roche Ltd
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Appendix 3 Safety Plan:  Management of Identified and 
Potential Risks
TABLE OF CONTENTS
A31
A32
A33
A34
A34.1
A34.1.1
A34.2
A34.3
A34.4
A35
Amyloid-Related Imaging AbnormalIties 
Injection Reactions and Hypersensitivity 
Immunogenicity
Risks Associated with PET Tracers
Risks Associated with Radiation
Radiation Exposure
[18F]-Florbetaben (Amyloid PET Tracer)
[18F]-Flutemetamol (Amyloid PET Tracer)
[18F]-MK-6240 (Tau PET Tracer) 
Management Rules for Amyloid-Related Imaging 
Abnormalities


Appendix 3:  Safety Plan:  Management of Identified and Potential Risks
Gantenerumab—F. Hoffmann-La Roche Ltd
169/Protocol WN42444, Version 2
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 current Gantenerumab Investigator's Brochure for a complete 
summary of safety information.
A31
AMYLOID-RELATED IMAGING ABNORMALITIES
Amyloid-related imaging abnormalities are one of the most significant adverse events 
reported in therapies against aggregated forms of amyloid (A). These findings 
appear to be dependent on dose-, time-, and apolipoprotein E (APOE) 4 status 
(Piazza and Winblad 2016).
The mechanism underlying the development of amyloid-related imaging 
abnormalitiesedema/effusion (ARIA-E) and amyloid-related imaging 
abnormalitieshemosiderin deposition (ARIA-H) during anti-amyloid treatment is not yet 
fully understood. Because anti-A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 hypothesis is 
consistent with experiences in previous and ongoing studies and with reported data from 
the long-term extension study of aducanumab treatment (Haeberlein et al. 2019; 
Lin et al. 2021).
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
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.
In the double-blind phase of Study WN25203, ARIA events were time (duration of 
treatment), dose, and APOE 4 allele status-dependent. The incidence of ARIA-E was 
0.8% in the placebo, 6.6% in the 105 mg gantenerumab, and 13.5% in the 225 mg 
gantenerumab groups. For ARIA-H, the incidence was 13.2% in the placebo, and 22.9% 
and 16.2% in the 105 mg and 225 mg gantenerumab treatment groups, respectively. 
The rates of new ARIA-E were highest between 3 and 6 months of treatment (3.8% and 
7.5% in the 105 mg and 225 mg gantenerumab groups, respectively) and decreased 
substantially after the first 9 months of treatment (incidence of up to 2.3% in the 225 mg 


Appendix 3:  Safety Plan:  Management of Identified and Potential Risks
Gantenerumab—F. Hoffmann-La Roche Ltd
170/Protocol WN42444, Version 2
gantenerumab group in approximately 2 years). The median MRI Barkhof Grand Total 
Score (BGTS; Barkhof et al. 2013) of these findings was 3. Most ARIA events were 
asymptomatic and did not lead to clinically significant consequences. A total of 
5 participants (1.8%) from the 105 mg gantenerumab group and 6 participants (2.3%) 
from the 225 mg gantenerumab group experienced symptoms related to ARIA findings; 
the most commonly reported symptom was headache (5 participants). Other symptoms 
reported with ARIA-E included visual disturbances (left eye diplopia and upper left 
quadrantanopia), focal seizure (dysarthria/ aphasia that lasted for 10 minutes), anxiety, 
hyperreflexia, confusional state, disturbance in attention, cognitive disorder, malaise, 
and dizziness.
Symptomatic ARIAs were of mild severity and were non-serious except for 1 serious 
adverse event of focal seizure.
Following the futility analysis for Study WN25203, treatment in the double-blind phase
was discontinued in July 2017 (median double-blind treatment duration: 68 weeks) and
consenting participants transitioned into an open-label extension (OLE).
In the double-blind phase of Study WN28745, the frequency of ARIA-E was 1.5% and
11.5% in the placebo and gantenerumab groups, respectively. The frequency of ARIA-H
was 11.8% and 15.1% in the placebo and gantenerumab groups, respectively.
The median BGTS of ARIA-E was 3. Most ARIAs were asymptomatic and did not lead 
to clinically significant consequences. Two participants reported CNS adverse events as
symptoms of ARIAs: 1 participant (0.5%) in the placebo group reported irritability that
was mild in intensity and non-serious, and 1 participant (0.5%) in the gantenerumab
group reported headache that was moderate in intensity and non-serious.
The OLEs of Studies WN25203 and WN28745 were recently completed (last participant, 
last visit [LPLV] occurred and databases are closed). As of 3 December 2020, in the 
OLE part of the Study WN25203, all 154 patients dosed with gantenerumab in the OLE 
had at least 1 post-OLE baseline MRI scan.  Of these, 47 patients (30.5%) had new 
ARIA-E and 51 patients (33.1%) had new ARIA-H.  Additionally, 31 patients (20.1%) had 
new ARIA-E and new ARIA-H at any point during the OLE.
The majority of ARIA-E findings were asymptomatic, with 19 of 47 participants (40.4%) 
with ARIA-E reporting associated CNS adverse events. The CNS adverse events were 
mostly mild to moderate in intensity, non-serious, did not require permanent cessation of 
study treatment, and resolved with protocol-defined ARIA management rules. In 4 of 
19 patients with ARIA-E MRI findings who reported associated CNS adverse events, the 
events were reported as serious.  Three patients reported events of seizure (n2) and 
cerebral hematoma which was severe in intensity and one patient reported confusion 


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that was moderate in intensity.  Three serious adverse events were assessed as related 
to study treatment by the investigator.
Up to 11 January 2021, 219 of 225 participants dosed with gantenerumab in the OLE
phase of Study WN28745 had a post-baseline MRI scan; 71 of 219 participants (32.4%) 
had new ARIA-E (with or without ARIA-H), 75 patients (34.24%) had new ARIA-H 
(with or without ARIA-E), and 49 patients (22.3%) had both ARIA-E and ARIA-H.
The majority of ARIA-E events were asymptomatic, with 22 out of 71 participants (31%) 
with ARIA-E reporting associated CNS adverse events. The CNS adverse events were 
mostly mild to moderate in intensity, non-serious, did not require permanent cessation of 
study treatment, and resolved spontaneously with protocol-defined ARIA management 
rules. Four of the 22 participants (18%) reported serious events associated with 
ARIA findings (2 participants had seizure events which resolved without anti-epileptic 
medication, 1 participant had hemiplegia which resolved after treatment with 
dexamethasone, and 1 participant had ischemic stroke which improved [most of the 
symptoms, with the exception of disorientation, resolved]).
Study WN42444 will require an MRI scan documenting the absence of ARIA-E, 
5 ARIA-H, or disseminated leptomeningeal hemosiderosis prior to the first study drug
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 Section A35.
Safety findings, including individual participant and aggregate data, will be reviewed on a
regular basis by an unblinded iDMC.
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 glucorticosteroids may be considered.
Rules for management of participants who develop ARIA-E or ARIA-H are provided in in 
Section A35.
A32
INJECTION REACTIONS AND HYPERSENSITIVITY
Gantenerumab may cause a local injection-site reaction (ISR) 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.
In the double-blind phase of Study WN25203, the incidence of ISRs was 4.5%, 18.8%,
and 23.1% in the placebo, 105 mg gantenerumab, and 225 mg gantenerumab groups,


