Conditions: Alzheimer Disease
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 192
Healthy volunteers: no

Brief summary:
This is a Phase II, multicenter, open-label, single arm, PD study in participants with early (prodromal to mild) AD to evaluate the effect of a once weekly (Q1W) dosing regimen of gantenerumab on deposited amyloid as measured by change from baseline to Week 104 (primary) and Week 208 in brain amyloid positron emission tomography (PET). The administration of gantenerumab as a single injection of Q1W will be investigated in this study, to simplify the dosing regimen for participants.

Detailed description:

Arms:
arm 1: Participants will receive gantenerumab by subcutaneous (SC) injection at a dose of 120 mg every 4 weeks (Q4W) for 12 weeks, followed by 255 mg Q4W for 12 weeks, and 255 mg every 2 weeks (Q2W) for another 12 weeks, followed by the target dose 255 mg once weekly (Q1W) for up to Week 103. Participants who complete Week 104 visit will be given an option to take part in 2-year extension of the study to receive gantenerumab 255 mg Q1W for up to Week 207.

Interventions: intervention 1: Gantenerumab
Intervention descriptions: intervention 1: Gantenerumab will be administered by SC injection at a dose of 120 mg Q4W for 12 weeks, followed by 255 mg Q4W for 12 weeks, and 255 mg Q2W for another 12 weeks, followed by the target dose 255 mg Q1W for up to Week 103 and an optional dose of 255 mg Q1W for up to Week 207.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
A Phase II, Multicenter, Open-Label, Single Arm Study to Evaluate 
the Pharmacodynamic Effects of Once Weekly Administration of 
Gantenerumab in Participants with Early (Prodromal to Mild) 
Alzheimer’s Disease 
NCT Number: 
NCT04592341 
Document Date: 
Protocol Amendment Version 3: 16-May-2022 
 
 
 


CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche's local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Protocol WN29722, Version 3 
PROTOCOL 
TITLE: 
A PHASE II, MULTICENTER, OPEN-LABEL, 
SINGLE ARM STUDY TO EVALUATE THE 
PHARMACODYNAMIC EFFECTS OF ONCE 
WEEKLY ADMINISTRATION OF GANTENERUMAB 
IN PARTICIPANTS WITH EARLY (PRODROMAL 
TO MILD) ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: WN29722 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-001384-87 
IND NUMBER: 
102,266 
NCT NUMBER: 
NCT04592341 
TEST PRODUCT: 
Gantenerumab (RO4909832) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
APPROVAL: 
See electronic signature and date stamp on the final 
page of this document  


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
2/Protocol WN29722, Version 3 
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocols 
Version 
Date Final 
Country 
Version 
Date Final 
3 
See electronic 
date stamp on 
the final page of 
this document. 
 
 
 
2 
17 November 
2021 
 
 
 
1 
23 June 2020 
United Kingdom 
Addendum 1 
2 November 
2021 
 
 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
3/Protocol WN29722, Version 3 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol WN49722 has been amended primarily to include an optional 2-year extension 
after 2 years in the study.  The changes to the protocol, along with a rationale for each 
change, are summarized below: 
 
The study has been updated to include the optional 2-year extension. The schedule 
of assessments until Week 103 remains unchanged and the benefitrisk profile of 
gantenerumab remains unchanged. The following sections have been updated: 
- 
A rationale for adding the 2-year extension has been included. The extension of 
the study from Weeks 104 to 208 will allow the collection of additional long-term 
safety and tolerability information of the once-a-week regimen, as well as 
additional exploratory long-term pharmacokinetic/pharmacodynamic and 
biomarker information (Sections 1.3.1 and 3.3.4) 
- 
The study design has been updated to indicate that participants who opt for the 
2-year extension will receive the final dose of study drug at Week 207. Final 
pharmacodynamic and efficacy assessments will be performed 1 week later at 
Week 208 (Sections 1.3.1, 3.1.1, 3.3.1, 4.3.2.1, 4.6.3, and 4.6.5). 
- 
Brain amyloid position emission tomography (PET) imaging assessment 
timepoints have been updated to include Weeks 156 and 208 (Sections 1.3.1 
and 3.1.1). 
- 
The study schema has been updated to include the 2-year extension from 
Week 104 to Week 208 (Section 3.1.1, Figure 4). 
- 
The end of the study has been updated to be 224 weeks after the last 
participant is enrolled.  The total duration of the study from screening of the first 
participant to the end of the study has been updated to be approximately 
5 years (Section 3.2). 
- 
Language has been added to explain that the 2-year extension is optional and 
participants must consent to participate (Section 2; Section 4.5.12 has been 
added and subsequent sections have been renumbered). 
- 
Additional visits during the study extension have been added, with the last visit 
in the study at open-label extension (OLE) Week 208 and the follow-up visit at 
OLE Week 224 (Sections 3.1.1, 4.6.5, and 4.7.1; Appendix 1, Tables 510). 
 
Background information on clinical studies has been updated to reflect that the OLE 
phase of Studies WN25203 and WN28745 have been completed (Section 1.2.1). 
Data from the studies relating to amyloid-related imaging abnormalities and injection 
site reaction risks have been updated (Sections 5.1.1.1 and 5.1.1.2).  
 
The objectives have been updated primarily to include the Week 208 timepoint in 
the respective endpoints (Section 2). The following changes have been made: 
- 
The secondary and biomarker endpoints have been updated to include a 
change from baseline to Week 208  


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
4/Protocol WN29722, Version 3 
- 
The change from baseline up to Week 208 in deposited amyloid as measured 
by brain amyloid PET centiloid levels has been added as an exploratory 
biomarker endpoint 
- 
The change from baseline to Week 208 has been included for the exploratory 
efficacy scales and home administration questionnaire 
 
During the course of the study, an autoinjector may become available in 
participating countries, if approved by local health authorities and Institutional 
Review Boards. Use of this device will be optional for participants who receive study 
treatment administration at home or at the site (Section 4.3.2). Reporting 
requirements for the autoinjector have also been updated (Section 5.4.4).  
 
The Medical Monitor has changed, and the Medical Monitor contact information has 
been deleted from Emergency Medical Contacts to avoid the inclusion of outdated 
telephone numbers in the protocol.  The protocol refers to the Emergency Medical 
Call Center Help Desk, which will always have an up-to-date list of Medical Monitor 
and Medical Responsible contact information (Section 5.4.1). 
 
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 
5/Protocol WN29722, Version 3 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ......................................... 12 
PROTOCOL SYNOPSIS .................................................................................... 13 
1. 
BACKGROUND ............................................................................ 26 
1.1 
Background on Alzheimer's Disease ....................................... 26 
1.2 
Background on Gantenerumab ................................................ 26 
1.2.1 
Nonclinical and Clinical Studies ............................................... 27 
1.3 
Study Rationale and BenefitRisk Assessment ....................... 28 
1.3.1 
Study Rationale ....................................................................... 28 
1.3.2 
BenefitRisk Rationale ............................................................ 34 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 36 
3. 
STUDY DESIGN ........................................................................... 38 
3.1 
Description of the Study ........................................................... 38 
3.1.1 
Overview of Study Design........................................................ 38 
3.1.2 
Internal Monitoring Committee ................................................. 41 
3.2 
End of Study and Length of Study ........................................... 41 
3.3 
Rationale for Study Design ...................................................... 41 
3.3.1 
Rationale for Gantenerumab Dose and Titration Schedule ..... 41 
3.3.2 
Rationale for Study Population ................................................ 42 
3.3.3 
Rationale for Open Label Design ............................................. 43 
3.3.4 
Rationale for Treatment Duration ............................................. 43 
3.3.4.1 
Rationale for Optional Treatment Extension ........................... 44 
3.3.5 
Rationale for Interim Analysis .................................................. 44 
3.3.6 
Rationale for Primary Outcome Measure:  Brain Amyloid 
Load as Determined by Positron Emission Tomography ......... 44 
3.3.7 
Rationale for Pharmacokinetic Sampling ................................. 45 
3.3.8 
Rationale for Biomarker Assessments ..................................... 46 
3.3.8.1 
Positron Emission Tomography ............................................... 46 
3.3.8.2 
Brain Volumetry, Connectivity, and Fiber Tract Integrity .......... 46 
3.3.8.3 
Blood Biomarkers .................................................................... 47 
3.3.9 
Rationale for Home Administration Questionnaire ................... 48 
4. 
MATERIALS AND METHODS ...................................................... 48 


 
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4.1 
Participants .............................................................................. 48 
4.1.1 
Inclusion Criteria ...................................................................... 48 
4.1.2 
Exclusion Criteria ..................................................................... 50 
4.1.2.1 
Exclusions Related to Central Nervous System Disorders ...... 50 
4.1.2.2 
Imaging-Related Criteria .......................................................... 51 
4.1.2.3 
Cardiovascular Disorders ........................................................ 52 
4.1.2.4 
Hepatic and Renal Disorders ................................................... 52 
4.1.2.5 
Infections and Immune Disorders ............................................ 52 
4.1.2.6 
Metabolic and Endocrine Disorders ......................................... 53 
4.1.2.7 
Exclusions Related to Medications .......................................... 53 
4.1.2.8 
Other Exclusions ...................................................................... 55 
4.2 
Method of Treatment Assignment and Blinding ....................... 56 
4.2.1 
Treatment Assignment ............................................................. 56 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 56 
4.3.1 
Study Treatment Formulation and Packaging .......................... 56 
4.3.1.1 
Gantenerumab ......................................................................... 56 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 56 
4.3.2.1 
Gantenerumab ......................................................................... 57 
4.3.3 
Positron Emission Tomography Tracers .................................. 58 
4.3.4 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 59 
4.3.5 
Continued Access to Gantenerumab ....................................... 60 
4.4 
Concomitant Therapy .............................................................. 61 
4.4.1 
Permitted Therapy ................................................................... 61 
4.4.2 
Prohibited Therapy .................................................................. 62 
4.5 
Study Assessments ................................................................. 62 
4.5.1 
Informed Consent Forms and Screening Log .......................... 63 
4.5.2 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 63 
4.5.3 
Physical Examinations ............................................................. 63 
4.5.4 
Vital Signs ................................................................................ 64 
4.5.5 
Positron Emission Tomography Scan ...................................... 64 
4.5.6 
Home Administration Assessments ......................................... 65 


 
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4.5.6.1 
Clinical Dementia Rating Scale ................................................ 66 
4.5.6.2 
Alzheimer’s Disease Assessment ScaleCognitive 
Subscale .................................................................................. 66 
4.5.6.3 
Mini-Mental State Examination ................................................ 67 
4.5.6.4 
Verbal Fluency Task ................................................................ 67 
4.5.6.5 
Coding ..................................................................................... 67 
4.5.6.6 
Alzheimer’s Disease Cooperative StudyActivities of Daily 
Living Inventory ........................................................................ 67 
4.5.6.7 
Home Administration Questionnaire ........................................ 67 
4.5.6.8 
Electronic Assessment of Rating Scales ................................. 67 
4.5.7 
Columbia-Suicide Severity Rating Scale ................................. 68 
4.5.8 
Brain Magnetic Resonance Imaging ........................................ 68 
4.5.9 
Healthy Volunteer Magnetic Resonance Imaging Scans for 
Site Qualification ...................................................................... 69 
4.5.10 
Laboratory, Biomarker, and Other Biological Samples ............ 70 
4.5.10.1 
Standard Laboratory Samples ................................................. 70 
4.5.10.2 
Pharmacokinetic Samples ....................................................... 70 
4.5.10.3 
Samples for Immunogenicity Analysis ..................................... 71 
4.5.10.4 
Biomarker Samples ................................................................. 72 
4.5.11 
Electrocardiograms .................................................................. 73 
4.5.12 
Optional Procedures ................................................................ 73 
4.5.13 
Optional Samples for Research Biosample Repository ........... 74 
4.5.13.1 
Overview of the Research Biosample Repository .................... 74 
4.5.13.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 74 
4.5.13.3 
Sample Collection .................................................................... 75 
4.5.13.4 
Confidentiality .......................................................................... 75 
4.5.13.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 76 
4.5.13.6 
Withdrawal from the Research Biosample Repository ............. 76 
4.5.13.7 
Monitoring and Oversight ......................................................... 77 
4.6 
Timing of Study Assessments .................................................. 77 
4.6.1 
Screening and Pretreatment Assessments .............................. 77 
4.6.2 
Assessments at Baseline ......................................................... 79 


 
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4.6.3 
Assessments during the Treatment Period .............................. 80 
4.6.4 
Procedures for New Magnetic Resonance Imaging 
Findings ................................................................................... 81 
4.6.5 
Assessments at Study Completion or Early Termination 
Visit and at Follow-Up .............................................................. 81 
4.6.6 
Unscheduled Assessments...................................................... 82 
4.7 
Treatment, Participant, Study, and Site Discontinuation .......... 82 
4.7.1 
Study Treatment Discontinuation ............................................. 82 
4.7.2 
Participant Discontinuation from the Study .............................. 83 
4.7.3 
Study Discontinuation .............................................................. 84 
4.7.4 
Site Discontinuation ................................................................. 84 
5. 
ASSESSMENT OF SAFETY ......................................................... 84 
5.1 
Safety Plan .............................................................................. 84 
5.1.1 
Risks Associated with Gantenerumab ..................................... 84 
5.1.1.1 
Amyloid-Related Imaging Abnormalities .................................. 84 
5.1.1.2 
Injection Reactions and Hypersensitivity ................................. 87 
5.1.1.3 
Immunogenicity ........................................................................ 88 
5.1.2 
Risks Associated with Amyloid PET Tracer ............................. 89 
5.1.2.1 
Risks Associated with Radiation .............................................. 89 
5.1.2.2 
Florbetaben.............................................................................. 89 
5.1.2.3 
Flutemetamol ........................................................................... 90 
5.1.3 
Management of Participants Who Experience Adverse 
Events ...................................................................................... 90 
5.1.3.1 
Dose Modifications and Treatment Interruption ....................... 90 
5.2 
Safety Parameters and Definitions .......................................... 92 
5.2.1 
Adverse Events ........................................................................ 93 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 93 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 94 
5.2.4 
Selected Adverse Events ......................................................... 95 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 95 
5.3.1 
Adverse Event Reporting Period .............................................. 95 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
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5.3.2 
Eliciting Adverse Event Information ......................................... 96 
5.3.3 
Assessment of Severity of Adverse Events ............................. 96 
5.3.4 
Assessment of Causality of Adverse Events............................ 97 
5.3.5 
Procedures for Recording Adverse Events .............................. 97 
5.3.5.1 
ARIA Findings .......................................................................... 97 
5.3.5.2 
Injection Reactions .................................................................. 98 
5.3.5.3 
Diagnosis versus Signs and Symptoms ................................... 98 
5.3.5.4 
Adverse Events That Are Secondary to Other Events ............. 98 
5.3.5.5 
Persistent or Recurrent Adverse Events .................................. 99 
5.3.5.6 
Abnormal Laboratory Values ................................................... 99 
5.3.5.7 
Abnormal Vital Sign Values ................................................... 100 
5.3.5.8 
Abnormal Liver Function Tests .............................................. 100 
5.3.5.9 
Deaths ................................................................................... 101 
5.3.5.10 
Preexisting Medical Conditions .............................................. 101 
5.3.5.11 
Lack of Efficacy or Worsening of Alzheimer’s Disease .......... 101 
5.3.5.12 
Hospitalization or Prolonged Hospitalization .......................... 101 
5.3.5.13 
Cases of Overdose, Medication Error, Drug Abuse, or 
Drug Misuse ........................................................................... 102 
5.3.5.14 
Clinical Outcome Assessment Data ....................................... 104 
5.3.5.15 
Safety Biomarker Data ........................................................... 104 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................. 104 
5.4.1 
Medical Monitors and Emergency Medical Contacts ............. 105 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest ........................................ 105 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................... 105 
5.4.2.2 
Events That Occur after Study Drug Initiation ........................ 105 
5.4.3 
Reporting Requirements for Pregnancies .............................. 106 
5.4.3.1 
Pregnancies in Female Participants ...................................... 106 
5.4.3.2 
Abortions................................................................................ 106 
5.4.3.3 
Congenital Anomalies/Birth Defects ...................................... 107 
5.4.4 
Reporting Requirements for Medical Device Complaints ....... 107 
5.5 
Follow-Up of Participants after Adverse Events ..................... 107 
5.5.1 
Investigator Follow-Up ........................................................... 107 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
10/Protocol WN29722, Version 3 
5.5.2 
Sponsor Follow-Up ................................................................ 108 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period .................................................................... 108 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............. 108 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....... 109 
6.1 
Determination of Sample Size ............................................... 109 
6.2 
Summaries of Conduct of Study ............................................ 109 
6.3 
Summaries of Demographics and Baseline Characteristics .. 109 
6.4 
Primary and Secondary Endpoint Analyses ........................... 110 
6.4.1 
Primary Endpoint ................................................................... 110 
6.4.2 
Secondary Endpoint .............................................................. 110 
6.5 
Safety Analyses ..................................................................... 110 
6.6 
Pharmacokinetic/Pharmacodynamic Analyses ...................... 111 
6.7 
Biomarker Analyses ............................................................... 112 
6.8 
Exploratory analyses ............................................................. 112 
6.9 
Interim Analysis ..................................................................... 113 
6.9.1 
Planned Interim Analysis ....................................................... 113 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 113 
7.1 
Data Quality Assurance ......................................................... 113 
7.2 
Electronic Case Report Forms ............................................... 113 
7.3 
Electronic Clinical Outcome Data .......................................... 114 
7.4 
Source Data Documentation .................................................. 114 
7.5 
Use of Computerized Systems .............................................. 115 
7.6 
Retention of Records ............................................................. 115 
8. 
ETHICAL CONSIDERATIONS .................................................... 115 
8.1 
Compliance with Laws and Regulations ................................ 115 
8.2 
Informed Consent .................................................................. 116 
8.3 
Institutional Review Board or Ethics Committee .................... 117 
8.4 
Confidentiality ........................................................................ 117 
8.5 
Financial Disclosure ............................................................... 118 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 118 


 
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9.1 
Study Documentation ............................................................ 118 
9.2 
Protocol Deviations ................................................................ 118 
9.3 
Management of Study Quality ................................................ 119 
9.4 
Site Inspections ..................................................................... 119 
9.5 
Administrative Structure ......................................................... 119 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 119 
9.7 
Protocol Amendments ........................................................... 120 
10. 
REFERENCES............................................................................ 122 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 37 
Table 2 
Adverse Event Severity Grading Scale ....................................... 96 
 
 
LIST OF FIGURES 
Figure 1 
Gantenerumab Concentrations (Intravenous and 
Subcutaneous) and Plaque Binding (Mice) ................................. 31 
Figure 2 
Amyloid PET SUVR Percentage Change from Baseline by 
Time per Category of Plasma Concentration .............................. 32 
Figure 3 
Marked and Consistent Reduction of Amyloid Load in 
Participants Receiving High-Dose Gantenerumab ...................... 34 
Figure 4 
Study Schema ............................................................................. 41 
Figure 5 
Order of Screening Assessments ............................................... 78 
 
 
LIST OF APPENDICES 
Appendix 1 
 Schedule of Activities ............................................................... 128 
Appendix 2 
 Management Rules for Amyloid-Related Imaging 
Abnormalities ............................................................................ 169 
Appendix 3 
 National Institute on Aging-Alzheimer’s Association Criteria 
for Mild Alzheimer’s Disease ..................................................... 171 
Appendix 4 
 National Institute on Aging-Alzheimer’s Association Criteria 
for Prodromal Alzheimer’s Disease (Mild Cognitive 
Impairment due to Alzheimer’s Disease .................................... 173 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
12/Protocol WN29722, Version 3 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE II, MULTICENTER, OPEN-LABEL, 
SINGLE ARM STUDY TO EVALUATE THE 
PHARMACODYNAMIC EFFECTS OF ONCE 
WEEKLY ADMINISTRATION OF GANTENERUMAB 
IN PARTICIPANTS WITH EARLY (PRODROMAL TO 
MILD) ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: WN29722 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-001384-87 
IND NUMBER: 
102,266 
NCT NUMBER: 
NCT04592341 
TEST PRODUCT: 
Gantenerumab (RO4909832) 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
13/Protocol WN29722, Version 3 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE II, MULTICENTER, OPEN-LABEL, SINGLE ARM STUDY 
TO EVALUATE THE PHARMACODYNAMIC EFFECTS OF ONCE 
WEEKLY ADMINISTRATION OF GANTENERUMAB IN 
PARTICIPANTS WITH EARLY (PRODROMAL TO MILD) 
ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: 
WN29722 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-001384-87 
IND NUMBER: 
102,266 
NCT NUMBER: 
NCT04592341 
TEST PRODUCT: 
Gantenerumab (RO4909832) 
PHASE: 
II 
INDICATION: 
Alzheimer's disease 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacodynamics, pharmacokinetics, and safety of gantenerumab 
in participants with early (prodromal to mild) Alzheimer's disease (AD).  Specific objectives and 
corresponding endpoints for the study are outlined below. 
Primary Objective 
Corresponding Endpoint 
 
To evaluate the PD effect of a 
Q1W dosing regimen of 
gantenerumab on brain amyloid 
load as determined by PET 
imaging in participants with early 
(prodromal to mild) AD  
 
The change from baseline to Week 52 and to 
Week 104 in deposited amyloid as measured by 
brain amyloid PET CL levels a  
Secondary Objective 
Corresponding Endpoint 
 
To evaluate caregiver overall 
satisfaction and confidence with 
home administration  
 
Responses to home administration questionnaire 
(Caregiver) up to Week 52, Week 104 a and 
Week 208 b 
Safety Objective 
Corresponding Endpoints 
 
To assess the safety of 
gantenerumab in participants with 
early (prodromal to mild) AD 
 
Nature, frequency, severity, and timing of adverse 
events and serious adverse events 
 
Physical examinations (including neurologic 
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 
injection-site reactions 
 
Presence of ADAs during the study relative to the 
presence of ADAs at baseline 


 
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14/Protocol WN29722, Version 3 
PK/PD Objectives 
Corresponding Endpoints 
 
To characterize the PK profile of 
gantenerumab using a new titration 
scheme and especially at the 
Q1W dosing frequency 
 
To assess the PD effect of the 
dosing frequency (e.g., Q1W, 
Q2W) on brain amyloid 
 
Plasma concentration of gantenerumab 
(administered subcutaneously) at 
specified timepoints 
 
The influence of dosing frequency information on 
the performance of a quantitative PK-PD model 
developed based on PK and PET from this and 
previous studies (e.g., WN29922 and WN39658) a 
Exploratory Biomarker Objective 
Corresponding Endpoints 
 
To evaluate the pharmacodynamic 
effect of gantenerumab at the Q1W 
dosing regimen on plasma and 
MRI and PET biomarkers 
 
Change from baseline in plasma biomarkers 
(including, but not limited to, phosphorylated tau 
and NFL) to Week 104 and Week 208 b 
 
Change from baseline to Week 104 and Week 
208 b in functional brain connectivity, as measured 
by resting-state functional MRI (where available) 
 
Change from baseline to Week 104 and Week 
208 b in integrity of white matter, as measured by 
DTI-MRI (where available)  
 
MRI-derived measurements over time, such as 
volumetric changes in whole brain, ventricles, 
hippocampus, or other structures, in all 
participants. 
 
The change from baseline up to Week 208 in 
deposited amyloid as measured by brain amyloid 
PET CL levels b 
Exploratory Objectives 
Corresponding Endpoints 
 
To compare the effect of a Q1W to 
a Q2W dosing regimen on amyloid 
reduction using external controls 
 
To evaluate the effects of 
gantenerumab at the Q1W dosing 
on cognitive and functional 
endpoints 
 
To evaluate patient overall 
satisfaction with at home 
administration 
 
The change from baseline to Week 52 and to 
Week 104 in deposited amyloid as measured by 
brain amyloid PET compared with the change in 
the pivotal WN29922 and WN39658 studies  
 
The change from baseline to Week 104 and Week 
208 b in the following: 
− 
The CDR-SOB 
− 
MMSE total score 
− 
ADAS-Cog11 and ADAS-Cog13 
− 
Verbal Fluency Task 
− 
Coding 
− 
ADCS-ADL 
 
Responses to home administration questionnaire 
(Patient) up to Week 104 and Week 208 b 


 
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AD  Alzheimer's disease; ADA  anti-drug antibody; ADAS-Cog11  Alzheimer Disease 
Assessment ScaleCognition, Subscale 11; ADAS-Cog13  Alzheimer Disease Assessment 
ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer Disease Cooperative Study 
Group-Activities of Daily Living; ARIA-E  amyloid-related imaging abnormalitiesedema/effusion; 
ARIA-H  amyloid-related imaging abnormalitieshemosiderin deposition; CDR  Clinical Dementia 
Rating; CDR-GS  Clinical Dementia Rating global score; CDR-SOB  Clinical Dementia 
RatingSum of Boxes; CL  Centiloid; C-SSRS  ColumbiaSuicide Severity Rating Scale; 
DTI  diffusion tensor imaging; MMSE  Mini-Mental State Examination; MRI  magnetic resonance 
imaging; NFL  neurofilament light chain; PD  pharmacodynamic; PET  positron emission 
tomography; PK  pharmacokinetic; Q1W  once a week; Q2W  every 2 weeks; Q4W  every 
4 weeks, SAP Statistical Analysis Plan. 
a The primary analysis is at Week 104, and details concerning interim analyses which will 
consider Week 52 outcomes are described in the relevant protocol sections and SAP. 
b   Week 208 assessments are optional and only required if participants take part in the 2-year 
extension 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
Study WN29722 is a Phase II, multicenter, open-label, single arm, pharmacodynamic (PD) 
study in participants with early (prodromal to mild) AD to evaluate the effect of a once weekly 
(Q1W) dosing regimen on deposited amyloid as measured by change from baseline to 
Weeks 52 and 104 in brain amyloid positron emission tomography (PET).  The dosing regimen 
being evaluated in current Phase III studies (WN29922 and WN39658) is gantenerumab 
120 mg SC every 4 weeks (Q4W) for 12 weeks, followed by 255 mg SC Q4W for 12 weeks, and 
510 mg SC Q4W for 12 weeks, prior to reaching the target dose of 510 mg SC Q2W.  As an 
alternative to administering two 255-mg injections every 2 weeks (Q2W) at the target dose, the 
administration of gantenerumab as a single injection of 255 mg Q1W will be investigated in this 
study, to simplify the dosing regimen for patients and caregivers and to provide additional 
flexibility and convenience depending on individual patient's needs and preferences.  In 
addition, Phase II Study WN29722 will evaluate the feasibility of home administration by study 
partners (non-professional caregivers), which is particularly relevant in conjunction with a Q1W 
dosing regimen. 
Participants will be selected on the basis of a clinical diagnosis of probable AD (consistent with 
the National Institute on Aging/Alzheimer’s Association [NIA-AA] Diagnostic Criteria and 
Guidelines for probable) or prodromal AD (consistent with the NIA-AA diagnostic criteria and 
guidelines for mild cognitive decline due to AD). 
Eligible participants will be 5090 years old, inclusive, and must have increased brain amyloid 
as indicated by positive amyloid PET scan by visual read.  At the time of screening, participants 
must have a Mini-Mental State Examination (MMSE) score  22 points and a Clinical Dementia 
Rating global score (CDR-GS) of 0.5 or 1.0.  To confirm objective memory impairment, 
participants must have a Clinical Dementia Rating (CDR) memory domain score  0.5. 
In addition, all eligible participants should have a study partner (non-professional caregiver) who 
is willing and judged as capable of administering SC injections (exceptions can be made for 
participants who are able to attend weekly clinic visits or who are able to have weekly home 
nursing [HN]/site staff visits). 
Neuroradiologic evaluation will use a standard magnetic resonance imaging (MRI) protocol 
(including T2*-weighted gradient−recalled echo [GRE] and fluid−attenuated inversion recovery 
[FLAIR]).  Screening MRIs will be read by a central reader who will exclude participants with 
other structural causes of dementia, significant cerebral vascular pathology, more than five 
microbleeds, disseminated leptomeningeal hemosiderosis, or evidence of a prior cerebral 
macrohemorrhage.  
Participants will be eligible for the study whether or not they are receiving standard-of-care 
symptomatic medications for AD (e.g., cholinesterase inhibitors or memantine, combination, or 
a medical food supplement).  Intake of these medications must have been stable for  3 months 
prior to screening and until start of study treatment.  All eligible participants have to meet 
eligibility criteria.   


 
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The study will consist of a screening period of up to 8 weeks for each participant who agrees to 
participate, signs the Informed Consent Form, and is eligible for the study.  Eligible participants 
will then undergo the baseline visit (Day 1), when they will receive the first dose following 
completion of all relevant assessments.  Participants will be enrolled in an open-label treatment 
period of 104 weeks or 208 weeks for participants who take part in the optional 2-year 
extension.  The PET scans will be performed at screening (will be considered as baseline 
evaluation), Weeks 52, 104, 156, and 208 using florbetaben as the tracer at all sites (in 
exceptional circumstances, the use of flutemetamol may be acceptable at sites where 
florbetaben is not available, but only after prior written approval from the Sponsor).  Participants 
will be treated according to the following dosing regimen:  120 mg Q4W (Day 1, Week 4, and 
Week 8), then 255 mg Q4W (Weeks 12, 16, and 20), and then 255 mg Q2W for 12 weeks 
(Weeks 24, 26, 28, 30, 32, and 34), followed by the target dose 255 mg Q1W (Weeks 36207).  
Before reaching the maximum target dose (i.e., 255 mg Q1W), a minimum of three doses during 
the 120-mg Q4W and 255-mg Q4W dosing periods, and a minimum of six doses during 255-mg 
Q2W dosing period must be administered prior to uptitration.  Participants who do not take part 
in the optional 2-year extension will receive the final dose of study drug at Week 103 and final 
efficacy and PD assessments will be performed 1 week later at Week 104.  Participants who do 
not enter an extension study after week 104 will have an additional follow-up visit 16 weeks after 
the Week 104 visit for safety assessments (Week 120 follow-up visit).  Participants who take 
part in the optional 2-year extension will receive the final dose of study drug at Week 207 and 
final efficacy and PD assessments will be performed 1 week later (Week 208).  Eligible 
participants may qualify for continued access or ongoing extension studies after Week 208 as 
outlined in the protocol.  Participants who do not enter an extension study will have an 
additional follow-up visit 16 weeks after the Week 208 visit for safety assessments (Week 240 
follow-up visit).    
Depending on the site and individual participant/caregiver suitability, participants will have the 
option to receive SC injections of gantenerumab at the site or at home by study staff, a home 
nurse, or a study partner (non-professional caregiver) after a defined period of appropriate 
training and supervision.  During the course of the study, an autoinjector may become 
available in participating countries, if approved by local health authorities and Institutional 
Review Boards (IRBs) (use of this device will be optional for participants who receive study 
treatment administration at home or at the site). For more details on study treatment 
administration, see the protocol. 
Participants will undergo brain MRI examinations for safety monitoring and longitudinal changes 
in brain structure.  MRI scans will be read by a central MRI reader (for more details regarding 
imaging-related criteria, see the protocol).  Participants will also undergo standard tests to 
monitor safety (blood tests, ECG), as well as the ColumbiaSuicide Severity Rating Scale 
(C-SSRS) to monitor for suicidality, tests for cognition, and function.  Blood samples for 
assessment of plasma biomarkers for AD and amyloid-related imaging abnormality (ARIA), 
pharmacokinetics, and exploratory genetic markers, and for the measurement of antibodies 
directed against gantenerumab will be obtained from all participants.  
Participants who do not meet the criteria for participation in this study (screen failure) may 
qualify for re-screening at the investigator's discretion as described in the protocol.  Participants 
must re-sign the consent form prior to re-screening.  The investigator will record reasons for 
screen failure in the screening log. 
NUMBER OF PARTICIPANTS 
A total of 192 participants have been enrolled in participating countries.  A total of 38 centers in 
8 countries worldwide have participated in this study.  
TARGET POPULATION 
Inclusion Criteria 
Participants must meet the following criteria for study entry: 
 
Ability to provide written consent signed by the participant (co-signed by the participant’s 
legally authorized representative, if required by the local regulations, guidelines, and 
independent Ethics Committee [EC] or Institutional Review Board [IRB]) 
 
Age 5090 years old at screening, inclusive 


 
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 
Probable AD dementia (consistent with NIA-AA core clinical criteria for probable AD 
dementia) or prodromal AD (consistent with the NIA-AA diagnostic criteria and guidelines 
for mild cognitive decline due to AD)  
 
Availability of a person (referred to as the study partner [non-professional caregiver] 
throughout this protocol) who: 
− 
Agrees to participate throughout the duration of study 
− 
Has sufficient cognitive and physical capacity including visual, auditory, and motor 
functioning, and is willing and capable of administering SC injections, as determined by 
the investigator (exceptions can be made for participants for which weekly clinic visits 
or weekly HN visits are possible) 
− 
In the investigator’s judgment, has frequent and sufficient contact (e.g., 5 times per 
week or approximately 10 hours per week) with the participant  
− 
In the investigator’s judgment, is able to provide accurate information regarding the 
participant’s cognitive and functional abilities, agrees to provide information at clinic 
visits (which requires study partner (non-professional caregiver) input for scale 
completion), and signs the necessary consent form. 
− 
Is fluent in the language used at the site and 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 study duration. 
Every effort should be made to have same study partner (non-professional 
caregiver) participate throughout the duration of the study.  
 
Fluency in the language of the tests used at the study site 
 
Willingness and ability to complete all aspects of the study (including MRI, clinical 
genotyping, and PET imaging) 
The participant should be capable of completing assessments either alone or with the 
help of the study partner (non-professional caregiver). 
 
Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to perform the 
neuropsychological testing (eye glasses and hearing aids are permitted) 
 
Evidence of AD pathological process, as confirmed by amyloid PET scan by qualitative read 
by the core/central PET laboratory 
 
Prodromal or mild symptomatology, as defined by a screening MMSE score  22 and 
CDR-GS of 0.5 or 1.0, as well as a CDR memory domain score  0.5  
 
If the participant is receiving symptomatic AD medications, a stable dosing regimen for at 
least 3 months prior to screening and until start of study treatment 
 
Agreement not to donate blood or blood products for transfusion for the duration of the 
study and for 1 year after final dose of study drug 
 
Agreement not to participate in other research studies for the duration of this trial, unless 
these are related Roche sponsored non-interventional studies. 
 
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 16 weeks after the final dose of 
study drug 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).  The definition of 
childbearing potential may be adapted for alignment with local guidelines or 
regulations.  
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 


 
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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 acceptable methods of contraception. 
If required per local guidelines or regulations, locally recognized adequate methods of 
contraception and information about the reliability of abstinence will be described in the 
local Informed Consent Form. 
 
Exclusion Criteria 
Exclusions Related to Central Nervous System Disorders 
Participants who meet any of the following criteria related to CNS disorders will be excluded 
from study entry: 
 
Any evidence of a condition other than AD that may affect cognition, including, but not 
limited to, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, 
Parkinson disease, corticobasal syndrome, Creutzfeldt-Jakob disease, progressive 
supranuclear palsy, frontotemporal lobar degeneration, Huntington disease, normal 
pressure hydrocephalus, seizure disorder, delirium or hypoxia 
 
History or presence of clinically evident systemic vascular disease (e.g., clinically significant 
carotid/vertebral artery stenosis or plaque, aortic aneurysm) that in the opinion of the 
investigator has the potential to affect cognitive function 
 
History or presence of clinically evident cerebrovascular disease (e.g., intracranial or 
cerebral vascular malformations, aneurysm, intracranial macrohemorrhage)  
Participants with asymptomatic developmental venous anomalies may be eligible after 
discussion with the Medical Monitor. 
 
History or presence of posterior reversible encephalopathy syndrome 
 
History or presence of any stroke with clinical symptoms within the past 12 months, or 
documented history within the last 6 months of an acute event that is consistent, in the 
opinion of the investigator, with a transient ischemic attack 
 
History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) CNS trauma (e.g., cerebral contusion) 
 
History or presence of intracranial mass (e.g., glioma, meningioma) that could potentially 
impair cognition 
 
Presence of infections that affect brain function or history of infections that resulted in 
neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, and viral or bacterial meningitis 
and encephalitis) 
 
History or presence of systemic autoimmune disorders that potentially cause progressive 
neurologic disease with associated cognitive deficits (e.g., multiple sclerosis, lupus 
erythematosus, anti-phospholipid antibody syndrome, and Behçet disease) 
 
History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder 
History of major depression is acceptable if participant has had no episode within the 
past year or is considered in remission, or depression is controlled by treatment. 
 
At risk for suicide in the opinion of the investigator 
 
Alcohol and/or substance abuse or dependence (according to the criteria specified in the 
Diagnostic and Statistical Manual of Mental Disorders, Version 5) within the past 2 years  
Nicotine use is allowed. 
Marijuana use is not allowed and must be discontinued at least 3 months before 
screening. 
 
Imaging-Related Criteria 
Participants who meet any of the following imaging criteria will be excluded from study entry: 
 
According to the central MRI reader, MRI evidence of any of the following:  
− 
 2 lacunar infarcts 


 
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− 
Any territorial infarct  1 cm3 
− 
Any white matter lesion that corresponds to an overall Fazekas score of 3 that requires 
at least one confluent hyperintense lesion on the FLAIR sequence, which is  20 mm in 
any dimension 
 
More than five combined microbleeds and areas of leptomeningeal hemosiderosis 
(i.e., cumulative ARIA-H) on MRI (and not including any disseminated leptomeningeal 
hemosiderosis) based on the review performed by the central reader prior to start of study 
treatment 
 
Presence of any other significant cerebral abnormalities, including ARIA-E, as assessed on 
MRI 
 
Inability to tolerate MRI procedures or 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 eyes, skin, or body that would contraindicate an 
MRI scan, or any other clinical history or examination finding that, in the judgment of the 
investigator, would pose a potential hazard in combination with MRI 
 
Cardiovascular Disorders 
Participants who meet any of the following criteria related to cardiovascular disorders will be 
excluded from study entry: 
 
History or presence of clinically symptomatic atrial fibrillation requiring maintenance therapy  
Participants who experienced non-valvular atrial fibrillation that resolved more than 
1 year ago and was not associated with prior stroke are eligible. 
 