Appendix 3:  Safety Plan:  Management of Identified and Potential Risks
Gantenerumab—F. Hoffmann-La Roche Ltd
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respectively. All ISRs were non-serious, and the majority were mild in intensity and
resolved without treatment. The most common signs and symptoms of ISRs included
injection-site erythema, pruritus, and rash. Two participants (0.3%) discontinued study
treatment due to an ISR.
In the double-blind phase of Study WN28745, the incidence of ISRs was 1.0% and 9.4%
in the placebo and gantenerumab groups, respectively. All ISRs were non-serious and
mild in intensity; the vast majority resolved without treatment. The most common signs
and symptoms of ISRs included injection-site erythema, pruritus, hemorrhage, and rash.
No participants discontinued study treatment due to an ISR.
Up to 11 January 2021 ISRs have been reported in 36.4% of participants
(56 of 154 participants) treated with gantenerumab in the OLE phase of 
Study WN25203. The most frequently reported ISRs (10%) were injection-site 
erythema (49 participants [31.8%]) and injection-site swelling (18 participants [11.7%]).
All ISRs were non-serious and mild except 1 which was of moderate intensity, and the 
majority resolved without treatment. Overall, 3 of 56 participants (5.4%) who had an ISR 
received treatment, which included topical steroids and antihistamines.
Up to 11 Jan 2021 March 2020, ISRs have been reported in 40.0 % of participants
(90 of 225 participants) treated with gantenerumab in the OLE phase of 
Study WN28745. The most frequently reported ISRs (10%) were injection-site 
erythema (67 participants [29.8%]). All ISRs were non-serious, with the majority being 
mild and resolving without treatment. One participant (0.4%) experienced a severe 
event (injection-site pain after receiving a 600 mg dose via a pump, resulting in dose 
modification [i.e., dose escalation was delayed]); this ISR resolved within 24 hours.
Overall, 10 of 90 participants (11.1%) who had an ISR received treatment, which 
included topical steroids and antihistamines.
Detailed information on the characteristic signs and symptoms of ISRs 
(e.g., erythema, pruritus) will be recorded on a dedicated electronic Case Report Form 
(eCRF) page (see Section A27.2 for details on recording of ISRs).
As with administration of any exogenous protein, a potential exists for the development
of hypersensitivity reactions, including anaphylaxis. A hypersensitivity reaction may
present during any injection, although typically would not present during the first 
injection. For subsequent injections, more severe injection reaction symptoms than 
previously experienced, or new severe symptoms, should prompt consideration of a 
potential hypersensitivity reaction.
A potential exists for the occurrence of systemic injection reactions, which are related to
cytokine release and/or other chemical mediators. These may be clinically


Appendix 3:  Safety Plan:  Management of Identified and Potential Risks
Gantenerumab—F. Hoffmann-La Roche Ltd
173/Protocol WN42444, Version 2
indistinguishable from hypersensitivity reactions, including anaphylaxis. In comparison 
to hypersensitivity reactions, systemic injection reactions could occur on first exposure to
study drug in participants with no history of prior opportunities for sensitization.
On each dosing day, after all assessments prior to dosing have been completed 
(see the schedule of activities in Section 1.3), the study drug will be administered SC at 
room temperature (full details are provided in the Pharmacy Manual). Study site 
personnel administering study drug must not be involved with any efficacy assessments 
or safety evaluations.
During the initial dose escalation period, participants should be observed for a minimum 
of 2 hours after dosing for the first 4 doses of study drug administration, and then for a 
minimum of 1 hour after all remaining doses (i.e., dose 5 and beyond). During the 
post-progression dose escalation period, participants should be observed for at least 
2 hours after injections at Week 1P, Week 5P, Week 9P and Week 13P. 
The observation time may be reduced to at least 1 hour following all other 
administrations.  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, the drug administrator must remain with the participant for a minimum 
of 1 hour after each injection. Participants self-administering the study drug must also 
be observed for a minimum of 1 hour after each injection by their study partner or 
another suitably trained individual (i.e., postdose observer).
Rescue medications to treat anaphylactic and anaphylactoid reactions must be available
at the clinical trial site. Participants and their study partners will be alerted to watch for 
signs of anaphylactic and anaphylactoid reactions, and given emergency contact 
information to use as soon as possible if any such signs are noted.
The investigator may order any pertinent laboratory tests, including an unscheduled
anti-drug antibody (ADA) test, in the event any hypersensitivity reaction occurs.
If anaphylaxis or a serious hypersensitivity reaction occurs, the study drug must be
discontinued permanently, and any remaining study drug doses should be returned to
the study site (if applicable). Blood samples for the presence of ADAs and PK/PD will be
obtained.
A3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.