Within the last year, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction) 
Heart failure classified as New York Heart Association Class I or II cardiac disease is 
allowed if not associated with hospitalization within the previous 12 months. 
 
Uncontrolled hypertension (e.g., blood pressure generally  160 mmHg systolic 
or  95 mmHg diastolic) 
 
Hepatic and Renal Disorders 
Participants who meet any of the following criteria related to hepatic and renal disorders will be 
excluded from study entry: 
 
Chronic kidney disease, indicated by creatinine clearance 30 mL/min to be calculated by 
the central laboratory using the Cockcroft-Gault formula 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  
 
Infections and Immune Disorders 
Participants who meet any of the following criteria related to infections and immune disorders 
will be excluded from study entry: 
 
History of, or known to currently have HIV infection, or hepatitis B or hepatitis C infection 
that has not been adequately treated in the opinion of the investigator, or history of 
spirochete infection of the CNS (e.g., syphilis, Lyme disease, or borreliosis) 
 
Systemically, clinically significantly immunocompromised participants, owing to continuing 
effects of immune-suppressing medication 
 
Metabolic and Endocrine Disorders 
Participants who meet any of the following criteria related to metabolic and endocrine disorders 
will be excluded from study entry: 
 
Abnormal thyroid function as indicated by abnormal screening tests that are judged to be 
clinically significant by the investigator, or abnormal thyroid function that requires a new 
treatment or an adjustment of current treatment 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
20/Protocol WN29722, Version 3 
A participant may be re-screened if there is no improvement in cognition in the 
investigator's judgment after 3 months of adequate treatment for thyroid function. 
 
Participants with evidence of folic acid deficiency (as indicated by folic acid level below the 
lower limit of normal) or vitamin B-12 deficiency (as indicated by vitamin B-12 level below 
the lower limit of normal and/or methylmalonic acid levels above ULN) 
A participant may be re-screened if there is no improvement in cognition after 3 months 
of adequate treatment for folic acid or vitamin B-12 deficiency. 
 
Screening hemoglobin A1c (HbA1c)  8% (retesting is permitted if slightly elevated) or poorly 
controlled insulin-dependent diabetes (including hypoglycemic episodes) 
A participant may be re-screened after 3 months to allow optimization of 
diabetic control. 
 
Exclusions Related to Medications 
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 or active immunotherapy (vaccine) that is 
being evaluated to prevent or postpone cognitive decline 
 
Any passive immunotherapy (immunoglobulin) or other long-acting biologic agent that is 
under evaluation to prevent or postpone cognitive decline within 1 year of screening 
 
Any other investigational treatment within 5 half-lives or 4 months prior to screening, 
whichever is longer 
 
Any previous administration of GV-971 
Participants receiving GV-971 or planning to take GV-971 during the study are not 
eligible.   
 
Any previous treatment with medications specifically intended to treat Parkinson symptoms 
or any other neurodegenerative disorder within 1 year of screening and with no plans to 
initiate such medications prior to study start  
Certain medications are acceptable if the participant is taking the medicine for a 
non-neurodegenerative disorder, such as restless leg disorder (e.g., pramipexole). 
 
Typical antipsychotic or neuroleptic medication within 6 months of screening and with no 
planned changes prior to study start except as brief treatment for a non-psychiatric 
indication (e.g., emesis) 
Atypical antipsychotic medications are not allowed except for intermittent short-term 
use and will need to be discontinued 2 days or at least 5 half-lives (whichever is 
longer) prior to any neurocognitive assessment. 
 
Anticoagulation medications within 3 months of screening with no plans to initiate any prior 
to start of study treatment 
Anti-platelet treatments (e.g., aspirin, clopidogrel, and dipyridamol) are permitted. 
Short-term, perioperative use of anticoagulant medications will not result in permanent 
discontinuation from the study; however, for any such use it is recommended to 
prospectively seek advice from the Medical Monitor and temporary study drug 
interruption may be required. 
 
Chronic use of opiates or opioids (including long-acting opioid medication) within 3 months 
of screening with no plans to initiate any prior to study start  
Intermittent short-term use of short-acting opioid medications for pain is permitted 
except within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive 
assessment.  
 
Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) within 
1 month of screening and throughout the study 
 
Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before screening 
and with no plans to initiate any prior to study start 


 
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Intermittent short-term use of benzodiazepines, buspirone, or short-acting hypnotic 
medication for sleep or anxiety is allowed except within 2 days or 5 half-lives 
(whichever is longer) prior to any neurocognitive assessment.  
 
Other Exclusions 
Participants who meet any of the following criteria will be excluded from study entry: 
 
Other causes of intellectual disability that may account for cognitive deficits observed at 
screening (e.g., static encephalopathy, closed brain injury, mental retardation)  
This may be based on, for example, participant’s sufficient education or 
work experience. 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during the study 
 
Clinically significant abnormal screening blood 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, in the opinion 
of the investigator, 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 of gantenerumab excipients 
 
Any other severe or unstable medical condition that, in the opinion of the investigator or 
Sponsor, could be expected to progress, recur, or change to such an extent that it could put 
the participant at special risk, bias the assessment of the clinical or mental status of the 
participant to a significant degree, interfere with the participant’s ability to complete the 
study assessments, or would require the equivalent of institutional or hospital care 
 
Residence in a skilled nursing facility such as a convalescent home or long-term care 
facility 
Participants who subsequently require residence in such facilities during the study may 
continue in the study and be followed for PD and safety data, provided that they have a 
study partner (non-professional caregiver) who meets the minimum requirement. 
 
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 
 
END OF STUDY 
The end of the study is defined as the date when the last participant, last visit occurs or the date 
at which the last data point required for statistical analysis or safety follow-up is received for the 
last participant, whichever occurs later.  The end of the study is expected to occur 224 weeks 
after the last participant is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
LENGTH OF STUDY 
The total length of the study, from screening of the first participant to the end of the study, is 
expected to be approximately 5 years. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal product (IMP) for this study is gantenerumab. 
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Gantenerumab 


 
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Gantenerumab will be administered by SC injection, at a dose of 120 mg Q4W (Day 1, Week 4, 
and Week 8), then 255 mg Q4W (Weeks 12, 16, and 20), and then 255 mg Q2W for 12 weeks 
(Weeks 24, 26, 28, 30, 32, and 34), followed by the target dose 255 mg Q1W (Weeks 36207).  
Before reaching the maximum target dose (i.e., 255 mg Q1W), a minimum of three doses during 
the 120-mg Q4W and 255 mg Q4W dosing periods, and a minimum of six doses during the 
255mg Q2W dosing period must be administered prior to uptitration. 
Depending on the site and individual participant/caregiver suitability, participants will have the 
option to receive SC injections of gantenerumab at the site and (after a defined period of 
appropriate training and supervision of a caregiver) at home by study staff, home nurse, or 
study partner (non-professional caregiver). During the course of the study, an autoinjector 
may become available in participating countries, if approved by local health authorities and 
IRBs (use of this device will be optional for participants who receive study treatment 
administration at home or at the site).  Participants will receive SC injections of gantenerumab 
by the investigator or an appointed qualified study staff for the first three doses of 
gantenerumab at the clinic.  If participants have a study partner (non-professional caregiver) 
who is willing and judged capable of administering SC injections, this caregiver will receive 
training and observe dose administration at the first three dosing visits (i.e., Day 1, Week 4, and 
Week 8), and the injections will be done by the caregiver under staff supervision at the next four 
visits (i.e., Weeks 12, 16, 20, and 24).  Following this supervised dosing at the clinic, 
subsequent dosing may be administered by the caregiver at home except for doses that 
coincide with a clinic visit, in which case the caregiver should administer the injection in clinic 
under investigator/study staff supervision.  Study staff will document the outcome of the 
supervised administration.  
The investigator will determine whether the participant is suitable for home administration by the 
study partner (non-professional caregiver), a home nurse, or appropriate study staff (according 
to local regulations).  
At subsequent visits, the investigator will determine if the study partner (non-professional 
caregiver) continues to be suitable to perform home administration.  If at any time the 
investigator or caregiver determines that home administration by the caregiver is unsuitable, 
then study drug must be administered at home or in the clinic by a home nurse or study staff.  
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/or caregiver to 
elicit, in a non-leading way, information on medication errors and adverse events that may have 
occurred in the home setting.  Therefore, there will be contact between the study staff and the 
participant/caregiver at least every 4 weeks.  The study staff is encouraged to have more 
frequent calls with a particular participant/caregiver if considered appropriate by the investigator.  
In addition, participants/caregivers will 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, or medication errors. 
Training and supportive materials will be provided to the site and to the study partner 
(non-professional caregiver).  Following the in-person instructional training and supervised 
administration at the site, adequate supply of gantenerumab will be provided. 
For Q4W injections, a time window of  7 days is allowed for dosing.  For Q4W injections, the 
recommended minimum time between doses is 3 weeks.  The maximum recommended time 
between doses should not exceed 6 weeks.  For both the Q2W injections and Q1W injections, 
the time window for dosing is  3 days.  If the administration is not possible on the scheduled 
dosing day, the study medication 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 medication dosing resumed in accordance with the 
original dosing schedule.  Always return to the initial planned schedule or subsequent 
doses/visits. 
Regardless of dose, each participant will undergo up to a total of 184 dosing visits and home 
administrations as applicable in the study.  Injections will be administered as one 0.8-mL 
(120-mg) dose or one 1.7-mL (255-mg) dose subcutaneously to the abdomen. 
Positron Emission Tomography Tracers  


 
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All participants who are otherwise eligible at screening will be assessed for the presence of 
brain amyloid consistent with AD by PET imaging.  The permitted amyloid PET ligands will be 
florbetaben (all sites) and flutemetamol (in exceptional circumstances, the use of flutemetamol 
may be acceptable at sites where florbetaben is not available, but only after prior written 
approval from the Sponsor).  Florbetaben or flutemetamol will be provided in accordance with 
approved national and/or local standards.  
According to E.U. guidance, PET tracers, as used in the context of this study, are designated as 
non-IMP.  In some regions, according to local regulations, these PET tracers may be 
considered to be an IMP. In countries where the PET radioligands are approved for marketing, 
the approved local product information will be provided, and in countries where they are not 
approved for marketing, the Investigator’s Brochures will be provided.   
STATISTICAL METHODS 
PRIMARY ANALYSIS 
The primary endpoint for this study is the change from baseline to Week 104 in brain amyloid 
load, as assessed by amyloid PET imaging using florbetaben as ligand and quantified on the CL 
conversion scale, in participants exposed to a Q1W administration regimen of SC 
gantenerumab.  For the purposes of analysis, the screening amyloid PET scan may be 
considered the baseline evaluation. 
Details about the primary estimand definition and corresponding statistical model specification, 
including handling of missing data will be described in the Statistical Analysis Plan (SAP).  For 
example, a linear mixed-effects model with change from baseline as dependent variable, and 
baseline value and visit as covariate may be used. 
Descriptive summary statistics of the change from baseline to Week 104 in brain amyloid CL 
load will also be produced.  Descriptive summaries of the primary endpoint will present the 
mean, standard deviation, median, and minimum and maximum.  
To evaluate the impact of different amyloid PET radioligands on the quantification of the PD 
effect of gantenerumab, a supplementary analysis will be performed similarly to the primary 
endpoint on the sample of participants scanned with florbetaben or flutemetamol in this study (if 
applicable). 
DETERMINATION OF SAMPLE SIZE  
Determination of sample size is relative to the sample of participants assessed by amyloid PET 
imaging using florbetaben.  The sample size for this study is determined as the number of 
participants needed for the estimated change from baseline to Week 104 in amyloid PET load to 
fall into a 10 CL confidence interval around its true value.  With a standard deviation of 25.67 
CL, 192 participants are sufficient to fulfill this criterion.  
The standard deviation of amyloid reduction was estimated using amyloid PET data from the 
ongoing studies WN25203 and WN28745 OLEs (based on a cutoff date of 14 October 2019), 
yielding a value of 25.67 CL. 
Uncertainties of the parameters affecting the estimation (e.g., drop-out rate, study drug 
discontinuation rate, and standard deviation) were assumed to be equivalent to a decrease in 
sample size of up to around 35% and were corrected for accordingly.  This drop-out rate is 
calculated based on the ongoing Study WN28745 OLE at Week 104.  A sample size increase 
may be considered if factors external to the study would warrant a change to the sample size 
assumption.  
INTERIM ANALYSIS 
An interim analysis will be conducted on the latest data cut available at the time of the primary 
analysis for Studies WN29922 and WN39658.  The maximum sample available at this timepoint 
with valid screening and Week 52 PET scans will be included in the analysis. 
Change from baseline in amyloid PET load with the Q1W regimen will be assessed at Week 52.  
This may be compared with the predictions of the PK-PET model for this timepoint.  At the time 
of the interim analysis, all available PK and safety data, responses to the Caregiver part of the 
home administration questionnaire, and exploratory endpoints may be reported descriptively as 
supporting evidence.  The interim analysis will not impact the conduct of the study, i.e., early 
termination for futility or efficacy will not be considered. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
A 
amyloid 
AD 
Alzheimer’s disease 
ADA 
anti-drug antibody 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale Cognition 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study 
GroupActivities of Daily Living 
ADL 
activities of daily living 
APOE 
apolipoprotein E 
APOE 4 
apolipoprotein E gene allele 4 
ARIA 
amyloid-related imaging abnormality  
ARIA-E 
amyloid-related imaging abnormalityedema/effusion  
ARIA-H 
amyloid-related imaging abnormalityhemosiderin 
deposition 
AUC 
area under the concentrationtime curve 
BGTS 
Barkhof grand total score  
BOLD 
blood oxygenation level-dependent  
Cav 
average concentration 
Cmax 
maximum concentration observed 
CDR 
Clinical Dementia Rating 
CDR-GS 
Clinical Dementia Rating global score 
CFR 
Code of Federal Regulations 
CL 
Centiloid 
COA 
clinical outcome assessment 
COVID-19 
coronavirus disease 2019 
CRO 
contract research organization 
CSF 
cerebral spinal fluid 
C-SSRS 
ColumbiaSuicide Severity Rating Scale 
CT 
computed tomography 
DTI 
diffusion tensor imaging 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FA 
fractional anisotropy 
FcR 
Fc receptor 
FDA 
Food and Drug Administration 
FLAIR 
fluid-attenuated inversion recovery 
GRE 
gradient-recalled echo 
HbA1c 
hemoglobin A1c 
HIPAA 
Health Insurance Portability and Accountability Act 
HN 
home nursing 
ICH 
International Council for Harmonisation 


 
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Abbreviation 
Definition 
IMC 
Internal Monitoring Committee 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
IRB 
Institutional Review Board 
ISR 
injection-site reaction 
IxRS 
interactive voice or web-based response system 
MAD 
multiple ascending dose 
MCI 
mild cognitive impairment 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NIA-AA 
National Institute on Aging/Alzheimer’s Association 
OLE 
open-label extension 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PK 
pharmacokinetic 
p-tau 
phosphorylated tau 
Q1W 
once a week 
Q2W 
every 2 weeks 
Q4W 
every 4 weeks 
RBR 
Research Biosample Repository 
rs-fMRI 
resting-state functional magnetic resonance imaging 
SAP 
Statistical Analysis Plan 
SUVR 
standardized uptake value ratio 
ULN 
upper limit of normal 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 


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


 
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Gantenerumab is manufactured by cell culture of a recombinant Chinese hamster ovary 
K1 mammalian cell line and subsequent purification of the antibody.  Gantenerumab 
drug substance manufacturing was optimized during development to improve process 
robustness and increase overall process yield, leading to several generations of 
manufacturing process (G1, G2, G3, and G4).  Drug material manufactured by the 
G4 process is used in pivotal Phase III clinical trials (Studies WN29922 and WN39658) 
and will be used in this study. 
1.2.1 
Nonclinical and Clinical Studies 
Nonclinical evidence has suggested that monoclonal anti-A antibodies may be able to 
remove and reduce deposition of A aggregates from the brain.  In transgenic animal 
models of AD, vaccination with A or passive immunization with anti-A antibodies 
resulted in decreased amyloidosis and in improvement of memory function in some 
transgenic models of cognitive function (Janus et al. 2000).  Accumulating clinical 
evidence also supports that monoclonal anti-A antibodies can bind A and promote its 
clearance (Salloway et al. 2009; Ostrowitzki et al. 2012; Klein et al. 2019), reduce 
deposition of A aggregates, and reduce markers of neurodegeneration in the 
cerebrospinal fluid (CSF; Roche Research Report No. 1066251).  In a Phase I study with 
the anti-A monoclonal antibody aducanumab, reduction of deposited amyloid as shown 
on brain amyloid positron emission tomography (PET) imaging was associated with a 
time- and dose-related slowing of cognitive decline (Sevigny et al. 2016).  Because the 
pathological changes associated with AD develop decades before clinical symptoms 
emerge, it is thought that earlier intervention may be more effective in arresting or 
delaying disease progression (Sevigny et al. 2016).  Consequently, therapies targeting 
this process have the potential to significantly alter the progression of the disease.  
Gantenerumab, a fully human monoclonal antibody targeting aggregated forms of A, 
such as A oligomers, fibrils, and plaques, is expected to address this need 
(Bohrmann et al. 2012). 
Gantenerumab has been investigated in 10 completed Phase I clinical studies:  3 single 
ascending dose studies in healthy volunteers and patients with mild to moderate AD 
(Studies BN18726, JP22474, and BP30042); 2 multiple ascending dose (MAD) studies 
of patients with mild to moderate AD (Studies NN19866 and JP22431); and 
4 bioavailability studies in healthy subjects1 study comparing the IV and SC 
formulations of gantenerumab (Study WP22461), 2 studies comparing lyophilized and 
high-concentration liquid formulations of gantenerumab (Studies WP27951 and 
BP29113), and 1 study comparing drug substance manufactured through the third and 
fourth generation (G3 and G4) processes (Study WP40052).  A tolerability study that 
compared injection-site pain between faster and slower SC administration of 
gantenerumab was also conducted (WP39322).  Overall, a total of 543 subjects have 
participated in the Phase I studies; of these participants, 406 healthy volunteers and 
101 patients with mild to moderate AD have received gantenerumab.  