Appendix 3:  Safety Plan:  Management of Identified and Potential Risks
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For the management of suspected immunogenicity-associated
hypersensitivity/anaphylaxis, see section above.
A34
RISKS ASSOCIATED WITH PET TRACERS
A34.1 RISKS ASSOCIATED WITH RADIATION
The risks associated with radiation in Study WN42444 are considered minimal, owing to
the low dose of tracer that is administered and based on nonclinical and clinical
experience available to date. The principal risks associated with positron emission 
tomography (PET) imaging are those associated with IV line placement, the discomfort 
associated with acquisition of the images while keeping the head stable in the scanner, 
and radiation exposure because of the radiotracer dose and transmission or CT 
scanning. The most frequently reported adverse events with amyloid radioligands are 
described in Sections A34.2 and A34.3, and the most frequently reported adverse 
events with the tau radioligand MK-6240 are described in Section A34.4).
Other adverse reactions could be related in part to the PET scan apparatus and
procedures; careful attention should be taken to make the participant aware of the
planned procedures and to maximize participant comfort in the scanner. 
Venous catheter insertion can be associated with bruising, infection, or clot formation. 
Using proper placement techniques will minimize such risks. Experience in previous 
human clinical trials has revealed no clinically-meaningful changes in vital signs,
electrocardiogram, or laboratory changes following treatment with PET tracers.
The potential for drug-drug interactions with PET tracers is not presently known.
Since PET tracers are administered at trace-level doses, no clinically-relevant drug 
interactions with concomitant medications is expected.
A34.1.1
Radiation Exposure
The dose of whole-body effect radiation resulting from the recommended injected
radioactivity is similar for [18F]-Florbetaben, [18F]-Flutemetamol, and [18F]-MK-6240 and is 
well-below the maximum annual effective dose limitations recommended in the 
United States, the European Union, and other countries where PET imaging will be 
used. The recommended 300 MBq dose of [18F]-Florbetaben results in a 5.8-mSv 
absorbed dose, the 185-MBq dose of [18F]-Flutemetamol results in 5.9 mSv, and the 
185-MBq dose of [18F]-MK-6240 results in 5.4 mSv. Additional radiation dose results
from CT or transmission scan used for attenuation correction of the PET emission data.
The CT scan in PET/CT scanners will be configured as a low-dose CT and will add
approximately 0.1 mSv to the dose from PET tracers. In dedicated PET scanners
without CT scans, the transmission scan adds only a negligible amount of radiation
dose.


Appendix 3:  Safety Plan:  Management of Identified and Potential Risks
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175/Protocol WN42444, Version 2
Radiation exposure for [18F]-Florbetaben, [18F]-Flutemetamol, and [18F]-MK-6240 doses 
can be found in their respective Investigator’s Brochures and in the Technical 
Operations Manual. Refer to local and national guidelines for recommended annual 
radiation exposure. For comparison, the annual dose associated with the natural 
background is 2.4 mSv. The recommended maximum annual whole-body dose from 
research scans in the United States is 50 mSv. In the European Union, 10 mSv per year 
is the recommended maximum dose for research scans, corresponding to a risk 
category “Category IIb” with a “minor to intermediate” level of risk 
(Verbruggen et al. 2008). Positron emission tomography scans should only be 
performed if the investigator has determined that a participant's total past and planned 
annual radiation exposure does not exceed local guidelines.
A34.2 [18F]-FLORBETABEN (AMYLOID PET TRACER)
The most commonly reported adverse reactions after injection of [18F]-Florbetaben 
(occurring in at least 1% of subjects) are injection-site pain (3.1%), and injection or 
application-site erythema (1.4%). [18F]-Florbetaben contains up to 33 mg (i.e., 1.4 mmol)
of sodium per dose. This should be taken into account for participants on a 
sodium-controlled diet. [18F]-Florbetaben contains up to 1200 mg of ethanol per dose, 
which is equivalent to 30 mL of beer or 12.5 mL of wine per dose.
In countries where [18F]-Florbetaben PET radioligand is approved for marketing, for more
information see the approved local product information. In countries where the
[18F]-Florbetaben PET radioligand is not approved for marketing, the 
Investigator’s Brochure will be provided.
A34.3 [18F]-FLUTEMETAMOL (AMYLOID PET TRACER)
The most commonly reported adverse reactions after injection of flutemetamol are
flushing (2%), chest discomfort (1%), dizziness (1%), headache (1%), increased blood 
pressure (1%), nausea (1%), and anaphylactic reaction (0.5%). [18F]-Flutemetamol 
contains up to 41 mg (i.e., 1.8 mmol) of sodium per dose. This should be taken into 
account for participants on a sodium-controlled diet. [18F]-Flutemetamol contains up to 
552 mg of ethanol per dose, which is equivalent to 14 mL of beer or 6 mL of wine per 
dose.
In countries where [18F]-Flutemetamol PET radioligand is approved for marketing, for 
more information see the approved local product information. In countries where the
[18F]-Flutemetamol PET radioligand is not approved for marketing, the Investigator’s 
Brochure will be provided.


Appendix 3:  Safety Plan:  Management of Identified and Potential Risks
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176/Protocol WN42444, Version 2
A34.4 [18F]-MK-6240 (TAU PET TRACER)
There are no adverse reactions to [18F]-MK-6240. Potential risks include pain and 
bleeding from venous or arterial catheterization or an IV infusion reaction
([18F]-MK-6240 Investigator’s Brochure, Version F, dated June 2021). 
[18F]-MK-6240 contains up to 32.4 mg of sodium (81 mg of sodium chloride) and 1 mL of 
ethanol per dose.
The [18F]-MK-6240 PET radioligand is not approved for marketing in any country. 
For more information, the Investigator’s Brochure will be provided.
A35
MANAGEMENT RULES FOR AMYLOID-RELATED IMAGING 
ABNORMALITIES
Participants on target dose 510 mg SC Q2W: Before reaching the maximum target 
dose 510 mg Q2W, a minimum of 3 doses during 120 mg Q4W, 255 mg Q4W, and 
510 mg Q4W dosing periods must be administered prior to dose escalation. Participants 
will undergo brain MRI examinations prior to dose increases (predose escalation MRI 
scans) to 510 mg Q4W and 510 mg Q2W and according to the schedule of activities 
once the target dose is achieved (see Section 1.3). These predose escalation MRI 
scans will determine eligibility for the next dose escalation dose. The investigators may 
choose to perform additional MRI monitoring for ARIA at any time.
Participants on target dose 255 mg SC Q1W: Before reaching the maximum target 
dose 255 mg Q1W, a minimum of 3 doses during 120 mg Q4W and 255 mg Q4W dosing 
periods, and a minimum of 6 doses during the 255 mg Q2W dosing period must be 
administered prior to dose escalation. Participants will undergo brain MRI examinations 
prior to dose increases (predose escalation MRI scans) to 255 mg Q2W and 255 mg 
Q1W and according to the schedule of activities once the target dose is achieved
(see Section 1.3). These predose escalation MRI scans will determine eligibility for the 
next dose escalation dose. The investigators may choose to perform additional MRI 
monitoring for ARIA at any time.
Participants will be eligible for dose escalation if there is no new ARIA-E; or if the new 
ARIA-E is mild (Bioclinica severity1) and asymptomatic; or if the ARIA-E is resolved 
(Bioclinica severity0, asymptomatic), and if the criteria for permanent treatment
discontinuation because of ARIA-H have not been met.
In addition, the dose adjustment and discontinuation rules for MRI findings specified in 
Table A31 will apply.
Additional measures for at-home administration: Every 4 weeks, except when there 
is an in-person clinic visit, the investigator or an appointed qualified study staff will have 






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Table A31Management Rules for Amyloid-Related Imaging Abnormalities
(cont.)
Source:  Bracoud et al. 2017.
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; Q1W every week; 
Q2W every 2 weeks; Q4W every 4 weeks.
Notes:

The investigator may choose to perform additional MRI monitoring for ARIA at any time

Symptomatic ARIA-E is defined as onset or worsening of CNS symptom(s) that is/are 
attributable to ARIA-E MRI findings in the judgment of the Principal Investigator

Disseminated LH is defined as more than 3 focal leptomeningeal hemosiderosis
cumulatively

If ARIA-E and disseminated LH co-occur, the more conservative management rule will 
apply

Any other new significant MRI findings will be reviewed by the investigator and appropriate 
dose action will be taken

In exceptional cases, as determined by the investigator:
1) Q4W MRI monitoring may no longer be necessary in case of an ARIA-E that is 
asymptomatic with Bioclinica severity 1 and considered stable over consecutive MRI 
images; or a symptomatic ARIA-E for which the imaging evidence of ARIA-E has 
resolved but the CNS symptoms continue
2) study drug can be either reintroduced or up-titrated, as applicable, in case of an 
asymptomatic ARIA-E that has stabilized at Bioclinica severity 1; or a symptomatic 
ARIA-E for which the imaging evidence of ARIA-E has resolved but the CNS symptoms 
continue.

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)

A plasma biomarker 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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bapineuzumab in pateints with Alzheimer’s disease. Alzheimer Dis Assoc Disord
2010;24:198203.
Bracoud L, Fiebach JB, Purcell DD, et al. [P1047]: Validation of a simple severity scale 
for assessing ARIA-E. Alzheimer’s Assoc 2017;13:P2534.
Haeberlein SB, von Hehn C, Tian Y, et al. EMERGE and ENGAGE topline results: 
two Phase 3 studies to evaluate aducanumab in patients with early alzheimer’s 


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Gantenerumab—F. Hoffmann-La Roche Ltd
180/Protocol WN42444, Version 2
disease [resource on the Internet] 2019. Available from :
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Sperling R, Salloway S, Brooks DJ, et al. Amyloid-related imaging abnormalities in 
patients with Alzheimer’s disease treated with bapineuzumab: a retrospective 
anaysis. Lancet Neurol 2012;11:2419.
Verbruggen A, Coenen HH, Deverre J, et al. Guideline to regulations for 
radiopharmaceuticals in early phase clinical trials in the EU. Eur J Nucl Med Mol 
Imaging 2008;35:214451.


Gantenerumab—F. Hoffmann-La Roche Ltd
181/Protocol WN42444, Version 2
Appendix 4 Contraceptive and Barrier Guidance
TABLE OF CONTENTS
A41.
Pregnancies in Female Participants
A42.
Abortions
A43.
Abnormal Pregnancy Outcomes


Appendix 4:  Contraceptive and Barrier Guidance
Gantenerumab—F. Hoffmann-La Roche Ltd
182/Protocol WN42444, Version 2
A4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 17 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 the investigator becomes 
aware of the pregnancy), either by faxing or by scanning and e-mailing the form, using 
the fax number or e-mail address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event electronic Case Report Form (eCRF).  The investigator 
should discontinue study treatment 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 or 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.
Attempts should be made to collect and report infant health information.  When permitted 
by the site, an Authorization for the Use and Disclosure of Infant Health Information 
would need to be signed by one or both parents (as per local regulations) to allow for 
follow-up on the infant.  If the authorization has been signed, the infant's health status at 
birth should be recorded on the Clinical Trial Pregnancy Reporting Form.  In addition, the 
Sponsor may collect follow-up information on the infant's health status at 6 and 
12 months after birth.
A4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 the 
investigator becomes aware of the event; see Section A25).
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 the investigator becomes aware of the event; 
see Section A25).  A therapeutic or elective abortion performed for reasons other than 
an underlying maternal or embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.


Appendix 4:  Contraceptive and Barrier Guidance
Gantenerumab—F. Hoffmann-La Roche Ltd
183/Protocol WN42444, Version 2
A43.
ABNORMAL PREGNANCY OUTCOMES
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, birth defect, ectopic pregnancy) in a female participant exposed to 
study treatment 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 the investigator becomes aware of the event; see Section A25).


Gantenerumab—F. Hoffmann-La Roche Ltd
184/Protocol WN42444, Version 2
Appendix 5 Reporting Requirements for Medical Device 
Complaints
In this study, the vial adapter may be provided to the participant or study partner 
(non-professional caregiver), in countries where it has been approved, to aid study drug
administration in the home setting is considered a medical device.  The investigator must 
report all device deficiencies to the Sponsor in the form of a medical device complaint.  
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance, and it can include malfunctions, use 
errors, and inadequate labeling.  In reporting a medical device complaint, the 
investigator should document as much information as possible on the Investigational 
Medicinal Product Deviation Form, including the product batch number, as reported on 
the blister, and forward the form to the Sponsor immediately (i.e., no more than 24 hours 
after the investigator becomes aware of the event; refer to the Pharmacy Manual for 
further details).  If the medical device deficiency results in an adverse event to the study 
participant, the event must be reported on the Adverse Event electronic Case Report 
Form (CRF) and submitted through the EDC system.  If the event fulfills seriousness 
criteria, the Adverse Event eCRF must be completed immediately (i.e., no more than 
24 hours after the investigator becomes aware of the event), as outlined in 
Section A25.