 
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Based on results of the MAD study (NN19866) and of the relative bioavailability study 
(WP27951), the dosing regimens of 105 mg SC every 4 weeks (Q4W; equivalent to 
60 mg IV Q4W) and 225 mg SC Q4W (equivalent to 130 mg IV Q4W) were initially 
selected for the Phase III Studies WN25203 and WN28745.  Following the results of the 
WN25203 futility analysis, these studies were converted into open-label 
extensions (OLEs) to examine the safety and tolerability of a higher dose of 
gantenerumab (1200 mg SC Q4W).  
Overall, 383 participants enrolled in the OLEs of Studies WN25203 and WN28745.   
As of 1 May 2019, 363 participants had been exposed to G3 gantenerumab doses 
higher than 225 mg, and 309 participants reached the target 1200mg dose.  
Continuous monitoring of safety data and magnetic resonance imaging (MRI) findings by 
the Sponsor has not identified any new safety signals in these ongoing studies.  
Injection-site reactions (ISRs) and amyloid-related imaging abnormalities (ARIAs) remain 
the only identified risks for gantenerumab.  These OLE studies were completed 
respectively in 2020 and in 2021, and participants who did not discontinue study 
treatment at the end of the prescribed study period were provided an option to enroll in 
an open-label rollover study to evaluate the safety and tolerability of long-term 
administration of gantenerumab (WN41874).  
Based on safety results from OLE Studies WN25203 and WN28745, and on data from 
the PET sub studies that confirmed the pharmacodynamic (PD) effects of gantenerumab 
treatment (1200 mg SC Q4W) on A plaque reduction (Klein et al. 2019), two pivotal 
multicenter, Phase III studies in participants with early (prodromal to mild) AD were 
initiated:  WN29922 (Graduate 1) and WN39658 (Graduate 2).  These studies are 
examining the efficacy, safety, and tolerability of gantenerumab uptitrated to 510 mg 
every 2 weeks (Q2W) dosing; these studies are currently ongoing and are expected to 
be completed in 2023.   
Refer to the Gantenerumab Investigator's Brochure for details on nonclinical and clinical 
studies. 
1.3 
STUDY RATIONALE AND BENEFITRISK ASSESSMENT 
1.3.1 
Study Rationale 
Study WN29722 is a Phase II, multicenter, open-label study in participants with early 
(prodromal to mild) AD to evaluate the PD effect of a once weekly (Q1W) dosing 
regimen on deposited amyloid, as measured by brain amyloid PET imaging at Week 52, 
Week 104 (primary analysis), Week 156, and Week 208.  To obtain additional 
long- term safety and tolerability follow-up information about the Q1W dosing 
regimen, as well as exploratory long-term pharmacokinetic (PK)/PD and biomarker 
information, participants will be followed through to the Week 208 timepoint on target 
dose.   


 
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In the pivotal studies (WN29922 and WN39658), the target dose is administered as two 
injections of 255 mg SC Q2W (510 mg SC Q2W), delivered by a healthcare 
professional.  In the future, a further option is administration of gantenerumab in a more 
flexible setting with study partners (non-professional caregivers) administering doses.  In 
this case, when dosing is no longer connected to a need for a health care professional 
interaction, a Q1W home administration with a single injection of 255 mg SC may be a 
preferred regimen for some patients. 
Study WN29722 will investigate a 255 mg Q1W administration schedule mandating only 
one single injection per dosing day and the option of health care professional or study 
party (non-professional caregiver) assisted home administration.   
The dosing regimen in Study WN29722 (see Figure 4) is 120 mg Q4W (at Day 1, 
Week 4, and Week 8), then 255 mg Q4W (Weeks 12, 16, and 20), and then 255 mg 
Q2W (Weeks 24, 26, 28, 30, 32, and 34), followed by 255 mg Q1W (Weeks 36207). 
The regimen will differ in dosing frequency from the pivotal trials starting at Week 24; 
however, the total 4-weekly dose and the overall titration schedule of gantenerumab (by 
4-weekly average) will remain the same as studied in the ongoing pivotal Phase III 
studies (WN29922 and WN39658).  Both dosing regimens reach target dose of 1020 mg 
every 4 weeks (divided 510 mg SC Q2W in the pivotal studies or 255 mg SC Q1W in 
Study WN29722) at Week 36.  The average exposure (area under the 
concentrationtime curve [AUC]) is expected to be very similar based on population PK 
modelling from available data. 
Currently, approved therapies for AD focus on symptomatic approaches that target 
synaptic function and cognitive enhancement (Cummings 2004).  However, the amyloid 
hypothesis suggests that overproduction of A or failure to effectively clear this peptide 
contributes to AD (Selkoe and Hardy 2016) and that accumulation of A peptides is a 
factor contributing to AD progression (Sun et al. 2015).  Thus, the targeting of A and 
subsequent displacement of A from the brain is a rational approach to modify 
AD progression. 
Accumulating clinical evidence supports that monoclonal anti-Aβ antibodies can bind Aβ 
and promote its clearance (Salloway et al. 2009; Ostrowitzki et al. 2012; 
Sevigny et al. 2016; Klein et al. 2019), reduce deposition of Aβ aggregates, and reduce 
markers of neurodegeneration in CSF (Ostrowitzki et al. 2017).  A Phase I study of 
aducanumab (Sevigny et al. 2016) and a Phase II study of BAN2401 
(Swanson et al. 2018) suggested that reduction of deposited amyloid, as seen on brain 
amyloid PET imaging, was associated with a dose-related slowing of cognitive decline. 
The association between microglial-driven removal of aggregated brain amyloid and 
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gantenerumab exhibits linear pharmacokinetics, the AUC from Time 0 to infinity after 
single dose reflects the steady state exposure after multiple doses. 
Internal (Report No. 1040966, Figure 1) and external (Hang et al 2015a) information 
suggest that the effect of monoclonal antibodies like gantenerumab on plaque removal is 
driven by the total exposure and not maximum concentration observed (Cmax).  In a 
nonclinical study, the binding of gantenerumab on cerebral Aβ1−42 aggregates was 
investigated in transgenic PS2APP mice (Report No. 1040966).  Plaque binding was 
assessed 3 weeks after administration of single doses of gantenerumab at 10 mg/kg IV, 
10 mg/kg SC, or 20 mg/kg SC.  This amyloid-β plaque binding data was compared with 
exposure data from a PK study in satellite groups treated under the same experimental 
conditions (Report No. 1037575).  Results shown in Figure 1 indicate that while Cmax is 
expectedly different across dose and administration route, minimal differences were 
seen in AUC at comparable doses of gantenerumab using IV or SC administration.  
Further, the degree of plaque binding (analogous to target engagement) was similar, 
regardless of administration route.  


 
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Figure 1 Gantenerumab Concentrations (Intravenous and Subcutaneous) 
and Plaque Binding (Mice) 
 
AUC  area under the concentrationtime curve; AUC0-504h  area under the concentration–time 
curve from 0 to 504 hours; Cmax  maximum concentration observed; PK  pharmacokinetic. 
LEFT PANEL:  Plasma PK parameters Cmax (upper plot) and AUC0-504h (lower plot) in the satellite 
C57/Bl6 mice. 
RIGHT PANEL:  Gantenerumab binding to plaque measured 3 weeks after administration of 
single doses.  Plaque binding across dose groups was related to AUC with no apparent 
correlation to Cmax values. 
 
In clinical trials, PET standardized uptake value ratio (SUVR) data using florbetapir 
reported for aducanumab (Hang et al. 2015a) and gantenerumab (WN25203) have been 
compared based on the average plasma concentration observed in each participant.  
The observed similarities in change from baseline PET SUVR values for aducanumab 
and gantenerumab when stratified by the average concentration (Cav) indicates that 
exposure is indeed the driver of plaque removal.  As aducanumab was administered IV 
in the PRIME study, the Cmax values were significantly higher (mean Cmax of 250 g/mL 
in the 10-mg/kg dose group) than the gantenerumab Cmax concentrations tested in 
Study WN25203 (mean Cmax of 17 g/mL in the 225-mg dose group).  The addition of 
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to 1200 mg have been tested, matched the results observed with aducanumab 
(see Figure 2).   
Figure 2 Amyloid PET SUVR Percentage Change from Baseline by Time 
per Category of Plasma Concentration 
 
Cav  average concentration; DB  double blind; CFB  change from baseline; MR  Marguerite 
RoAD (WN28745); OLE  open-label extension; PET  positron emission tomography; 
SR  SCarlet RoAD (WN25203); SUVR  standardized uptake value ratio. 
Note:  Gantenerumab (Study WN25203 DB) data is shown in yellow, aducanumab (PRIME 
Phase 1b) data is shown in blue, and gantenerumab (Study WN28745 OLE) data is shown in 
red.  Five different average concentration categories are displayed (from left to right):  placebo, 
<10 μg/mL, 10−20 μg/mL, 20−40 μg/mL, and >40 μg/mL. 
 
In line with the Sponsor`s hypothesis, that exposure (AUC) is the primary driver for 
amyloid removal, the authors of a recent aducanumab publication (Hang et al. 2015b) 
concluded that amyloid plaque removal was significantly correlated with aducanumab 
serum exposure Cav.  Important to note is that amyloid reduction during treatment 
happens on a time scale of months, whereas fluctuations in plasma concentrations 
(peak-to-trough) have a time scale of days, supporting the hypothesis that the total 
exposure (or Cav) rather than the peak concentration is the main driver for amyloid 
removal. 


 
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Based on the established similarities between gantenerumab and aducanumab, a model 
characterizing the relationship between plasma drug concentration (PK) and PET 
response (i.e., the PD effect on amyloid load in the brain) was derived from both 
gantenerumab Study WN25203 data and aducanumab PRIME study data to determine 
the target dose of gantenerumab for the WN25203 OLE and WN28745 OLE studies.  In 
the OLE studies, gantenerumab 1200 mg SC Q4W was predicted to achieve plasma 
levels comparable to aducanumab 10 mg/kg IV Q4W and to be associated with a 
comparable amyloid brain reduction, which, in the case of aducanumab, was associated 
with a statistically significant clinical effect after one year of treatment.  To minimize the 
occurrence of ARIAedema/effusion (ARIA-E) while achieving the target dose within a 
reasonable time frame, several titration schedules have been explored in the 
WN25203 OLE and WN28745 OLE studies. 
Gantenerumab PK-PET models of amyloid reduction have been confirmed by PET data 
using florbetapir F 18 (Amyvid) from the OLE studies (Klein et al. 2019b) and a marked 
and consistent reduction of amyloid load in participants receiving high-dose 
gantenerumab (1200 mg SC Q4W) was observed (Figure 3; Klein et al. 2019).  An 
important anchor for interpreting PET results is the threshold for amyloid positivity, which 
is the quantitative threshold that best discriminates pathologically verified absence of 
plaques or sparse plaques from moderate to frequent plaques.  A Centiloid value (CL) of 
24 is generally recognized as the amyloid positivity threshold for florbetapir 
(Klein et al. 2019).  Results from these ongoing studies show that following two years of 
treatment, 51% of subjects achieved below-threshold PET SUVR signals based on 
quantitative measures (see Figure 3, panel B).   


 
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Figure 3 Marked and Consistent Reduction of Amyloid Load in 
Participants Receiving High-Dose Gantenerumab 
 
MR-DBA  Marguerite RoAD (WN28745) pretreated subgroup; MR-DBP  Marguerite RoAD 
(WN28745) non-pretreated subgroup; OLE  open-label extension; SR  SCarlet RoAD 
(WN25203) subgroup; SUVR  standardized uptake value ratio. 
a Analyzed using a mixed-model for repeated measures. 
 
In summary, data from nonclinical and clinical studies suggest that target engagement 
as shown by PET SUVR amyloid reduction depends on average exposure rather than 
Cmax.  Hence, a change in dosing frequency while maintaining average exposure is 
expected to have the same effect on amyloid removal.  Evidence suggests that total 
dose, rather than dosing frequency, drives the treatment effect of gantenerumab to 
stimulate microglial−driven removal of aggregated brain amyloid.  Therefore, it is 
expected that the target dose of 510 mg SC Q2W administered in the ongoing 
Phase III studies can also be administered as 255 mg SC Q1W without altering the 
treatment effect. 
1.3.2 
BenefitRisk Rationale 
Nonclinical characterization of gantenerumab did not show relevant safety findings.  No 
differences between gantenerumab and placebo groups have been observed in 
laboratory parameters, physical and neurologic examinations, vital signs, or ECG 
parameters in clinical studies. 
The identified risks of gantenerumab treatment are ARIAs and ISRs.  Safety data, 
including MRI findings, are continuously monitored in all ongoing studies, and no new 
safety signals have been identified. 


 
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Refer to Section 5.1.1 for information on anticipated risks for gantenerumab and risk 
mitigation measures, including guidelines for managing adverse events associated with 
gantenerumab. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of gantenerumab may be found in the 
Gantenerumab Investigator's Brochure. 
Overall BenefitRisk Summary 
The benefitrisk assessment of gantenerumab treatment in Study WN29722 is based on 
the following: 
 
Gantenerumab has shown evidence of amyloid plaque reduction (i.e., observed 
evidence of brain amyloid reduction) and, thus, shows potential benefit in slowing 
the progression of AD. 
 
Nonclinical and clinical studies suggest that target engagement as shown by PET 
SUVR amyloid reduction is not Cmax-driven but rather depends on average 
exposure.  Therefore, it is expected that the target dose of 510 mg SC Q2W 
administered in the ongoing Phase III studies can also be administered as 255 mg 
SC Q1W without altering the treatment effect. 
 
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, and do not require permanent 
cessation of treatment.  ARIAs are manageable with MRI monitoring and dose 
intervention algorithms, as detailed in Section 5.1.3. 
 
No new safety signals have been identified from the ongoing Phase III studies with 
gantenerumab with doses of up to 510 mg Q2W, which supports the safety of 
continued administration of gantenerumab uptitrated to the target dose in the current 
and planned studies, including Study WN29722.  A higher ARIA risk is not expected 
in Study WN29722 compared with the Q2W regimen in the ongoing Phase III 
studies because the Q1W regimen will provide the same gantenerumab exposure 
with a lower Cmax.  The Sponsor’s Internal Monitoring Committee (IMC) will evaluate 
safety data on a regular basis, including the incidence and nature of adverse events, 
serious adverse events, adverse events of special interest, ARIA-E, 
ARIAhemosiderin deposition (ARIA-H), and ISRs and will make appropriate 
recommendations (see Section 3.1.2). 
 
Study WN29722 will provide the opportunity to enable an additional dosing regimen 
(i.e., a single injection of 255 mg SC Q1W), which will benefit individuals who prefer 
this approach. 
 
The overall risk of compromising the study effectiveness by introducing flexible care 
options, including home administration by study partners (non-professional 
caregivers), is deemed to be low.  Mitigations are put in place to closely monitor and 
control the proper administration of the medication throughout the study.  These 
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benefit is to provide a convenient option of home administration for the caregivers 
and the patients who would like to take advantage of this opportunity. 
 
Based on its mechanism of action, there is no reason to believe that gantenerumab 
administration would compromise the immunologic reaction of the body.  This is 
supported by the nonclinical and clinical data collected through the development 
program of gantenerumab, where there has been no indication that gantenerumab 
administration compromised immune system or made individuals more susceptible 
to infections.  Thus, there are no data or biological rationale suggesting that 
gantenerumab administration could increase the risk of infection by severe acute 
respiratory syndrome coronavirus 2 or more severe coronavirus disease 2019 
(COVID-19) outcomes.  Whereas people with AD, because of advanced age, may 
be in a higher-risk group for COVID-19, participation in Study WN29722 is not 
expected to increase that risk.  
 
Based on the available information, no interactions between gantenerumab or the 
PET tracers used in this study and the COVID-19 vaccines are expected to occur, 
and no other safety concerns have been identified that would prohibit the 
vaccination of participants enrolled in the studies where gantenerumab is being 
investigated for the treatment of AD.  Just as with other vaccinations (e.g., 
influenza), the administration of COVID-19 vaccines will be considered as a 
concomitant medication in this study.  
 
Overall, the anticipated benefitrisk profile of the target dose of gantenerumab of 255 mg 
SC Q1W supports a clinical trial with this dosing regimen in the population with early 
(prodromal to mild) AD. 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the pharmacodynamics, pharmacokinetics, and safety of 
gantenerumab in participants with early (prodromal to mild) AD.  Specific objectives and 
corresponding endpoints for the study are outlined in Table 1 below. 


 
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Table 1 
Objectives and Corresponding Endpoints 
Primary Objective 
Corresponding Endpoint 
 
To evaluate the PD effect of a Q1W 
dosing regimen of gantenerumab on 
brain amyloid load as determined by 
PET imaging in participants with 
early (prodromal to mild) AD  
 
The change from baseline to Week 52 and to 
Week 104 in deposited amyloid as measured by brain 
amyloid PET CL levels a 
Secondary Objective 
Corresponding Endpoint 
 
To evaluate caregiver overall 
satisfaction and confidence with 
home administration  
 
Responses to home administration questionnaire 
(Caregiver) up to Week 52, Week 104 a and Week 
208 b 
Safety Objective 
Corresponding Endpoints 
 
To assess the safety of 
gantenerumab in participants with 
early (prodromal to mild) AD 
 
Nature, frequency, severity, and timing of adverse 
events and serious adverse events 
 
Physical examinations (including neurologic 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 
injection-site reactions 
 
Presence of ADAs during the study relative to the 
presence of ADAs at baseline 
PK/PD Objectives 
Corresponding Endpoints 
 
To characterize the PK profile of 
gantenerumab using a new titration 
scheme and especially at the 
Q1W dosing frequency 
 
To assess the PD effect of the 
dosing frequency (e.g., Q1W, Q2W) 
on brain amyloid 
 
Plasma concentration of gantenerumab (administered 
subcutaneously) at specified timepoints 
 
The influence of dosing frequency information on the 
performance of a quantitative PK-PD model 
developed based on PK and PET from this and 
previous studies (e.g., WN29922 and WN39658) a 
Exploratory Biomarker Objective 
Corresponding Endpoints 
 
To evaluate the pharmacodynamic 
effect of gantenerumab at the Q1W 
dosing regimen on plasma and MRI 
and PET biomarkers 
 
Change from baseline in plasma biomarkers 
(including, but not limited to, phosphorylated tau and 
NFL) to Week 104 and Week 208 b (see Section 4.5.9) 
 
Change from baseline to Week 104 and Week 208 b in 
functional brain connectivity, as measured by resting-
state functional MRI (where available) 
 
Change from baseline to Week 104 and Week 208 b in 
integrity of white matter, as measured by DTI-MRI 
(where available) 
 
MRI-derived measurements over time, such as 
volumetric changes in whole brain, ventricles, 
hippocampus, or other structures, in all participants. 
 
The change from baseline up to Week 208 in 
deposited amyloid as measured by brain amyloid PET 
CL levels b 
 


 
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Table 1 
Objectives and Corresponding Endpoints (cont.)  
Exploratory Objectives 
Corresponding Endpoints 
 
To compare the effect of a Q1W to a 
Q2W dosing regimen on amyloid 
reduction using external controls 
 
To evaluate the effects of 
gantenerumab at the Q1W dosing on 
cognitive and functional endpoints 
 
To evaluate patient overall 
satisfaction with at home 
administration 
 
The change from baseline to Week 52 and to 
Week 104 in deposited amyloid as measured by brain 
amyloid PET compared with the change in the pivotal 
WN29922 and WN39658 studies   
 
The change from baseline to Week 104 and Week 
208 b in the following: 
− 
The CDR-SOB 
− 
MMSE total score 
− 
ADAS-Cog11 and ADAS-Cog13 
− 
Verbal Fluency Task 
− 
Coding 
− 
ADCS-ADL 
 
Responses to home administration questionnaire 
(Patient) up to Week 104 and Week 208 b 
AD  Alzheimer's disease; ADA  anti-drug antibody; ADAS-Cog11  Alzheimer Disease Assessment 
ScaleCognition, Subscale 11; ADAS-Cog13  Alzheimer Disease Assessment ScaleCognition, 
Subscale 13; ADCS-ADL  Alzheimer Disease Cooperative Study Group- Activities of Daily Living; 
ARIA-E  amyloid-related imaging abnormalitiesedema/effusion; ARIA-H  amyloid-related imaging 
abnormalitieshemosiderin deposition; CDR-SOB  Clinical Dementia RatingSum of Boxes; 
CL  Centiloid; C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion tensor imaging; 
MMSE  Mini-Mental State Examination; MRI  magnetic resonance imaging; NFL  neurofilament light 
chain; PD  pharmacodynamic; PET  positron emission tomography; PK  pharmacokinetic; Q1W  once 
a week; Q2W  every 2 weeks; Q4W  every 4 weeks, SAP Statistical Analysis Plan. 
a The primary analysis is at Week 104 and details concerning interim analyses which will consider 
Week 52 outcomes are described in Section 3.3.5 and 6.9 and the SAP. 
b Week 208 assessments are optional and only required if participants take part in the 2-year 
extension 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
Study WN29722 is a Phase II, multicenter, open-label, single arm, PD study in 
participants with early (prodromal to mild) AD to evaluate the effect of a Q1W dosing 
regimen on deposited amyloid as measured by change from baseline to 
Weeks 52 and 104 in brain amyloid PET.  The dosing regimen being evaluated in 
current Phase III studies (WN29922 and WN39658) is gantenerumab 120 mg SC Q4W 
for 12 weeks, followed by 255 mg SC Q4W for 12 weeks, and 510 mg SC Q4W for 
12 weeks, prior to reaching the target dose of 510 mg SC Q2W.  As an alternative to 
administering two 255-mg injections Q2W at the target dose, the administration of 
gantenerumab as a single injection of 255 mg Q1W will be investigated in this study, to 
simplify the dosing regimen for patients and caregivers and to provide additional 
flexibility and convenience depending on individual patient's needs and preferences.  In 


 
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addition, Phase II Study WN29722 will evaluate the feasibility of home administration by 
study partners (non-professional caregivers), which is particularly relevant in conjunction 
with a Q1W dosing regimen. 
A total of 192 participants have been enrolled in participating countries.  A total of 
38 centers in 8 countries worldwide have participated in this study.  
Participants will be selected on the basis of a clinical diagnosis of probable AD 
(consistent with the National Institute on Aging/Alzheimer’s Association [NIA-AA] 
Diagnostic Criteria and Guidelines for probable AD; McKhann et al. 2011) or prodromal 
AD (consistent with the NIA-AA diagnostic criteria and guidelines for mild cognitive 
decline due to AD; Albert et al. 2011). 
Eligible participants will be 5090 years old, inclusive, and must have increased brain 
amyloid as indicated by positive amyloid PET scan by visual read.  At the time of 
screening, participants must have a Mini-Mental State Examination (MMSE) score 
 22 points and a Clinical Dementia Rating global score (CDR-GS) of 0.5 or 1.0.  To 
confirm objective memory impairment, participants must have a Clinical Dementia Rating 
(CDR) memory domain score  0.5. 
In addition, all eligible participants should have a study partner (non-professional 
caregiver) who is willing and judged as capable of administering SC injections 
(exceptions can be made for participants who are able to attend weekly clinic visits or 
who are able to have weekly home nursing [HN]/site staff visits). 
Neuroradiologic evaluation will use a standard MRI protocol (including T2*-weighted 
gradient−recalled echo [GRE] and fluid−attenuated inversion recovery [FLAIR]).  
Screening MRIs will be read by a central reader who will exclude participants with other 
structural causes of dementia, significant cerebral vascular pathology, more than five 
microbleeds, disseminated leptomeningeal hemosiderosis, or evidence of a prior 
cerebral macrohemorrhage.  
Participants will be eligible for the study whether or not they are receiving 
standard-of-care symptomatic medications for AD (e.g., cholinesterase inhibitors or 
memantine, combination, or a medical food supplement).  Intake of these medications 
must have been stable for  3 months prior to screening and until start of study 
treatment.  All eligible participants have to meet eligibility criteria as detailed in 
Section 4.1.   
The study will consist of a screening period of up to 8 weeks for each participant who 
agrees to participate, signs the Informed Consent Form, and is eligible for the study.  
Eligible participants will then undergo the baseline visit (Day 1), when they will receive 
the first dose following completion of all relevant assessments.  Participants will be 
enrolled in an open-label treatment period of up to 208 weeks.  The PET scans will be 


 
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performed at screening (will be considered as baseline evaluation), Weeks 52,104, 156, 
and 208, using florbetaben as the tracer at all sites (in exceptional circumstances, the 
use of flutemetamol may be acceptable at sites where florbetaben is not available, but 
only after prior written approval from the Sponsor).  Participants will be treated according 
to the following dosing regimen:  120 mg Q4W (Day 1, Week 4, and Week 8), then 
255 mg Q4W (Weeks 12, 16, and 20), and then 255 mg Q2W for 12 weeks (Weeks 24, 
26, 28, 30, 32, and 34), followed by the target dose 255 mg Q1W (Weeks 36207).  
Before reaching the maximum target dose (i.e., 255 mg Q1W), a minimum of three 
doses during the 120-mg Q4W and 255-mg Q4W dosing periods, and a minimum of six 
doses during 255-mg Q2W dosing period must be administered prior to uptitration.  
Participants who opt for the 2-year extension of Study WN29722 will receive the final 
dose of study drug at Week 207. Final PD and efficacy assessments will be performed 1 
week later at Week 208.  Eligible participants may qualify for continued access or 
ongoing extension studies as outlined in Section 4.3.5.  Participants who do not enter 
an extension study will have an additional follow-up visit 16 weeks after the Week 208 
visit for safety assessments (Week 224 follow-up visit). 
Participants who do not opt for the 2-year extension of Study WN29722, will receive 
the final dose of study drug at Week 103. Final PD and efficacy assessments will be 
performed 1 week later at Week 104.  Eligible participants may qualify for continued 
access or ongoing extension studies as outlined in Section 4.3.5.  Participants who do 
not enter an extension study will have an additional follow-up visit 16 weeks after the 
Week 104 visit for safety assessments (Week 120 follow-up visit).   
Depending on the site and individual participant/caregiver suitability, participants will 
have the option to receive SC injections of gantenerumab at the site or at home by study 
staff, a home nurse, or a study partner (non-professional caregiver) after a defined 
period of appropriate training and supervision.  For more details on study treatment 
administration, see Section 4.3.2.1. 
Participants will undergo brain MRI examinations for safety monitoring and longitudinal 
changes in brain structure.  MRI scans will be read by a central MRI reader (for more 
details regarding imaging-related criteria, see Section 4.1.2.2).  Participants will also 
undergo standard tests to monitor safety (blood tests and ECG), as well as the 
ColumbiaSuicide Severity Rating Scale (C-SSRS) to monitor for suicidality, tests for 
cognition, and function.  Blood samples for assessment of plasma biomarkers for AD 
and ARIA, pharmacokinetics, and exploratory genetic markers, and for the measurement 
of antibodies directed against gantenerumab will be obtained from all participants.  
Participants who do not meet the criteria for participation in this study (screen failure) 
may qualify for re-screening at the investigator's discretion as described in Section 4.6.  
Participants must re-sign the consent form prior to re-screening.  The investigator will 
record reasons for screen failure in the screening log (see Section 4.5.1). 


 
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Figure 4 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 
Figure 4 Study Schema 
 
D  day; Q1W  once a week; Q2W  every 2 weeks; Q4W  every 4 weeks; W  week. 
a Treatment period W104207 is optional and only for participants who consent to the 
optional 2-year extension. 
 
3.1.2 
Internal Monitoring Committee 
The incidence, severity, and nature of adverse events, serious adverse events, ARIA-E 
and ARIA-H, and laboratory abnormalities will be assessed on a regular basis by the 
Sponsor’s IMC, as documented in the IMC Charter. 
3.2 
END OF STUDY AND LENGTH OF STUDY 
The end of the study is defined as the date when the last participant, last visit occurs or 
the date at which the last data point required for statistical analysis or safety follow-up is 
received for the last participant, whichever occurs later.  The end of the study is 
expected to occur 224 weeks after the last participant is enrolled. 
In addition, the Sponsor may decide to terminate the study at any time. 
The total length of the study, from screening of the first participant to the end of the 
study, is expected to be approximately 5 years. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Gantenerumab Dose and Titration Schedule 
The dosing regimen in the pivotal WN29922 and WN39658 studies is as follows:  
120 mg Q4W (Day 1, Week 4, and Week 8), then 255 mg Q4W (Weeks 12, 16, and 20), 
and then 510 mg Q4W (Weeks 24, 28, and 32), followed by 510 mg Q2W 
(Weeks 36103).  This schedule enables titration to target dose within 9 months, with 


 
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predicted overall ARIA-E rate of approximately 26% based on the current ARIA-E hazard 
model.  The low starting doses and gradual increase in dosing (i.e., slow titration 
schedule) are expected to reduce the risk of ARIA-E for both apolipoprotein E (APOE) 
carriers and non-carriers.  A higher ARIA risk is not expected in Study WN29722 
compared with the Q2W regimen in the ongoing Phase III studies because the 
Q1W regimen will provide the same gantenerumab exposure with a lower Cmax. 
The dosing regimen in the current study (WN29722) will start with 120 mg Q4W (Day 1, 
Week 4, and Week 8), followed by 255 mg Q4W (Weeks 12, 16, and 20), and 255 mg 
Q2W (Weeks 24, 26, 28, 30, 32, and 34), followed by the target dose 255 mg Q1W 
(Weeks 36207). 
The regimen in the current study will differ in dosing frequency from the pivotal trials 
from Week 24 (with the start of 255 mg Q2W dosing).  The total monthly dose and the 
overall length of the titration schedule of gantenerumab will remain the same as studied 
in the ongoing pivotal WN29922 and WN39658 studies.  
Moreover, as presented in Section 1.2.1, data from nonclinical and clinical studies 
suggest that target engagement as shown by PET SUVR amyloid reduction is not 
Cmax-driven but rather depends on average exposure.  The target dose of 255 mg Q1W 
in this study is therefore expected to have the same effect on amyloid removal as the 
regimen in the pivotal studies. 
To provide patients and caregivers with a more flexible alternative to clinic visits, the 
feasibility of health care professional or study partner (non-professional caregiver) 
assisted home dosing will be assessed as part of the study.   
3.3.2 
Rationale for Study Population 
To compare the data obtained in this study with the Q2W dosing regimen in the ongoing 
pivotal Studies WN29922 and WN39658 in terms of change in PET amyloid load, the 
study population should be similar to the population in the pivotal studies. 
For this reason, participants in this study are required to meet standard research criteria 
for mild AD (according to the NIA-AA research criteria and guidelines for AD; 
see Appendix 3) or prodromal AD (according to the NIA-AA research criteria and 
guidelines for mild cognitive impairment (MCI) due to AD; see Appendix 4).  Note that 
the terms “prodromal AD” and “MCI due to AD” are considered to refer to the same 
population in this study and are defined according to NIA-AA research criteria and 
guidelines for MCI due to AD.  Thus, participants with prodromal AD will present with 
documented objective evidence of deficit in one cognitive domain.  Participants with mild 
AD must present with documented deficits in at least two cognitive domains and 
evidence of functional decline.  Overall, the population will have a MMSE between 22 
and 30 (inclusive) points and a CDR-GS of 0.5 or 1.0.  The MMSE score provides 
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participants have prodromal AD or cognitive and functional deficits consistent with 
mild AD.   
Gantenerumab is an antibody that targets A.  Thus, the study population should have 
documented evidence of amyloid pathology.  This participant selection approach is 
consistent with the NIA-AA research diagnostic criteria and guidelines for AD as well as 
with the Qualification Opinion from the European Medicines Agency’s Committee for 
Medicinal Products for Human Use on the use of CSF biomarkers for enrichment of trials 
in mild to moderate AD dementia (2012), and the U.S. Food and Drug Administration 
(FDA) draft guidance for early AD (2013).  Although the FDA’s guidance refers to the 
early stage of AD in which individuals present with clinical MCI, biomarkers of amyloid 
pathology are expected to add value to participant selection in mild AD studies, 
especially for anti-amyloid treatments (McKhann et al. 2011; Dubois et al. 2014, 2016).  
Biomarker enrichment is important for anti-amyloid therapy clinical trials because some 
results of early trials have demonstrated that approximately 20% of participants who are 
enrolled in trials based on a clinical diagnosis of AD alone may not have underlying 
amyloid pathology as assessed by amyloid PET (Doody et al. 2014; Salloway et al. 
2014).  
For enrollment in this study, biomarker evidence of Adeposition will be assessed by a 
centralized visual assessment of PET amyloid imaging, using florbetaben for participants 
at all sites (in exceptional circumstances, the use of flutemetamol may be acceptable at 
sites where florbetaben is not available, but only after prior written approval from the 
Sponsor). 
3.3.3 
Rationale for Open Label Design  
The primary objective of this study is to evaluate the PD effect of a gantenerumab 
Q1W dosing regimen on brain amyloid load as determined by PET in participants with 
early (prodromal to mild) AD.  Because the primary endpoint, change from baseline to 
Week 104 in deposited amyloid, is an objective biomarker endpoint, and because all 
cognitive and functional endpoints will be exploratory only, the study has an open-label 
design.   
3.3.4 
Rationale for Treatment Duration 
A 2-year treatment duration has been selected as the most appropriate duration for 
assessment of the primary endpoint (change from baseline [Day 1] to Week 104 in 
deposited amyloid as shown on brain amyloid PET), as the majority of participants in the 
WN25203 OLE and WN28745 OLE studies achieved below-threshold PET SUVR 
signals based on quantitative measures (see Figure 3 and Section 1.3).  To obtain 
additional timepoints for modeling and be in alignment with the schedule of imaging 
assessments in the pivotal Studies WN29922 and WN39658, PET scans will also be 
obtained at Week 52.  


 
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3.3.4.1 
Rationale for Optional Treatment Extension 
To obtain additional long-term safety and tolerability information about the Q1W 
dosing regimen, as well as additional exploratory long-term PK/PD and biomarker 
information, the study will be extended to 208 weeks in total.  
3.3.5 
Rationale for Interim Analysis 
An interim analysis of PD parameters will be conducted on the latest data cut available 
at the time of the primary analysis for Studies WN29922 and WN39658.  This analysis 
will include change from baseline in amyloid PET load at Week 52, and available PK, 
safety, and home administration data will be reported descriptively as supporting 
evidence.  The PK/PD models, using the titration scheme of the pivotal WN29922 and 
WN39658 studies and of the current study (WN29722), predict average amyloid 
reductions of approximately 35 CL and 67 CL at Weeks 52 and 104, respectively.  
At Week 24, the time when the dosing regimens for this study begin to differ from the 
pivotal studies, the predicted average amyloid reduction will be in the range of 10 CL, 
i.e., significantly lower than the later timepoints.  An interim analysis at 52 weeks will 
therefore provide meaningful information on the similarity or differences in amyloid 
reduction between different dosing regimens. 
This analysis is conducted to provide data regarding the Q1W regimen that may be 
included as part of the initial filing if appropriate. 
3.3.6 
Rationale for Primary Outcome Measure:  Brain Amyloid Load 
as Determined by Positron Emission Tomography 
The use of amyloid PET to measure reduction in amyloid has been selected as a 
primary endpoint in this study.  This approach is justified by the following: 
 
Substantial evidence supports the hypothesis that the primary mechanism of action 
for gantenerumab is clearance of A plaques via high-affinity binding to aggregated 
A, causing microglial activation and phagocytosis.  
 
Amyloid PET is a well-validated, quantitative method of measuring plaque burden 
in vivo in clinical studies of gantenerumab in AD and is therefore considered an 
accurate instrument for measuring potential differences in the PD effect of different 
dosing regimens. 
 
Clinical studies of gantenerumab and molecules with similar mechanisms of action 
have demonstrated significant time- and dose-dependent amyloid plaque reduction 
measured by amyloid PET, matching empirically derived, time- and AUC-dependent 
PK/PD models. 
 
Amyloid PET is a highly accurate measure of the PD effect of gantenerumab and is 
also a highly relevant biomarker based on recent group- and participant-level 
associations between amyloid PET reduction and clinical benefit observed with 
gantenerumab, aducanumab, and BAN2401. 
 


 
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To date, numerous in vitro, nonclinical, and clinical studies have demonstrated 
high-affinity binding of gantenerumab to aggregated forms of A and the plaque-lowering 
capability of this antibody.  While the exact mechanism of action is not fully understood, 
evidence supports the hypothesis that gantenerumab clears amyloid plaques via Fc 
receptor (FcR)-mediated microglial recruitment and phagocytosis, followed by 
lysosomal degradation as demonstrated for differential human macrophages 
(Bohrmann et al. 2012; Ostrowitzki et al. 2017).  A concentration-dependent reduction of 
amyloid plaque load has been seen via immunohistochemistry and quantitative image 
analysis ex vivo in post-mortem AD brain tissue slices.  Nonclinical in vivo PS2APP 
mouse studies have demonstrated dose-dependent binding of gantenerumab to amyloid 
plaques, and triple-labeled pathology studies have shown co-localization of 
gantenerumab bound to amyloid plaque adjacent to microglia cells. 
There is a large body of evidence showing that amyloid PET accurately quantifies in vivo 
amyloid plaque load in the brain (Klunk et al. 2004; Vandenberghe et. al. 2013).  
Quantitative SUVR has been shown to have high diagnostic accuracy in distinguishing 
pathologically confirmed amyloid burden levels of no plaques to sparse plaques from 
moderate to frequent plaques (Clark et al. 2011; Bullich et al. 2017).  The SUVR 
quantification method also correlates well on a continuous scale with multiple 
histopathology measures including global highest neuritic plaque count and A antibody 
immunohistochemistry (Clark et al. 2011; Choi et al., 2012; Joshi et al. 2012).  
Test/retest data of amyloid tracers show a low average coefficient of variation (worst 
case 1.94% using a whole cerebellum (Joshi et al. 2012; QIBA 2018).   
To reduce potential variability resulting from the use of different amyloid PET ligands, 
florbetaben will be used as the amyloid PET ligand for screening and longitudinal 
assessments by all sites (in alignment with the ongoing Phase III gantenerumab Studies 
WN29922 and WN39658).  In exceptional circumstances, the use of flutemetamol may 
be acceptable at sites where florbetaben is not available, but only after prior written 
approval from the Sponsor. 
Recently, a CL methodology has been proposed to translate SUVR values to a more 
intuitive scale that is less dependent on amyloid tracer, imaging processing 
methodology, and SUVR reference region (Klunk et al. 2015).  The CL scale is a linear 
regression transform of SUVR with anchors at 0 and 100, representing the mean 
amyloid burden of a young control and a typical AD participant group, respectively. 
3.3.7 
Rationale for Pharmacokinetic Sampling 
A sparse sampling schedule is being utilized to minimize participant burden and yet 
provide an adequate characterization of the population PK profile of gantenerumab, 
especially at the Q1W dosing regimen.  The PK data will be combined with available 
data from other gantenerumab studies (e.g., WN25203 OLE, WN28745 OLE, WN25203, 
WN28745) and will be used to assess exposure-response relationships for relevant 