Gantenerumab—F. Hoffmann-La Roche Ltd
185/Protocol WN42444, Version 2
Appendix 6 Mini-Mental State Examination 
(Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.
FORM A


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
186/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
187/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
188/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
189/Protocol WN42444, Version 2
FORM B


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
190/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
191/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
192/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
193/Protocol WN42444, Version 2
FORM C


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
194/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
195/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
196/Protocol WN42444, Version 2


Appendix 6:  Mini-Mental State Examination (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
197/Protocol WN42444, Version 2
REFERENCES
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”.  A practical method for 
grading the cognitive state of patients for the clinician. J Psychiatr Res 
1975;12:18998.
Jaeger J. Digit Symbol Substitution Test: the case for sensitivity over specificity in 
neuropsychological testing. J Clin Psychopharmacol 2018;38:5139.
Papp KV, Rentz DM, Orlovsky I, et al. Optimizing the preclinical Alzheimer’s cognitive 
composite with semantic processing: the PACC5. Alzheimer’s Dement (NY) 
2017;3:66877.
Papp KV, Buckley R, Mormino E, et al. Clinical meaningfulness of subtle cognitive 
decline on longitudinal testing in preclinical AD. Alzheimer’s Dement 
2020;16:55260.


Gantenerumab—F. Hoffmann-La Roche Ltd
198/Protocol WN42444, Version 2
Appendix 7 FCSRTIRDR (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.
FORM A


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
199/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
200/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
201/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
202/Protocol WN42444, Version 2
FORM B


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
203/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
204/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
205/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
206/Protocol WN42444, Version 2
FORM C


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
207/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
208/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
209/Protocol WN42444, Version 2


Appendix 7:  FCSRTIRDR (Preclinical Alzheimer’s Cognitive Composite5) Form A, B, 
and C
Gantenerumab—F. Hoffmann-La Roche Ltd
210/Protocol WN42444, Version 2
REFERENCES
Grober E, Buschke H. Genuine memory deficits in dementia. Developmental 
Neuropsychology 1987;3:1336.
Grobert E, Ocepek-Welikson K, Teresi JA. The Free and Cued Selective Reminding 
Test: evidence of psychometric adequacy. Psychology Science Quarterly 
2009;51:26682.
Grober E, Sanders AE, Hall C, et al. Free and cued selective reminding identifies very 
mild dementia in primary care. Alzheimer Dis Assoc Disord 2010;24:28490.
Grober E, Veroff AE, Lipton RB. Temporal unfolding of declining episodic memory on teh 
Free and Cued Selective Reminding Test in the predementia phase of Alzheimer’s 
disease: implications for clinical trials. Alzheimer’s Dement (Amst). 
2018;10:16171.
Papp KV, Rentz DM, Orlovsky I, et al. Optimizing the preclinical Alzheimer’s cognitive 
composite with semantic processing: the PACC5. Alzheimer’s Dement (NY) 
2017;3:66877.
Papp KV, Buckley R, Mormino E, et al. Clinical meaningfulness of subtle cognitive 
decline on longitudinal testing in preclinical AD. Alzheimer’s Dement 
2020;16:55260.


Gantenerumab—F. Hoffmann-La Roche Ltd
211/Protocol WN42444, Version 2
Appendix 8 LM III WMSIV (Preclinical Alzheimer’s Cognitive 
Composite5) Form A, B, and C
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.
FORM A


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
212/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
213/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
214/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
215/Protocol WN42444, Version 2
FORM B


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
216/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
217/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
218/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
219/Protocol WN42444, Version 2
FORM C


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
220/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
221/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
222/Protocol WN42444, Version 2


Appendix 8:  LM III WMSIV (Preclinical Alzheimer’s Cognitive Composite5) Form A, 
B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
223/Protocol WN42444, Version 2
REFERENCES
Papp KV, Rentz DM, Orlovsky I, et al. Optimizing the preclinical Alzheimer’s cognitive 
composite with semantic processing: the PACC5. Alzheimer’s Dement (NY) 
2017;3:66877.
Papp KV, Buckley R, Mormino E, et al. Clinical meaningfulness of subtle cognitive 
decline on longitudinal testing in preclinical AD. Alzheimer’s Dement 
2020;16:55260.
Wechsler D. Wechsler adult intelligence scale. Fourth Edition (WAISIV). 2008. 
San Antonio, TX: NCS Pearson.


Gantenerumab—F. Hoffmann-La Roche Ltd
224/Protocol WN42444, Version 2
Appendix 9 Coding WAISIV (Preclinical Alzheimer’s 
Cognitive Composite5) Form A, B, and C
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.
CODING MANUAL


Appendix 9:  Coding WAISIV (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
225/Protocol WN42444, Version 2


Appendix 9:  Coding WAISIV (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
226/Protocol WN42444, Version 2


Appendix 9:  Coding WAISIV (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
227/Protocol WN42444, Version 2


Appendix 9:  Coding WAISIV (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
228/Protocol WN42444, Version 2
FORM A


Appendix 9:  Coding WAISIV (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
229/Protocol WN42444, Version 2
FORM B


Appendix 9:  Coding WAISIV (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
230/Protocol WN42444, Version 2
FORM C


Appendix 9:  Coding WAISIV (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
231/Protocol WN42444, Version 2
REFERENCES
Papp KV, Rentz DM, Orlovsky I, et al. Optimizing the preclinical Alzheimer’s cognitive 
composite with semantic processing: the PACC5. Alzheimer’s Dement (NY) 
2017;3:66877.
Papp KV, Buckley R, Mormino E, et al. Clinical meaningfulness of subtle cognitive 
decline on longitudinal testing in preclinical AD. Alzheimer’s Dement 
2020;16:55260.
Wechsler, D. The measurement and appraisal of adult intelligence (1st edition) 1939. 
Baltimore: Williams and Wilkins Corporation.
Wechsler D. Wechsler adult intelligence scale. Fourth Edition (WAISIV). 2008. 
San Antonio, TX: NCS Pearson.


Gantenerumab—F. Hoffmann-La Roche Ltd
232/Protocol WN42444, Version 2
Appendix 10 Category Fluency (Preclinical Alzheimer’s 
Cognitive Composite5) Form A, B, and C
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.
FORM A


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
233/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
234/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
235/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
236/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
237/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
238/Protocol WN42444, Version 2
FORM B


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
239/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
240/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
241/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
242/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
243/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
244/Protocol WN42444, Version 2
FORM C


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
245/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
246/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
247/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
248/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
249/Protocol WN42444, Version 2


Appendix 10:  Category Fluency (Preclinical Alzheimer’s Cognitive Composite5) 
Form A, B, and C
Gantenerumab—F. Hoffmann-La Roche Ltd
250/Protocol WN42444, Version 2
REFERENCES
Clark LJ, Gatz M, Zheng L, et al. Longitudinal verbal fluency in normal aging, preclinical, 
and prevalent Alzheimer’s disease. Am J Alzheimers Dis Other Demen 
2009;24:4618.
Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment (4th revised 
edition). New York: Oxford University Press, 2004.
Papp KV, Rentz DM, Orlovsky I, et al. Optimizing the preclinical Alzheimer’s cognitive 
composite with semantic processing: the PACC5. Alzheimer’s Dement (NY) 
2017;3:66877.
Papp KV, Buckley R, Mormino E, et al. Clinical meaningfulness of subtle cognitive 
decline on longitudinal testing in preclinical AD. Alzheimer’s Dement 
2020;16:55260.
Pasquier F, Lebert F, Grymonprez L, et al. Verbal fluency in dementia of frontal lobe 
type and dementia of Alzheimer type. J Neurol Neurosurg 
Psychiatry1995;58:814.


Gantenerumab—F. Hoffmann-La Roche Ltd
251/Protocol WN42444, Version 2
Appendix 11 Clinical Dementia Rating Scale
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
252/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
253/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
254/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
255/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
256/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
257/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
258/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
259/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
260/Protocol WN42444, Version 2


Appendix 11:  Clinical Dementia Rating Scale
Gantenerumab—F. Hoffmann-La Roche Ltd
261/Protocol WN42444, Version 2
REFERENCES
Berg L. Clinical Dementia Rating (CDR). Psychopharmacol Bull 1988;24:6379.
Morris JC. The clinical dementia rating (CDR): current version and scoring rules. 
Neurology 1993;43:24124.
Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage 
Alzheimer’s disease. Arch Neurol 2001;58:397405.
O’Bryant SE, Lacritz LH, Hall J, et al. Validation of the new interpretive guidelines for the 
clinical dementia rating scale sum of boxes score in the national Alzheimer’s 
coordinating center database. Arch Neurol 2010;67:7469.


Gantenerumab—F. Hoffmann-La Roche Ltd
262/Protocol WN42444, Version 2
Appendix 12 Amsterdam Instrumental Activity of Daily Living 
QuestionnaireShort Version (A-IADL-Q-SV) Participant Version
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
263/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
264/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
265/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
266/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
267/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
268/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
269/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
270/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
271/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
272/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
273/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
274/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
275/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
276/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
277/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
278/Protocol WN42444, Version 2


Appendix 12:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
279/Protocol WN42444, Version 2
REFERENCE
Jutten RJ, Peeters CFW, Leijdesdorff SMJ, et al. Detecting functional decline from 
normal aging to dementia: Development and validation of a short version of the 
Amsterdam IADL Questionnaire. Alzheimers Dement (Amst) 2017;8:2635.


Gantenerumab—F. Hoffmann-La Roche Ltd
280/Protocol WN42444, Version 2
Appendix 13 Amsterdam Instrumental Activity of Daily Living 
QuestionnaireShort Version (A-IADL-Q-SV) Study Partner 
Version
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
281/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
282/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
283/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
284/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
285/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
286/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
287/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
288/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
289/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
290/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
291/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
292/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
293/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
294/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
295/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
296/Protocol WN42444, Version 2


Appendix 13:  Amsterdam Instrumental Activity of Daily Living QuestionnaireShort 
Version (A-IADL-Q-SV) Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
297/Protocol WN42444, Version 2
REFERENCE
Jutten RJ, Peeters CFW, Leijdesdorff SMJ, et al. Detecting functional decline from 
normal aging to dementia: Development and validation of a short version of the 
Amsterdam IADL Questionnaire. Alzheimers Dement (Amst) 2017;8:2635.


Gantenerumab—F. Hoffmann-La Roche Ltd
298/Protocol WN42444, Version 2
Appendix 14 CFIa Participant Version
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 14:  CFIa Participant Version
Gantenerumab—F. Hoffmann-La Roche Ltd
299/Protocol WN42444, Version 2
REFERENCES
Amariglio RE, Donohue MC, Marshall GA, et al. Tracking early decline in cognitive 
function in older individuals at risk for Alzheimer disease dementia: the Alzheimer’s 
Disease Cooperative Study Cognitive Function Instrument. JAMA Neurol 
2015;72:44654.
Li C, Neugroschl J, Luo X,et al. The utility of the Cognitive Function Instrument (CFI) to 
detect cognitive decline in non-demented older adults. J Alzheimers Dis 
2017;60:42737.
Walsh SP, Raman R, Jones KB, et al. ADCS Prevention Instrument Project: the Mail-In 
Cognitive Function Screening Instrument (MCFSI). Alzheimer Dis Assoc Disord 
2006;20:S1708.


Gantenerumab—F. Hoffmann-La Roche Ltd
300/Protocol WN42444, Version 2
Appendix 15 CFIa Study Partner Version
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 15:  CFIa Study Partner Version
Gantenerumab—F. Hoffmann-La Roche Ltd
301/Protocol WN42444, Version 2
REFERENCES
Amariglio RE, Donohue MC, Marshall GA, et al. Tracking early decline in cognitive 
function in older individuals at risk for Alzheimer disease dementia: the Alzheimer’s 
Disease Cooperative Study Cognitive Function Instrument. JAMA Neurol 
2015;72:44654.
Li C, Neugroschl J, Luo X,et al. The utility of the Cognitive Function Instrument (CFI) to 
detect cognitive decline in non-demented older adults. J Alzheimers Dis 
2017;60:42737.
Walsh SP, Raman R, Jones KB, et al. ADCS Prevention Instrument Project: the Mail-In 
Cognitive Function Screening Instrument (MCFSI). Alzheimer Dis Assoc Disord 
2006;20:S1708.


Gantenerumab—F. Hoffmann-La Roche Ltd
302/Protocol WN42444, Version 2
Appendix 16 Geriatric Depression Scale30
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 16:  Geriatric Depression Scale30
Gantenerumab—F. Hoffmann-La Roche Ltd
303/Protocol WN42444, Version 2


Appendix 16:  Geriatric Depression Scale30
Gantenerumab—F. Hoffmann-La Roche Ltd
304/Protocol WN42444, Version 2
REFERENCES
Sheikh JI, Yesavage JA, Brooks JO, et al. Proposed factor structure of the Geriatric 
Depression Scale. Int Psychogeriatr 1991;3:238.
Yesavage JA, Brink TL, Rose TL, et al. Development and validation of a geriatric
depression screening scale: a preliminary report. J Psychiatr Res 
19821983;17:3749.