 
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imaging, plasma PD biomarkers, and efficacy and safety outcomes in participants with 
early (prodromal to mild) AD, as appropriate. 
3.3.8 
Rationale for Biomarker Assessments  
3.3.8.1 
Positron Emission Tomography 
The definitive diagnosis of AD requires the presence of progressive dementia during life 
and the postmortem presence of neuropathological lesions (i.e., neuritic plaques 
composed of A aggregates and neurofibrillary tangles formed from 
hyper-phosphorylated tau protein [p-tau]).  However, imaging approaches using ligands 
that demonstrate high affinity for aggregated amyloid are able to provide an assessment 
of deposition in vivo, which can be evaluated over time (Clark et al. 2011).  
As detailed in Section 3.3.6, quantitative amyloid PET is an accurate biomarker of 
amyloid plaque burden for assessing target engagement and PD effect of gantenerumab 
treatment.  Change in amyloid burden as measured by amyloid PET will provide relevant 
data to assess potential differences in PD effect due to different dosing regimens. 
3.3.8.2 
Brain Volumetry, Connectivity, and Fiber Tract Integrity 
A characteristic feature of AD is neuronal destruction.  Such neuronal loss is 
demonstrated at a macroscopic level by progressive cerebral atrophy, which can be 
tracked on MRI (Fox and Kennedy 2009).  Multiple changes in brain anatomy beyond 
those associated with normal aging have been reported in participants with AD 
(e.g., enlarged ventricles, decreased cortical thickness, decreased total brain volume, 
and hippocampal atrophy), and there is evidence for strong correlations between these 
imaging biomarkers and functional cognitive measures (Li and Wahlund 2011).  Based 
on volumetric MRI measurements, the two most established markers of disease 
progression in longitudinal observational studies are hippocampal and whole brain 
atrophy (Fox et al. 2000, 2005; Jack et al. 2010), with ventricular expansion a related 
quantitative marker. 
Therefore, to quantify the effects of gantenerumab on neurodegeneration, whole brain 
volume, ventricular enlargement, and regional brain volume, changes will be assessed 
at screening and following treatment.  All MRI reads and volume measures will be 
conducted by the central reader. 
In addition to the structural brain volume changes, changes in brain functioning of 
participants will be assessed using a blood oxygenation level-dependent (BOLD) 
resting-state functional MRI (rs-fMRI) procedure (at sites where this procedure is 
available) with a paradigm-free procedure (Greicius et al. 2004; Filippi and Agosta 
2011).  Increased concentrations of A in the brains of participants with AD contribute to 
neuronal degeneration in the brain over time and have been associated with reduced 
functional connectivity of various brain networks using rs-fMRI (Sheline et al. 2010; 
Binnewijzend et al. 2012; Brier et al. 2012; Sheline and Raichle 2013).  Resting-state 
functional connectivity has been found to be decreased in brain regions such as the 


 
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hippocampus, the default mode network (regions such as precuneus, anterior cingulate, 
and parietal and temporal cortices), and cortical regions in which the functional 
connectivity is continuously decreased as disease progresses.  It has also been found to 
be decreased in cognitively normal elderly participants with brain amyloid deposition 
(Pittsburgh compound B  PET scans).  Alteration of the decreased brain functional 
connectivity has been shown using therapeutic interventions such as memantine 
(Lorenzi et al. 2011) or donepezil in participants with AD (Goveas et al. 2011; 
Solé-Padullés et al. 2013).  Increased brain functional connectivity was found already 
after 3 months of treatment with donepezil, which correlated with changes in cognitive 
measures such as the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog; 
Goveas et al. 2011; Solé-Padullés et al. 2013).  Therefore, therapeutic interventions, 
which act to remove A from the brains of participants with AD, may help to reverse the 
altered functional connectivity presumably caused by the accumulation of A in the 
brain. 
The integrity of white matter tracts will be assessed prior to and after treatment with 
gantenerumab using diffusion tensor imaging (DTI)-MRI techniques.  The DTI-MRI is 
based on the measurement of diffusion properties of water molecules in the axonal fiber 
tracts in white matter.  Whereas water molecules can diffuse isotropically in CSF, they 
are restricted axially in white matter bundles.  Widespread group differences in the 
degree of anisotropic diffusion, or fractional anisotropy (FA), has been seen between 
patients with AD and healthy subjects (Jack et al. 2015).  Greater FA values are thought 
to indicate greater white matter integrity.  Likewise, mean diffusivity, which measures the 
average rate of diffusion in all directions, has been shown to be higher in AD groups 
compared with healthy controls, presumably owing to increased white matter injury in 
patients with AD (Nir et al. 2013).  
At sites having the required software and hardware, rs-fMRI (BOLD rs-fMRI) and 
DTI-MRI will be performed when feasible during the same scanning session as the 
structural MRI to assess functional brain connectivity and fiber tract integrity before and 
after treatment with gantenerumab. 
3.3.8.3 
Blood Biomarkers 
AD is a heterogeneous disease.  Therefore, all participants may not be equally likely to 
benefit from treatment with gantenerumab.  Predictive biomarker samples collected prior 
to dosing will be assessed in an effort to identify those participants who are most likely to 
respond to gantenerumab.  PD biomarkers will be assessed to demonstrate evidence of 
biologic activity of gantenerumab in participants, to support selection of a recommended 
dose and dosing regimen, and to inform potential revisions to the PK sample collection 
schedule.  Further details on biomarkers are described in Section 4.5.10.4. 
Exploratory research on safety biomarkers may be conducted to support future drug 
development.  Research may include further characterization of a safety biomarker or 
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adverse events or can lead to improved adverse event monitoring or investigation.  For 
this study, 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 for this study. 
3.3.9 
Rationale for Home Administration Questionnaire 
Administering an injection at home will be a new experience for many caregivers and it is 
important to gather feedback on their comfort level doing so.  The home administration 
questionnaire will capture confidence, ease of use, convenience, and overall satisfaction 
with administering the medication from the study partner (non-professional caregiver) 
perspective (as a secondary outcome) and convenience and satisfaction from the patient 
perspective (as an exploratory outcome).  Patients with more advanced disease may 
have difficulty responding to questionnaires and their responses may not be reliable.  
Nevertheless, the study will attempt to capture responses from all patients.  It may be 
necessary to limit analysis of this endpoint to patients who are more cognitively able.  
4. 
MATERIALS AND METHODS  
4.1 
PARTICIPANTS 
This study has enrolled 192 participants with increased brain amyloid burden (defined 
according to PET criteria), objective memory impairment indicated by cognitive 
assessment, and a diagnosis of probable AD or prodromal AD based on relevant 
NIA-AA criteria during the global enrollment phase.  Additional criteria are defined in 
Sections 4.1.1 and 4.1.2. 
An increase in sample size may be considered in the event of changes to the sample 
size assumptions on the basis of data review or factors external to the study. 
4.1.1 
Inclusion Criteria 
Participants must meet the following criteria for study entry: 
 
Ability to provide written consent signed by the participant (co-signed by the 
participant’s legally authorized representative, if required by the local regulations, 
guidelines, and independent Ethics Committee [EC] or Institutional Review Board 
[IRB]) 
 
Age 5090 years old at screening, inclusive 
 
Probable AD dementia (consistent with NIA-AA core clinical criteria for probable AD 
dementia; McKhann et al. 2011) or prodromal AD (consistent with the NIA-AA 


 
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diagnostic criteria and guidelines for mild cognitive decline due to AD; 
Albert et al. 2011)  
 
Availability of a person (referred to as the study partner [non-professional caregiver] 
throughout this protocol) who: 
- 
Agrees to participate throughout the duration of study 
- 
Has sufficient cognitive and physical capacity including visual, auditory, and 
motor functioning, and is willing and capable of administering SC injections, as 
determined by the investigator (exceptions can be made for participants for 
which weekly clinic visits or weekly HN visits are possible) 
- 
In the investigator’s judgment, has frequent and sufficient contact (e.g., 5 times 
per week or approximately 10 hours per week) with the participant  
- 
In the investigator’s judgment, is able to provide accurate information regarding 
the participant’s cognitive and functional abilities, agrees to provide information 
at clinic visits (which requires study partner (non-professional caregiver) input 
for scale completion), and signs the necessary consent form. 
- 
Is fluent in the language used at the site and 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 study duration. 
Every effort should be made to have same study partner (non-professional 
caregiver) participate throughout the duration of the study.  
 
Fluency in the language of the tests used at the study site 
 
Willingness and ability to complete all aspects of the study (including MRI, clinical 
genotyping, and PET imaging) 
The participant should be capable of completing assessments either alone or 
with the help of the study partner (non-professional caregiver). 
 
Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to 
perform the neuropsychological testing (eye glasses and hearing aids are permitted) 
 
Evidence of AD pathological process, as confirmed by amyloid PET scan by 
qualitative read by the core/central PET laboratory 
 
Prodromal or mild symptomatology, as defined by a screening MMSE score  22 
and CDR-GS of 0.5 or 1.0, as well as a CDR memory domain score  0.5  
 
If the participant is receiving symptomatic AD medications, a stable dosing regimen 
for at least 3 months prior to screening and until start of study treatment 
 
Agreement not to donate blood or blood products for transfusion for the duration of 
the study and for 1 year after final dose of study drug 
 
Agreement not to participate in other research studies for the duration of this trial, 
unless these are related Roche-sponsored non-interventional studies. 
 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
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of  1% per year during the treatment period and for at least 16 weeks after the final 
dose of study drug 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or regulations.  
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
participant.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
If required per local guidelines or regulations, locally recognized adequate 
methods of contraception and information about the reliability of abstinence will 
be described in the local Informed Consent Form. 
 
4.1.2 
Exclusion Criteria 
4.1.2.1 
Exclusions Related to Central Nervous System Disorders 
Participants who meet any of the following criteria related to CNS disorders will be 
excluded from study entry: 
 
Any evidence of a condition other than AD that may affect cognition, including, but 
not limited to, frontotemporal dementia, dementia with Lewy bodies, vascular 
dementia, Parkinson disease, corticobasal syndrome, Creutzfeldt-Jakob disease, 
progressive supranuclear palsy, frontotemporal lobar degeneration, Huntington 
disease, normal pressure hydrocephalus, seizure disorder, delirium, or hypoxia 
 
History or presence of clinically evident systemic vascular disease (e.g., clinically 
significant carotid/vertebral artery stenosis or plaque, aortic aneurysm) that in the 
opinion of the investigator has the potential to affect cognitive function 
 
History or presence of clinically evident cerebrovascular disease (e.g., intracranial or 
cerebral vascular malformations, aneurysm, intracranial macrohemorrhage)  
Participants with asymptomatic developmental venous anomalies may be 
eligible after discussion with the Medical Monitor. 
 
History or presence of posterior reversible encephalopathy syndrome 
 
 


 
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 
History or presence of any stroke with clinical symptoms within the past 12 months, 
or documented history within the last 6 months of an acute event that is consistent, 
in the opinion of the investigator, with a transient ischemic attack 
 
History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) CNS trauma (e.g., cerebral contusion) 
 
History or presence of intracranial mass (e.g., glioma, meningioma) that could 
potentially impair cognition 
 
Presence of infections that affect brain function or history of infections that resulted 
in neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, and viral or bacterial 
meningitis and encephalitis) 
 
History or presence of systemic autoimmune disorders that potentially cause 
progressive neurologic disease with associated cognitive deficits (e.g., multiple 
sclerosis, lupus erythematosus, anti-phospholipid antibody syndrome, and 
Behçet disease) 
 
History of schizophrenia, schizoaffective disorder, major depression, or 
bipolar disorder 
History of major depression is acceptable if participant has had no episode 
within the past year or is considered in remission, or depression is controlled by 
treatment. 
 
At risk for suicide in the opinion of the investigator 
 
Alcohol and/or substance abuse or dependence (according to the criteria specified 
in the Diagnostic and Statistical Manual of Mental Disorders, Version 5) within the 
past 2 years  
Nicotine use is allowed. 
Marijuana use is not allowed and must be discontinued at least 3 months before 
screening. 
 
4.1.2.2 
Imaging-Related Criteria 
Participants who meet any of the following imaging criteria will be excluded from study 
entry: 
 
According to the central MRI reader, MRI evidence of any of the following:  
- 
 2 lacunar infarcts 
- 
Any territorial infarct  1 cm3 
- 
Any white matter lesion that corresponds to an overall Fazekas score of 3 that 
requires at least one confluent hyperintense lesion on the FLAIR sequence, 
which is  20 mm in any dimension 
 
More than five combined microbleeds and areas of leptomeningeal hemosiderosis 
(i.e., cumulative ARIA-H) on MRI (and not including any disseminated 


 
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leptomeningeal hemosiderosis) based on the review performed by the central 
reader prior to start of study treatment 
 
Presence of any other significant cerebral abnormalities, including ARIA-E, as 
assessed on MRI 
 
Inability to tolerate MRI procedures or 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 eyes, skin, or 
body that would contraindicate an MRI scan, or any other clinical history or 
examination finding that, in the judgment of the investigator, would pose a potential 
hazard in combination with MRI 
 
4.1.2.3 
Cardiovascular Disorders 
Participants who meet any of the following criteria related to cardiovascular disorders will 
be excluded from study entry: 
 
History or presence of clinically symptomatic atrial fibrillation requiring maintenance 
therapy  
Participants who experienced non-valvular atrial fibrillation that resolved more 
than 1 year ago and was not associated with prior stroke are eligible. 
 
Within the last year, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction) 
Heart failure classified as New York Heart Association Class I or II cardiac 
disease is allowed if not associated with hospitalization within the previous 
12 months. 
 
Uncontrolled hypertension (e.g., blood pressure generally  160 mmHg systolic 
or  95 mmHg diastolic) 
 
4.1.2.4 
Hepatic and Renal Disorders 
Participants who meet any of the following criteria related to hepatic and renal disorders 
will be excluded from study entry: 
 
Chronic kidney disease, indicated by creatinine clearance  30 mL/min to be 
calculated by the central laboratory using the Cockcroft-Gault formula 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  
 
4.1.2.5 
Infections and Immune Disorders 
Participants who meet any of the following criteria related to infections and immune 
disorders will be excluded from study entry: 
 
History of, or known to currently have HIV infection, or hepatitis B or hepatitis C 
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history of spirochete infection of the CNS (e.g., syphilis, Lyme disease, or 
borreliosis) 
 
Systemically, clinically significantly immunocompromised participants, owing to 
continuing effects of immune-suppressing medication 
 
4.1.2.6 
Metabolic and Endocrine Disorders 
Participants who meet any of the following criteria related to metabolic and endocrine 
disorders will be excluded from study entry: 
 
Abnormal thyroid function as indicated by abnormal screening tests that are judged 
to be clinically significant by the investigator, or abnormal thyroid function that 
requires a new treatment or an adjustment of current treatment 
A participant may be re-screened if there is no improvement in cognition in the 
investigator's judgment after 3 months of adequate treatment for thyroid 
function. 
 
Participants with evidence of folic acid deficiency (as indicated by folic acid level 
below the lower limit of normal) or vitamin B-12 deficiency (as indicated by 
vitamin B-12 level below the lower limit of normal and/or methylmalonic acid levels 
above ULN) 
A participant may be re-screened if there is no improvement in cognition after 
3 months of adequate treatment for folic acid or vitamin B-12 deficiency. 
 
Screening hemoglobin A1c (HbA1c)  8% (retesting is permitted if slightly elevated) or 
poorly controlled insulin-dependent diabetes (including hypoglycemic episodes) 
A participant may be re-screened after 3 months to allow optimization of 
diabetic control. 
 
4.1.2.7 
Exclusions Related to Medications 
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 or active immunotherapy (vaccine) 
that is being evaluated to prevent or postpone cognitive decline 
 
Any passive immunotherapy (immunoglobulin) or other long-acting biologic agent 
that is under evaluation to prevent or postpone cognitive decline within 1 year of 
screening 
 
Any other investigational treatment within 5 half-lives or 4 months prior to screening, 
whichever is longer 
 
Any previous administration of GV-971 
Participants receiving GV-971 or planning to take GV-971 during the study are 
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 
Any previous treatment with medications specifically intended to treat Parkinson 
symptoms or any other neurodegenerative disorder within 1 year of screening and 
with no plans to initiate such medications prior to study start  
Certain medications are acceptable if the participant is taking the medicine for a 
non-neurodegenerative disorder, such as restless leg disorder 
(e.g., pramipexole). 
 
Typical antipsychotic or neuroleptic medication within 6 months of screening and 
with no planned changes prior to study start except as brief treatment for a 
non-psychiatric indication (e.g., emesis) 
Atypical antipsychotic medications are not allowed except for intermittent short-
term use and will need to be discontinued 2 days or at least 5 -half-lives 
(whichever is longer) prior to any neurocognitive assessment. 
 
Anticoagulation medications within 3 months of screening with no plans to initiate 
any prior to start of study treatment 
Anti-platelet treatments (e.g., aspirin, clopidogrel, and dipyridamol) are 
permitted. 
Short-term, perioperative use of anticoagulant medications will not result in 
permanent discontinuation from the study; however, for any such use it is 
recommended to prospectively seek advice from the Medical Monitor and 
temporary study drug interruption may be required. 
 
Chronic use of opiates or opioids (including long-acting opioid medication) within 
3 months of screening with no plans to initiate any prior to study start  
Intermittent short-term use of short-acting opioid medications for pain is 
permitted except within 2 days or 5 half-lives (whichever is longer) prior to any 
neurocognitive assessment.  
 
Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) 
within 1 month of screening and throughout the study 
 
Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before 
screening and with no plans to initiate any prior to study start 
Intermittent short-term use of benzodiazepines, buspirone, or short-acting 
hypnotic medication for sleep or anxiety is allowed except within 2 days or 
5 half-lives (whichever is longer) prior to any neurocognitive assessment.  
 


 
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4.1.2.8 
Other Exclusions 
Participants who meet any of the following criteria will be excluded from study entry: 
 
Other causes of intellectual disability that may account for cognitive deficits 
observed at screening (e.g., static encephalopathy, closed brain injury, mental 
retardation)  
This may be based on, for example, participant’s sufficient education or 
work experience. 
 
Pregnancy or breastfeeding, or intention of becoming pregnant during the study 
 
Clinically significant abnormal screening blood 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, in the 
opinion of the investigator, 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 of gantenerumab excipients 
 
Any other severe or unstable medical condition that, in the opinion of the 
investigator or Sponsor, could be expected to progress, recur, or change to such an 
extent that it could put the participant at special risk, bias the assessment of the 
clinical or mental status of the participant to a significant degree, interfere with the 
participant’s ability to complete the study assessments, or would require the 
equivalent of institutional or hospital care 
 
Residence in a skilled nursing facility such as a convalescent home or long-term 
care facility 
Participants who subsequently require residence in such facilities during the 
study may continue in the study and be followed for PD and safety data, 
provided that they have a study partner (non-professional caregiver) who meets 
the minimum requirement. 
 