Gantenerumab—F. Hoffmann-La Roche Ltd
305/Protocol WN42444, Version 2
Appendix 17 Alzheimer’s Disease Clinical Global Impression of 
Cognitive Function Severity (AD-CGI-S)
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 17:  Alzheimer’s Disease Clinical Global Impression of Cognitive Function 
Severity (AD-CGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
306/Protocol WN42444, Version 2


Appendix 17:  Alzheimer’s Disease Clinical Global Impression of Cognitive Function 
Severity (AD-CGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
307/Protocol WN42444, Version 2
REFERENCE
Guy W, editor. ECDEU Assessment Manual for Pschopharmacology. 1976. Rockville, 
MD, U.S. Department of Health, Education and Welfare.


Gantenerumab—F. Hoffmann-La Roche Ltd
308/Protocol WN42444, Version 2
Appendix 18 Alzheimer’s Disease Participant Global Impression 
of Cognitive Function (AD-PGI-S)
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 18:  Alzheimer’s Disease Participant Global Impression of Cognitive Function 
(AD-PGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
309/Protocol WN42444, Version 2


Appendix 18:  Alzheimer’s Disease Participant Global Impression of Cognitive Function 
(AD-PGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
310/Protocol WN42444, Version 2


Appendix 18:  Alzheimer’s Disease Participant Global Impression of Cognitive Function 
(AD-PGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
311/Protocol WN42444, Version 2
REFERENCE
FDA. Patient-focused drug development guidance public workshop: Methods to identify 
what is important to patients and select, develop, or modify fit-for-purpose clinical 
outcomes assessments. [resource on the Internet] 2018b. Available from:
https://www.fda.gov/media/116277/download.


Gantenerumab—F. Hoffmann-La Roche Ltd
312/Protocol WN42444, Version 2
Appendix 19 Alzheimer’s Disease Study Partner Impression of 
Cognitive Function (AD-SPGI-S)
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 19:  Alzheimer’s Disease Study Partner Global Impression of Cognitive Function 
(AD-SPGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
313/Protocol WN42444, Version 2


Appendix 19:  Alzheimer’s Disease Study Partner Global Impression of Cognitive Function 
(AD-SPGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
314/Protocol WN42444, Version 2


Appendix 19:  Alzheimer’s Disease Study Partner Global Impression of Cognitive Function 
(AD-SPGI-S)
Gantenerumab—F. Hoffmann-La Roche Ltd
315/Protocol WN42444, Version 2
REFERENCE
FDA. Patient-focused drug development guidance public workshop: Methods to identify 
what is important to patients and select, develop, or modify fit-for-purpose clinical 
outcomes assessments. [resource on the Internet] 2018b. Available from:
https://www.fda.gov/media/116277/download.


Gantenerumab—F. Hoffmann-La Roche Ltd
316/Protocol WN42444, Version 2
Appendix 20 EuroQol EQ-5-D-5L IA
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 20:  EuroQol EQ-5-D-5L IA
Gantenerumab—F. Hoffmann-La Roche Ltd
317/Protocol WN42444, Version 2


Appendix 20:  EuroQol EQ-5-D-5L IA
Gantenerumab—F. Hoffmann-La Roche Ltd
318/Protocol WN42444, Version 2
REFERENCE
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208.


Gantenerumab—F. Hoffmann-La Roche Ltd
319/Protocol WN42444, Version 2
Appendix 21 EuroQol EQ-5D-5L IA Proxy
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 21:  EuroQol EQ-5-D-5L IA Proxy
Gantenerumab—F. Hoffmann-La Roche Ltd
320/Protocol WN42444, Version 2


Appendix 21:  EuroQol EQ-5-D-5L IA Proxy
Gantenerumab—F. Hoffmann-La Roche Ltd
321/Protocol WN42444, Version 2


Appendix 21:  EuroQol EQ-5-D-5L IA Proxy
Gantenerumab—F. Hoffmann-La Roche Ltd
322/Protocol WN42444, Version 2
REFERENCE
EuroQol Group. EuroQol: a new facility for the measurement of health-related quality of 
life. Health Policy 1990;16:199208.


Gantenerumab—F. Hoffmann-La Roche Ltd
323/Protocol WN42444, Version 2
Appendix 22 Repeatable Battery for the Assessment of 
Neuropsychological Status
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
324/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
325/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
326/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
327/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
328/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
329/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
330/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
331/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
332/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
333/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
334/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
335/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
336/Protocol WN42444, Version 2


Appendix 22:  Repeatable Battery for the Assessment of Neuropsychological Status
Gantenerumab—F. Hoffmann-La Roche Ltd
337/Protocol WN42444, Version 2
REFERENCE
Randolph C, Tierney MC, Mohr E, et al. The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp 
Neuropsychol 1998;20:3109.


Gantenerumab—F. Hoffmann-La Roche Ltd
338/Protocol WN42444, Version 2
Appendix 23 Diagnostic Classification Form (DCF)
Do not reproduce or distribute.  The Sponsor will provide sites with all instruments to 
be completed in this study.


Appendix 23:  Diagnostic Classification Form (DCF)
Gantenerumab—F. Hoffmann-La Roche Ltd
339/Protocol WN42444, Version 2


Appendix 23:  Diagnostic Classification Form (DCF)
Gantenerumab—F. Hoffmann-La Roche Ltd
340/Protocol WN42444, Version 2


Appendix 23:  Diagnostic Classification Form (DCF)
Gantenerumab—F. Hoffmann-La Roche Ltd
341/Protocol WN42444, Version 2


Appendix 23:  Diagnostic Classification Form (DCF)
Gantenerumab—F. Hoffmann-La Roche Ltd
342/Protocol WN42444, Version 2


Appendix 23:  Diagnostic Classification Form (DCF)
Gantenerumab—F. Hoffmann-La Roche Ltd
343/Protocol WN42444, Version 2


Gantenerumab—F. Hoffmann-La Roche Ltd
344/Protocol WN42444, Version 2
Appendix 24 Clinical Safety Laboratory Tests
The tests detailed in Table A241 will be performed by the central laboratory. See the 
schedule of activities (Section 1.3) for the testing timing and frequency.  
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.
Local laboratory results are only required in the event that the central laboratory results 
are not available in time for study treatment administration and/or response evaluation.  
If a local sample is required, it is important that a sample for central analysis be obtained 
at the same time.  Additionally, if the local laboratory results are used to make either a 
study treatment decision or a response evaluation, the results must be entered on the 
electronic Case Report Form.
Protocol-specific requirements for inclusion and exclusion of participants are detailed in 
Section 5.
Additional tests may be performed at any time during the study if determined to be 
necessary by the investigator or if required by local regulations.
For sampling procedures, storage conditions, and shipment instructions, see the 
Sample Handling and Logistics Manual.
Investigators must document their review of each laboratory safety report.


Appendix 2:  Clinical Safety Laboratory Tests
Gantenerumab—F. Hoffmann-La Roche Ltd
345/Protocol WN42444, Version 2
Table A241
Protocol-Required Safety Laboratory Assessments
Central Laboratory Tests
The following laboratory assessments will be performed at screening, baseline, Weeks 25, 53, 
79, 105, 131, 157, 183, 211, safety follow-up, unscheduled visits (as applicable), early 
termination visit as well as during the post-progression dose escalation period at Weeks 1P, 
25P and unscheduled visits (as applicable) (Section 1.3):

Serum chemistry: AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum 
albumin, creatine phosphokinase, sodium, potassium, bicarbonate, chlorine, calcium, 
glucose, BUN, and serum creatinine (and creatinine clearance calculated by the central 
laboratory)

Hematology:  hemoglobin, hematocrit, red blood cell count (with morphology), white blood 
cell count, basophils, eosinophils, lymphocytes, monocytes, neutrophils, and platelets
Urine for pregnancy test will be performed in women of childbearing potential (including those 
who have had a tubal ligation) at screening, prior to PET scans, at the safety follow-up visit or 
early termination study visit, or if suspected to have become pregnant, and 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.
In addition, the following laboratory assessments will be performed at screening, Weeks 53, 
105, 157, 211, safety follow-up, unscheduled visits (as applicable), early termination visit as well 
as during the post-progression dose escalation period at Week 1P (Section 1.3):

Metabolic tests: Hemoglobin A1C, total cholesterol, high-density lipoprotein, low-density 
lipoprotein, triglycerides, folic acid, vitamin B-12, methylmalonic acid, total thyroxine, free 
thyroxine, and thyroid-stimulating hormone levels 
These test should be collected as fasting samples (i.e. at least 4 hours after meals)

C-reactive protein

Prothrombin time
The following laboratory assessments will be performed at screening only (Table 1 and Table 4)

Viral serology: HIV, hepatitis B, and hepatitis C

Urine sample for drugs of abuse
At screening only, urine samples will be analyzed for the presence of the following drugs of 
abuse:  amphetamine, benzodiazepines, cannabinoids, opiates, cocaine, barbiturates, and 
methadone.  Results will be used to verify participant eligibility pertaining to drugs of abuse.  
Inconclusive results may be repeated once during the screening period.  
Investigators should use their best clinical judgment in cases where results may be 
erroneous (e.g., permitted use of opiates or ingestion of food/food supplements).

Urinalysis
At screening only, urinalysis will 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.
PET positron emission tomography.


Gantenerumab—F. Hoffmann-La Roche Ltd
346/Protocol WN42444, Version 2
Appendix 25 Abbreviations
Abbreviation
Definition
AIBL
Australian Imaging, Biomarker, and Lifestyle
AD
Alzheimer's disease
ADA
anti-drug antibody
ADNI
Alzheimer’s Disease Neuroimaging Initiative 
AD-CGI-S
Alzheimer’s disease Clinician Global Impression of Cognitive 
Function
AD-PGI-S
Alzheimer’s disease Participant Global Impression of 
Cognitive Function
AD-SPGI-S
Alzheimer’s disease Study Partner Global Impression of 
Cognitive Function
A-IADL-Q-SV
Amsterdam Instrumental Activities of Daily Living 
Questionnaire Short Version
APOE
apolipoprotein
ARIA-E
amyloid-related imaging abnormalityedema/effusion
ARIA-H
amyloid-related imaging abnormalityhemosiderin deposition
ATRI
Alzheimer’s Therapeutic Research Institute
BGTS
Barkhof Grand Total Score
CBF
cerebral blood flow
CDR
Clinical Dementia Rating
CDR-GS
Clinical Dementia Rating Global Score
CDR-SB
Clinical Dementia Rating Sum of Boxes
CFIa
Cognitive Function Instrument acute
CFT
category fluency test
ClinRO
clinician-reported outcome
COA
clinical outcome assessments
CRF
Case Report Form
CRO
Contract Research Organization
CSF
cerebrospinal fluid
CV
coefficient of variation
C-SSRS
Columbia-Suicide Severity Rating Scale
DCF
Diagnostic Classification Form
DMI
Delayed Memory Index
DTI
diffusion-tensor imaging
EC
Ethics Committee
eCOA
electronic clinical outcome assessment
eCRF
electronic Case Report Form
EDC
electronic data capture


Appendix 25:  Abbreviations
Gantenerumab—F. Hoffmann-La Roche Ltd
347/Protocol WN42444, Version 2
Abbreviation
Definition
EQ-5D-5L
EuroQol 5-Dimension 5-Level Questionnaire
FDA
U.S. Food and Drug Administration
FLAIR
fluid-attenuated inversion recovery
GCP
Good Clinical Practice
GDS-30
Geriatric Depression Scale-30 items
HABS
Harvard Aging Brain Study
iCAC
independent Clinical Adjudication Committee
ICF
Informed Consent Form
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IRB
Institutional Review Board
ISR
injection-site reaction
IxRS
interactive voice or Web-based response system
LP
lumbar puncture
MCI
mild cognitive impairment
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NCRAD
National Cell Repository for Alzheimer's Disease and Related 
Dementias
NfL
neurofilament light
NSDCR
not study drug or condition-related
ObsRO
observer-reported outcome
OLE
open-label extension
PACC-5
Preclinical Alzheimer’s Cognitive Composite-5
PerfO
performance outcome
PET
positron emission tomography
PK
pharmacokinetic
PRO
participant-reported outcome
Q1W
every 1 week
Q2W
every 2 weeks
Q4W
every 4 weeks
QoL
quality of life
RBANS
Repeatable Battery for the Assessment of Neuropsychological 
Status
RBR
Research Biosample Repository


Appendix 25:  Abbreviations
Gantenerumab—F. Hoffmann-La Roche Ltd
348/Protocol WN42444, Version 2
Abbreviation
Definition
SAP
Statistical Analysis Plan
SDCR
study drug or condition-related
ULN
upper limit of normal
WES
whole-exome sequencing