Planned or recent (within 12 months prior to screening) exposure to ionizing 
radiation that in combination with the planned administrations of the radioligand 
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4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment  
This is a non-randomized, open-label study.  After initial 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 assignment from an interactive voice or web-based 
response system (IxRS). 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is gantenerumab. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
Gantenerumab  
Gantenerumab will be supplied by the Sponsor as liquid formulation for SC 
administration.  Packaging of the study drug will be overseen by the Roche Clinical Trial 
Supplies Department and will bear a label with the identification required by local law, 
the protocol number, study drug identification, and dose.  The packaging and labeling 
will be in accordance with Roche standard and local regulations.  Upon receipt of the 
investigational products at the site, site personnel should check the product for damage 
and verify the proper identity, quantity, and integrity of the study drug.  Site personnel 
should report any deviations or product complaints to the monitor upon discovery.  For 
further details, please refer to the Gantenerumab Investigator’s Brochure. 
For information on the formulation and handling of gantenerumab, see the pharmacy 
manual and Gantenerumab Investigator’s Brochure. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
Refer to the pharmacy manual and other applicable manuals for detailed instructions on 
drug preparation, storage, and administration. 
Study treatment may be administered by a study partner (non-professional caregiver) at 
the participant's home or another suitable location depending on the individual 
participant/study partner (non-professional caregiver) suitability.  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 required for non-professional caregivers).  During the course of the study, an 
autoinjector may become available in participating countries, if approved by local 
health authorities and IRBs.  Use of this device will be optional for participants who 
receive study treatment administration at home or at the site. Study treatment may also 
be administered by a trained nursing professional at the participant's home or another 
suitable location, if the participant has given written informed consent to participate in 
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Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of overdose, 
medication error, drug abuse, or drug misuse, along with any associated adverse 
events, should be reported as described in Section 5.3.5.13.  If applicable, study 
partners (non-professional caregivers) will confirm completed administration in the home 
(non-clinic) setting using a caregiver diary (including date, time, correct injection location, 
and amount).  Further details will be described in the Caregiver Manual. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
participants who experience adverse events are provided in Section 5.1.3.1. 
4.3.2.1 
Gantenerumab 
Gantenerumab will be administered by SC injection, at a dose of 120 mg Q4W (Day 1, 
Week 4, and Week 8), then 255 mg Q4W (Weeks 12, 16, and 20), and then 255 mg 
Q2W for 12 weeks (Weeks 24, 26, 28, 30, 32, and 34), followed by the target dose 
255 mg Q1W (Weeks 36207).  Before reaching the maximum target dose (i.e., 255 mg 
Q1W), a minimum of three doses during the 120-mg Q4W and 255-mg Q4W dosing 
periods, and a minimum of six doses during the 255-mg Q2W dosing period must be 
administered prior to uptitration. 
The dosing schedule is shown Appendix 1. 
Depending on the site and individual participant/caregiver suitability, participants will 
have the option to receive SC injections of gantenerumab at the site and (after a defined 
period of appropriate training and supervision of a caregiver) at home by study staff, 
home nurse, or study partner (non-professional caregiver). 
Participants will receive SC injections of gantenerumab by the investigator or an 
appointed qualified study staff for the first three doses of gantenerumab at the clinic.  If 
participants have a study partner (non-professional caregiver) who is willing and judged 
capable of administering SC injections, this caregiver will receive training and observe 
dose administration at the first three dosing visits (i.e., Day 1, Week 4, and Week 8), and 
the injections will be done by the caregiver under staff supervision at the next four visits 
(i.e., Weeks 12, 16, 20, and 24).  Following this supervised dosing at the clinic, 
subsequent dosing may be administered by the caregiver at home except for doses that 
coincide with a clinic visit, in which case the caregiver should administer the injection in 
clinic under investigator/study staff supervision.  Study staff will document the outcome 
of the supervised administration.  
The investigator will determine whether the participant is suitable for home 
administration by the study partner (non-professional caregiver), a home nurse, or 
appropriate study staff (according to local regulations).  


 
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At subsequent visits as specified in the Appendix 1, the investigator will determine if the 
study partner (non-professional caregiver) continues to be suitable to perform home 
administration.  If at any time the investigator or caregiver determines that home 
administration by the caregiver is unsuitable, then study drug must be administered at 
home or in the clinic by a home nurse or study staff.  
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/or caregiver to elicit, in a non-leading way, information on medication errors and 
adverse events that may have occurred in the home setting.  Therefore, there will be 
contact between the study staff and the participant/caregiver at least Q4W.  The study 
staff is encouraged to have more frequent calls with a particular participant/caregiver if 
considered appropriate by the investigator.  In addition, participants/caregivers will 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, or 
medication errors. 
Training and supportive materials will be provided to the site and to the study partner 
(non-professional caregiver).  Following the in-person instructional training and 
supervised administration at the site, adequate supply of gantenerumab will be provided. 
For Q4W injections, a time window of  7 days is allowed for dosing.  For Q4W injections, 
the recommended minimum time between doses is 3 weeks.  The maximum 
recommended time between doses should not exceed 6 weeks.  For both the 
Q2W injections and Q1W injections, the time window for dosing is  3 days.  If the 
administration is not possible on the scheduled dosing day, the study medication 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 medication dosing resumed in accordance with the original dosing 
schedule.  Always return to the initial planned schedule or subsequent dose/visits. 
Regardless of dose, each participant will undergo up to a total of 80 dosing visits and 
home administrations as applicable in the study.  Injections will be administered as one 
0.8-mL (120-mg) dose or one 1.7-mL (255-mg) dose subcutaneously to the abdomen. 
4.3.3 
Positron Emission Tomography Tracers  
All participants who are otherwise eligible at screening will be assessed for the presence 
of brain amyloid consistent with AD by PET imaging.  The permitted amyloid PET 
ligands will be florbetaben (all sites) and flutemetamol (in exceptional circumstances, the 
use of flutemetamol may be acceptable at sites where florbetaben is not available, but 
only after prior written approval from the Sponsor).  Florbetaben or flutemetamol will be 
provided in accordance with approved national and/or local standards.  


 
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According to E.U. guidance, PET tracers, as used in the context of this study, are 
designated as non-IMP.  In some regions, according to local regulations, these PET 
tracers may be considered to be an IMP.  In countries where the PET radioligands are 
approved for marketing, the approved local product information will be provided, and in 
countries where they are not approved for marketing, the Investigator’s Brochures will be 
provided.   
For the safety reporting requirements dealing with the PET tracers used in this study, 
please refer to Section 5.7. 
4.3.4 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study will be provided by the Sponsor where 
required by local regulations.  The study site (i.e., investigator or other authorized 
personnel [e.g., pharmacist or home nurse]) is responsible for maintaining records of 
IMP delivery to the site, IMP inventory at the site, IMP use by each participant, IMP 
distribution to each participant, and disposition or return of unused IMP, thus enabling 
reconciliation of all IMP received and ensuring that participants are provided with doses 
specified by the protocol.  Used and unused IMP distributed to each participant will be 
returned by participant’s study partner (non-professional caregiver) to the study site and 
appropriately accounted for. 
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, using the 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 at the site and that any 
discrepancies have been reported and resolved before use of the IMPs.  All IMPs 
shipped to the site 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.  Participants will 
be provided with storage instructions for home dosing. 
For home dosing, study drug must be transported from the site to the participant’s home 
by the participant, caregiver, or a Sponsor-approved courier service, per local 
requirements.  If transported by the participant or caregiver, the study drug must be 
placed in a cooler with an ice pack to maintain the appropriate storage temperature.  The 
cooler and ice pack for study drug transport will be provided by the Sponsor or designee.  
Only participants enrolled in the study may receive the IMP, and only authorized staff 
may supply the IMP, and only authorized staff and study partners (non-professional 
caregivers) may administer the IMP. 


 
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The IMP 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. 
Refer to the pharmacy manual and/or the home administration manual and 
Gantenerumab Investigator's Brochure for information on IMP handling, including 
preparation and storage, and accountability.  
4.3.5 
Continued Access to Gantenerumab 
The Sponsor will offer continued access to Sponsor study drug (gantenerumab) free of 
charge to eligible participants in accordance with the Roche Global Policy on Continued 
Access to Investigational Medicinal Product, as outlined below. 
 
A participant will be eligible to receive Sponsor study drug (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 Sponsor study drug 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 Sponsor study drug (gantenerumab) after 
completing the study if any of the following conditions are met: 
 
The Sponsor study drug 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 drug or data suggest that the 
drug is not effective for AD. 
 
The Sponsor has reasonable safety concerns regarding the drug as treatment 
for AD. 
 
Provision of the drug is not permitted under the laws and regulations of the 
participant's country. 
 
Participant is eligible to enroll in an ongoing gantenerumab open-label study. 
 


 
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The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
Eligible participants may qualify for continued access or ongoing extension studies as 
outlined above. 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
participant from 3 months prior to screening to the study completion or discontinuation 
visit.  All such medications (including name, dose, administration schedule, start and end 
dates) should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  
4.4.1 
Permitted Therapy  
Participants are eligible for study participation whether or not they are receiving 
approved medication for AD (i.e., acetylcholinesterase inhibitors, memantine, and/or 
medical food supplements, where approved) with the exception of GV-971.  Participants 
who are receiving GV-971 or who are planning to receive GV-971 during the study are 
not eligible.  Information about background AD medication (e.g., drug name, dose, and 
start and stop dates, reason for interruption or modification) has to be captured on 
eCRF.   
Adding a new medication or changing the dose of a medication after start of study 
treatment should occur only for the treatment of an adverse event or in case of AD 
progression.  Whenever possible, a medication listed below should be used if 
appropriate. 
The following medications are permitted if the dose and dose regimen have been stable 
for at least 3 months prior to screening 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 for the treatment of depressive symptoms 
 
Over-the-counter and/or herbal medications, food additive, or any other agent or 
supplement intended to improve cognition or reduce cognitive decline 
 
Medications used to treat a mood or anxiety disorder given as 
maintenance treatment (with the exception of benzodiazepine) 
 
Intermittent use of short-acting (non-extended release) opioid medications for pain 
except within 2 days or 5 half-lives (whichever is the longer) of any cognitive 
assessment (up to a maximum of 3 consecutive days per month)  


 
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 
Intermittent use of benzodiazepines, including alprazolam, lorazepam, oxazepam, 
triazolam, or temazepam, or a one-time dose of diazepam or a short-acting hypnotic 
medication (e.g., zolpidem) if use is intermittent for sleep or anxiety, except within 
2 days or 5 half-lives (whichever is the longer) prior to any cognitive assessment 
 
A dose of benzodiazepine for pre-surgical and pre-imaging sedation at appropriate 
visits if allowed by the EC or IRB 
 
Intermittent use of centrally acting antihistamine medications except within 2 days or 
5 half-lives (whichever is the longer) prior to any cognitive assessment 
 
Under certain circumstances, initiation of anti-hemostasis medications during the 
study conduct 
Anticoagulation therapy lasting no longer than 3 weeks (e.g., temporary usage 
during surgery) is permitted.  Nevertheless, anticoagulation therapy may require 
temporary study drug interruption and advice from the Medical Monitor is 
recommended. 
 
Concomitant and excluded therapies for determination of participant eligibility are 
described in Section 4.1.2.7. 
Participants who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
4.4.2 
Prohibited Therapy 
Any medication that is prohibited before screening is also prohibited during conduct of 
the study (see Section 4.1.2.7).  If a participant receives any prohibited treatment during 
the study, the participant may be withdrawn from study treatment. 
4.5 
STUDY ASSESSMENTS  
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each participant. 
At applicable sites, certain study procedures may be performed by a HN professional at 
the participant's home or another suitable location to improve access and convenience 
for participants participating in the study.  The Sponsor has selected a healthcare 
company that is responsible for providing HN services for participating sites (the 
HN vendor).  The HN vendor is responsible for ensuring that all HN 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 HN services are appropriate for a participant and the 
participant gives written informed consent to participate in HN visits, the HN network 
communicates with the participant and the participant’s site.  The HN visits are 
scheduled on specified visit days to allow relevant procedures to be performed by the 
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4.5.1 
Informed Consent Forms and Screening Log 
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 (including screening evaluations).  Informed Consent 
Forms for enrolled participants and their study partners (non-professional caregivers) 
and for those who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that participants 
meet all eligibility criteria before enrollment.  The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
4.5.2 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
and use of alcohol and drugs of abuse.  In addition, all medications (e.g., prescription 
drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) 
used by the participant within 3 months prior to screening visit will be recorded.  
Demographic data will include age, sex, and self-reported race/ethnicity.  Medical history 
and demographic data will be collected at the screening visit only. 
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).  
4.5.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatologic, musculoskeletal, respiratory, 
gastrointestinal, genitourinary (optional), and neurologic systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
The schedule of activities indicates when complete physical examinations (including 
neurologic systems) are to be recorded (see Appendix 1). 
Limited, symptom-directed physical examinations should be performed per the schedule 
of activities (or as clinically indicated).  Changes from baseline abnormalities should be 
recorded in participant notes.  New or worsened clinically significant abnormalities 
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4.5.4 
Vital Signs 
Vital signs will include measurements of pulse rate and systolic and diastolic blood 
pressure.  Blood pressure and pulse rate should be taken when the participant is at rest 
and should not be measured unless at least 15 minutes have elapsed since the last 
blood draw.  The same arm should be used for all blood pressure measurements.  
Pulse rate will be determined and will be recorded as beats per minute.  If obtained 
manually, the pulse rate should be counted for a minimum of 20 seconds at each 
assessment. 
The schedule of activities indicates when vital signs (blood pressure and pulse rate) are 
to be recorded (see Appendix 1). 
4.5.5 
Positron Emission Tomography Scan 
Two radioligands may be used in this study:  florbetaben for participants at all sites (in 
exceptional circumstances, the use of flutemetamol may be acceptable at sites where 
florbetaben is not available, but only after prior written approval from the Sponsor). 
Screening PET scans must not be acquired prior to the availability of potentially 
exclusionary screening results in order to minimize radiation burden to participants.  To 
allow sufficient flexibility for scheduling of the screening PET scan, screening procedures 
(including central reading of the MRI scans) ideally should be completed within 
23 weeks before the screening PET scan is required. 
A positive PET scan using any amyloid tracer, acquired outside this study protocol is not 
permissible to confirm participant inclusion due to the longitudinal PET imaging 
requirements for all subjects enrolled in this study. 
After obtaining the signed Informed Consent Form at the clinical study site, the following 
assessments and procedures will be performed for all participants during each amyloid 
PET scanning session: 
 
The responsible physician or his or her designee at the PET imaging center will 
confirm a participant’s suitability for undergoing the PET imaging after a brief 
medical assessment, which may include weight.  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. 
 
The participant must void his or her bladder prior to scanning. 
 
Placement of an IV catheter into a forearm or antecubital vein for the injection of the 
investigational PET tracer must occur. 
 
A target dose of 300 [ 10%] MBq for florbetaben or 185 [ 10%] MBq for 
flutemetamol will be administered intravenously as a single slow bolus.  The cannula 


 
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will be immediately flushed with up to 515 mL of saline solution.  It is recognized 
that due to scheduling, transit, or manufacturing issues, from time to time, it is 
possible that an imaging center may be delivered a dose of amyloid radioligand that 
is less than the target dose.  In these cases, participants may still be injected.  
However, if the dose is  70% of the target dose, no injection should be performed 
and the participant should be rescheduled for imaging. 
 
A head fixation system (which may vary between the participating imaging centers) 
will be used.  Each participant will be placed horizontally with his or her head 
positioned in the PET camera’s field of view. 
 
A computed tomography (CT) or radioisotope transmission scan, for attenuation 
correction, should be performed prior to or immediately following the PET emission 
scan, using a low-dose CT or isotope transmission scan and encompass the entire 
head to include the brain from most superior cortical regions through the inferior 
portion of the cerebellum. 
 
At selected sites using florbetaben that can support dynamic imaging and imaging 
starting at the time of tracer injection, an optional early-frame PET scan of up to 
60 minutes in length will be acquired as soon as the infusion 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. 
 
After an uptake period targeting 90 ( 1) minutes, and at most 90 ( 5) minutes after 
administration of amyloid radioligand, the 20-minute brain PET imaging will begin. 
 
The participant will be discharged after a physician or designee has been assured of 
the participant’s well-being. 
 
Detailed instructions regarding the procedures for PET scan methodology, including 
scanning procedures can be found in the PET Technical Operations Manual. 
4.5.6 
Home Administration Assessments 
The assessments described in this section will be performed as outlined in the schedule 
of activities (see Appendix 1) and in the order specified in Section 4.6. 
Whenever possible, there should be consistency in the rater and study partner 
(non-professional caregiver) who complete the scales for each participant throughout the 
duration of the study.  Potential raters will receive training and be approved by the rating 
scale contract research organization (CRO) prior to being allowed to administer any 
cognitive assessments or rating scales in the study.  
Whenever possible, cognitive and functional assessments should be performed at the 
visit timepoints indicated in the schedule of activities (see Appendix 1).  However, in 
exceptional circumstances for post-Day 1 visits, if the study partner (non-professional 
caregiver), the primary rater, or even the participant cannot perform these assessments 
as per the schedule of activities, they may be performed up to 4 weeks out of window.  


 
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Given that cognitive and functional assessments used for eligibility and as exploratory 
outcome measures in this trial involve subjective judgment, the adequacy of participant 
and study partner (non-professional caregiver) interviews and ratings will be monitored 
by an endpoint reliability program administered by the rating scale vendor; this is 
considered an essential part of good research methodology.  For some eligibility 
assessments as well as for some other scales, audio recordings may be used for quality 
assurance purposes.  Prior studies have clearly demonstrated that the failure to 
adequately monitor such ratings can substantially increase the risks of failed trials 
(Becker and Greig 2008; Kobak 2010).  
4.5.6.1 
Clinical Dementia Rating Scale  
The CDR-GS characterizes a participant’s level of impairment according to the following 
categories:  0 (normal), 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate 
dementia), and 3 (severe dementia).  The Sum of Boxes score is a detailed quantitative 
general index that provides more information than the CDR-GS in patients with mild 
dementia (Berg 1988; Morris et al. 2001; O'Bryant et al. 2010) and is scored from 0 to 18 
with higher scores indicating greater impairment.  The CDR characterizes six domains:  
memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care.  The necessary information to make each rating is obtained 
through a semi-structured interview with the participant and a reliable informant or 
collateral source (e.g., a study partner [non-professional caregiver]). 
As much as is feasible, the CDR should be administered to an individual participant by 
the same assessor throughout the study and that assessor should not perform the 
MMSE, ADAS-Cog, Verbal Fluency Task, Coding, or Alzheimer’s Disease Cooperative 
Study GroupActivities of Daily Living (ADCS-ADL).  However, if in exceptional 
circumstances only this assessor is available to perform these other scales, then the 
CDR participant interview must be completed after the study partner (non-professional 
caregiver) interview but before ADAS-Cog, MMSE, Verbal Fluency Task, Coding, and 
other scales are completed.  Nevertheless, at screening, baseline, and Week 104, the 
CDR rater cannot perform other scales than the CDR.  In addition, the CDR rater should 
not be involved in safety assessments and especially should not receive information 
about any ARIA findings.  
4.5.6.2 
Alzheimer’s Disease Assessment ScaleCognitive Subscale 
The ADAS-Cog is the most frequently used scale to assess cognition in clinical trials for 
mild to moderate AD dementia (Rozzini et al. 2007; Connor and Sabbagh 2008; 
Ihl et al. 2012).  More specifically, the ADAS-Cog is a patient-based assessment that 
measures learning and memory, language production, language comprehension, 
constructional praxis, ideational praxis, and orientation.  The modified version will be 
used; it has 13 items and includes the addition of delayed word recall and a number of 
cancellation subtests, as well as use of only one trial for word recognition 
(Mohs et al. 1997).  Equivalent alternate forms of the word recall, word recognition, and 
number cancellation subtests will be used in successive test administrations.  


 
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4.5.6.3 
Mini-Mental State Examination 
The MMSE is a set of standardized questions used to evaluate possible cognitive 
impairment and help stage the severity level of this impairment (Folstein et al. 1975).  
The questions target six areas:  orientation, registration, attention, short-term recall, 
language, and constructional praxis/visuospatial abilities.  The MMSE is a patient-based 
assessment. 
4.5.6.4 
Verbal Fluency Task  
The category verbal fluency (e.g., animals) is a patient-based assessment that 
measures speed and flexibility of verbal thought.  Verbal fluency tests are sensitive tools 
for detecting dementia (Pasquier et al. 1995; Lezak et al. 2004) and for monitoring 
decline over time (Clark et al. 2009).  
4.5.6.5 
Coding 
The Coding, also called Digit Symbol Substitution Test (or DSST), is a subtest from the 
Wechsler Adult Intelligence ScaleFourth Edition (WAISIV; Wechsler 2008).  The 
Coding is a patient-based assessment that measures speed of processing and 
associative memory.  The test is known to be sensitive to disease progression 
(Lezak et al. 2004).  The 120-second version of the test will be used in this study. 
4.5.6.6 
Alzheimer’s Disease Cooperative StudyActivities of Daily 
Living Inventory  
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in patients with AD (Vellas et al. 2008).  The ADCS-ADL is a 23-item 
informant-based questionnaire that covers both basic activities of daily living (ADL) 
(e.g., eating and toileting) and more complex ADL or instrumental ADL (e.g., using the 
telephone, managing finances, preparing a meal).  It has a 4-week recall period.  Total 
scores range from 0 to 78, with higher scores indicating better functioning. 
4.5.6.7 
Home Administration Questionnaire 
The home administration questionnaire will be completed at site visits as specified in 
Appendix 1, and comprises 4 items to be completed by study partner (non-professional 
caregiver) and 2 items to be completed by participants.  The Caregiver portion of the 
questionnaire includes confidence with administration, convenience, ease of use, and 
overall satisfaction.  Each item is rated on a 4-point verbal Likert scale and respondents 
will be asked to consider their most recent at home administration in answering these 
questions.  Participants will complete satisfaction and convenience items with the same 
response options.  Responses to this questionnaire may be captured electronically and 
transferred to the database directly from the core laboratory. 
4.5.6.8 
Electronic Assessment of Rating Scales 
The following rating scales will be captured electronically and transferred to the 
database directly from the core laboratory:  ADAS-Cog, Verbal Fluency Task, Coding, 
ADCS-ADL, CDR, MMSE, and C-SSRS. 


 
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4.5.7 
Columbia-Suicide Severity Rating Scale 
The C-SSRS (https://cssrs.columbia.edu/) is an assessment tool used to assess the 
lifetime suicidality of a patient (C-SSRS at baseline) as well as any new instances of 
suicidality (C-SSRS since last visit).  The structured interview prompts recollection of 
suicidal ideation, including the intensity of the ideation, behavior, and attempts with 
actual or potential lethality.  The C-SSRS baseline will be collected at baseline and the 
C-SSRS since the last visit will be collected at subsequent visits as indicated in the 
schedule of activities (see Appendix 1). 
The assessment will be completed by a certified C-SSRS rater after he or she interviews 
the participant and the participant’s study partner (non-professional caregiver) during the 
study visit. 
4.5.8 
Brain Magnetic Resonance Imaging 
The MRI should be performed using 1.5-T or 3.0-T scanners, and wherever possible the 
same scanner should be used for an individual participant for the full duration of the 
study.  The MRI will be conducted at participant screening for safety monitoring, as a 
baseline measure of structural brain volumes, and as baseline information for the PET 
(for the schedule of activities, see Appendix 1). 
Where available, exploratory MRI techniques including rs-fMRI and DTI will also be 
acquired.  In addition, the screening MRI will be used to help determine whether the 
exclusion criteria are met (e.g., number of microbleeds, presence of mass lesions). 
The MRI will be used during the study to help assess safety such as the 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 a sign that emerges at a scheduled scan; contrast agent 
may be used in such a case of follow-up MRI scans if administration of contrast agent is 
considered safe for the participant according to local standards.  In addition, structural 
MRI (to assess whole brain and regional brain atrophy), fMRI, and DTI-MRI will be 
performed at multiple timepoints to determine potential treatment effects on MRI 
outcome measures (according to the schedule of activities). 
MRI scans will include the following sequences: 
 
3D T1-weighted GRE scans 
 
T2*-weighted GRE scans 
 
T2-weighted FLAIR scans 
 
BOLD rs-fMRI, if available (to assess resting-state functional connectivity at 
investigative sites having the required software and sequences) 
 
DTI-MRI, if available (to assess fiber tract integrity) 
 


 
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For details on the specific imaging sequences and acquisition times required, refer to the 
MRI Manual.  
All images (except BOLD fMRI and DTI-MRI) will be used to assess MRI inclusion and 
exclusion criteria. 
MRI scans will be reviewed by a central MRI core laboratory, which will perform the 
diagnostic reads and assessment of MRI outcome measures.  MRI scans should 
preferably be transferred to the central MRI core laboratory electronically.  Data transfer 
from individual study sites to the central MRI core laboratory may take up to 710 days, 
if not done electronically.  Upon receipt of the MRI scans from the study sites, the central 
MRI core laboratory will provide the diagnostic reads.  The MRI results must be made 
available to investigators prior to next dosing or prior to the Week 104 visit (refer to 
Section 5.1.3 for additional details on MRI safety management). 
MRI facility qualification and scan quality control will be performed by the central MRI 
core laboratory.  
Additional instructions regarding the procedures for MRI scan acquisition and transmittal 
to the central reading facility can be found in the MRI Manual. 
4.5.9 
Healthy Volunteer Magnetic Resonance Imaging Scans for Site 
Qualification 
As part of site qualification, one to two volunteers (preferably two) at each site should be 
recruited and scanned using the same machine and the same sequences to be used for 
site qualification before any participant is scanned in this study.  The choice of healthy 
volunteers is at the discretion of the investigator and/or the imaging center, and the 
volunteer must provide written consent to take part in the scanning calibration.  
Volunteers must not have any contraindications for MRI scanning (evaluation per local 
procedures at the imaging site), and they will not be enrolled in the study or undergo any 
other assessments as part of the trial.  If volunteer scans are acquired, they will be 
reviewed for suitable image quality and used for qualitative comparison with additional 
scans with the same volunteer acquired after certain events as follows:  at the time of a 
major upgrade to the site’s scanner, any other event deemed significant enough to affect 
image quality, or per central reader guidance.  This procedure will help ensure 
consistency in scanning quality over the duration of the study.  Two volunteers are ideal 
in case one volunteer is no longer readily available for test scanning.  
Additional instructions regarding the procedures for MRI facility qualification can be 
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4.5.10 
Laboratory, Biomarker, and Other Biological Samples 
4.5.10.1 
Standard Laboratory Samples 
Samples for the following laboratory tests will be sent to a central laboratory or a 
designee for analysis.  Instruction manuals and supply kits will be provided for all central 
laboratory assessments.   
 
Serum chemistry:  AST, ALT, ALP, total protein, total bilirubin, serum albumin, 
creatine phosphokinase, sodium, potassium, calcium, BUN, and serum creatinine 
(and creatinine clearance calculated by the central laboratory) 
HbA1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive 
protein, folic acid, vitamin B-12, methylmalonic acid, T4, free T4, and TSH 
levels will also be assessed according to the schedule of activities. 
 
Hematology:  hemoglobin, hematocrit, RBC count (with morphology), WBC count, 
platelets, basophils, eosinophils, lymphocytes, monocytes, and neutrophils 
 
Screening serology:  HIV, hepatitis B, and hepatitis C 
 
Coagulation:  PT and aPTT 
 
Urine for drugs of abuse:   
At screening only, urine samples will be analyzed for the presence of the 
following drugs:  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. 
 
Urine for pregnancy test 
Urine pregnancy testing will be performed at screening, within 24 hours before 
a PET scan, after the last study drug dose and if a woman is suspected to have 
become pregnant (only for women of childbearing potential including those who 
have had a tubal ligation), and at the site for any other female participants if 
required by local regulations.  If a urine pregnancy test is positive, it must be 
confirmed by a serum pregnancy test at the central laboratory. 
 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual. 
4.5.10.2 
Pharmacokinetic Samples 
Blood samples will be collected for measurement of plasma concentrations of 
gantenerumab as specified in the schedule of activities (see Appendix 1).  


 
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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. 
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. 
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.  
Remaining volumes from these samples may also be used for any further 
RO4909832-related exploratory analyses or assay development/validation experiments. 
An additional PK sample for the assessment of plasma concentrations of gantenerumab 
will be obtained as soon as is practical (e.g., at an unscheduled visit) once the site 
becomes aware of the occurrence or worsening of ARIA-E, or occurrence of ARIA-H 
meeting discontinuation criteria. 
Genetic analyses will not be performed on these plasma samples.  Participant 
confidentiality will be maintained. 
The PK 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). 
4.5.10.3 
Samples for Immunogenicity Analysis 
Antibodies to gantenerumab will be evaluated in plasma samples collected from all 
participants according to the schedule of activities (see Appendix 1).  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.   
The detection of antibodies to gantenerumab will be performed through use of a 
validated assay method under the supervision of the Sponsor.  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) following the last 
participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of immune responses to gantenerumab. 


 
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Remaining volumes from these samples may also be used for further characterization of 
potential immune responses and for any RO4909832-related exploratory analyses or 
assay development/validation experiments. 
4.5.10.4 
Biomarker Samples 
The following biomarker samples will be collected, as applicable, from participants at all 
sites: 
 
Blood samples for genotyping apolipoprotein E gene allele 4 (APOE ε4) status, 
clusterin (apolipoprotein J) genotypes, and FcR genotype 
APOE ε4 status will be determined and will be unblinded to the Sponsor, but 
blinded to the investigator and participant.  Investigators and participants will 
have access to this information if they elect to at the end of the study.  If already 
known, the APOE ε4 status will still need to be confirmed.  In addition, as much 
as possible, participant APOE ε4 status should remain blinded to the site and 
central MRI readers. 
 
Blood samples for RNA extraction 
The sample may be used to evaluate clusterin messenger RNA and other 
exploratory genetic markers in peripheral blood.  
An additional sample 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, or resolved ARIA-E). 
 
Plasma samples for exploratory research on biomarkers and biomarker assay  
The sample may be used to evaluate biomarkers including, but not limited to, 
A, tau, neurofilament light chain, and neurogranin.  
An additional sample 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, or resolved ARIA-E). 
 
Screening blood (for RNA extraction) and plasma 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. 
Biomarker samples will be collected according to the schedule outlined in Appendix 1.  
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 4.5.13), blood and plasma biomarker 


 
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samples will be destroyed no later than 5 years after the final Clinical Study Report has 
been completed. 
When a participant withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the participant specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 
4.5.11 
Electrocardiograms 
Single 12-lead ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1), and may be obtained at unscheduled timepoints 
as indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  The ECG recordings must be 
performed after the participant has been resting in a supine position for at least 
5 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws, and brain MRI scans).  
Circumstances that may induce changes in heart rate, including environmental 
distractions (e.g., television, radio, conversation), should be avoided during the pre-ECG 
resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the participant's 
permanent study file at the site.   
The centrally provided electrocardiograph machine should record the following:  heart 
rate, QRS duration, and RR, PR, and QT intervals and transferred to the Sponsor 
database from the core laboratory. 
4.5.12 
Optional Procedures 
Consenting participants will enter an optional 2-year extension after Week 104 until 
Week 208.  Participants that consent to the optional extension will be required to 


 
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complete the procedures and assessments described in Tables 1-3 and 5-10 in 
Appendix 1. 
The Informed Consent Form will contain a separate section that addresses the optional 
2-year extension.  A separate, specific signature will be required to document a 
participant’s agreement to undergo the optional extension.  The investigator should 
document whether or not the patient has given consent to participate and (if applicable) 
the date(s) of consent, by completing the Informed Consent Form. The investigator 
should document whether or not the study partner has given consent to participate and 
(if applicable) the date(s) of consent, by completing Study Partner Informed Consent 
Form. 
4.5.13 
Optional Samples for Research Biosample Repository 
4.5.13.1 
Overview of the Research Biosample Repository 
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future. 
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.13.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.13.2) 
will not be applicable at that site. 


 
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4.5.13.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to gantenerumab or AD: 
 
Leftover blood from the clinical genotyping sample and clinical RNA sample, plasma 
biomarker sample, and any derivatives thereof (e.g., DNA, RNA, proteins, peptides) 
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via whole genome sequencing (WGS), whole exome sequencing 
(WES), or other genomic analysis methods.  Genomics is increasingly informing 
researcher's understanding of disease pathobiology.  The WGS and the 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 patients 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 RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
4.5.13.4 
Confidentiality 
The RBR samples and associated data will be labeled with a unique participant 
identification number. 
Participant medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
participant, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication. 


 
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Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.13.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of participation in the RBR.  Participants will 
be told that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a participant's agreement to provide optional RBR samples.  
Participants who decline to participate will not provide a separate signature. 
The investigator should document whether or not the participant has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.13.6 
Withdrawal from the Research Biosample Repository 
Participants who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed.  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 Subject Withdrawal Form and must enter the 
date of withdrawal on the RBR Research Sample Withdrawal of Informed Consent 
eCRF.  If a participant wishes to withdraw consent to the testing of his or her RBR 
samples after closure of the site, the investigator must inform the Sponsor by emailing 
the study number and participant number to the following email address: 
global_rcr-withdrawal@roche.com 
A participant's withdrawal from this study does not, by itself, constitute withdrawal of 
consent for testing of RBR samples.  Likewise, a participant's withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from this study. 


 
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4.5.13.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to participant participation in the RBR for the purposes of 
verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples. 
4.6 
TIMING OF STUDY ASSESSMENTS 
4.6.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled participants and for participants who are not subsequently enrolled will be 
maintained at the study site.  After providing written informed consent, participants who 
are willing to participate in the study will undergo all screening assessments within 
8 weeks prior to the baseline visit, as detailed in the schedule of activities 
(see Appendix 1).  Participants must fulfill all the entry criteria for participation in the 
study and the results must be available prior to the baseline visit.  
It is recommended that the MMSE assessment will be completed at first.  In case the 
participant would not qualify based on the MMSE inclusion criteria, re-screening of the 
participant is not allowed. 
In case of an abnormal laboratory or ECG result at screening that may normalize upon 
retest, investigators have the option to repeat the tests (prior to baseline and within the 
8-week screening window) once to confirm the test results before enrolling a participant 
at baseline. 
In rare cases in which a MRI scan needs to be repeated or any other unexpected delay 
due to logistical or technical reasons, the screening period may be extended by some 
days.  Extending the screening period beyond 8 weeks must be approved by the Medical 
Monitor and should be for exceptional circumstances only; careful scheduling should 
remain a priority. 
The recommended order of screening assessments is shown in Figure 5. 


 
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Figure 5 Order of Screening Assessments 
 
ECG  electrocardiogram; MRI  magnetic resonance imaging; PET  positron emission 
tomography. 
 
The recommended order of clinical assessments and rating scales at screening is shown 
below. 
Participant Assessments 
Study Partner (Non-Professional Caregiver) 
Assessments 
1. MMSE  
2. CDR (participant interview) 
CDR (study partner [non-professional caregiver] 
input) 
CDR  Clinical Dementia Rating; MMSE  Mini-Mental State Examination. 
 
PET scan and MRI scan at screening should be performed only once all other screening 
results are available and none exclude the participant from the trial. 
If a participant does not qualify on the basis of applicable tests other than the MMSE, the 
participant may be re-screened again after at least 3 months have elapsed if recruitment 
for the study is still ongoing. 
As noted in the exclusion criteria (see Section 4.1.2), participants may be re-screened 
after appropriate treatment if they were originally excluded for abnormal thyroid, folic 
acid, vitamin B-12, or HbA1c results.  Other laboratory tests that would exclude the 
participant may be repeated once (as an unscheduled laboratory assessment) if it is 
suspected that the abnormal result is transient and likely to be normal on repeat. 


 
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Participants may be re-screened if the protocol is amended such that they would satisfy 
the amended criteria and if recruitment for the study is still ongoing.  In this case, all 
screening assessments must be repeated with the exception of PET scan within eligible 
ranges.  Given that APOE status will not change over time, there is no need to repeat 
clinical genotyping in case of re-screening.  
Participants may be re-screened if there is a substantial change in the participant’s 
condition (e.g., a disallowed medication was stopped) and if recruitment for the study is 
still ongoing and all eligibility criteria are met. 
It is suggested that screening tests with the exception of MRI scan and PET scan be 
performed within 1 to 2 weeks of signing the Informed Consent Form (to allow adequate 
time for the remaining tests).  As soon as all the results are available, and none exclude 
the participant from the trial, PET scan and MRI scan should be performed, if required.   
It will take several days to receive the results of the MRI.  On occasion, the originally 
scheduled MRI day may need to be postponed and in the case of the MRI, it may need 
to be repeated.  Therefore, the scheduling of these tests needs to be done carefully and 
should begin as soon as possible. 
Roche may keep information about screening test results, medical history, and 
demographic information for all participants (including non-eligible participants) for future 
development of diagnostic tests related to A, APOE genotype, and AD, as well as 
additional analyses. 
4.6.2 
Assessments at Baseline 
To be enrolled into the study and to receive the study drug, participants must have no 
significant change in medical, psychiatric, or neurologic conditions or change in 
medication since screening.  The recommended order of assessments and rating scales 
is as follows: 
 
Clinical assessments (e.g., CDR, MMSE, and ADAS-Cog), including all those that 
require study partner (non-professional caregiver) input, should be completed before 
any invasive safety assessments. 
 
Vital sign measurements, ECGs, blood draws for clinical laboratory assessments, 
PK, anti-drug antibody (ADA), and plasma biomarker sampling, and urine samples 
are recommended to be conducted following scale assessments and must be 
performed prior to study drug administration. 
 


 
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The recommended order of clinical assessments/rating scales at baseline is as follows: 
Participant Assessments 
Study Partner (Non-Professional Caregiver) 
Assessments 
1. ADAS-Cog13 
2. CDR (participant interview) 
10-min break (optional) 
3. MMSE 
4. Coding 
5. Verbal Fluency Task 
10-min break (optional) 
6. C-SSRS 
1. CDR (study partner [non-professional 
caregiver] input) 
2. ADCS-ADL 
ADAS-Cog13  Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; 
ADCS-ADL  Alzheimer’s Disease Cooperative Study-Activities of Daily Living; 
CDR  Clinical Dementia Rating; C-SSRS  ColumbiaSuicide Severity Rating Scale; 
MMSE  Mini-Mental State Examination.  
 
If assessments are split over 2 days, all safety assessments must be performed on the 
same day as the study drug administration. 
4.6.3 
Assessments during the Treatment Period 
In the treatment period, participants will receive up to 80 SC administrations of study 
drug over the course of 103 weeks.  The final efficacy and PD assessments are 
scheduled at Week 104, 1 week after the final dose for those participants who do not 
take part in the 2-year extension. 
Participants who take part in the 2-year extension will receive up to 184 SC 
administrations of study drug over the course of 207 weeks.  The final efficacy and PD 
assessments are scheduled at Week 208, 1 week after the final dose. 
The same recommended order of clinical assessments and rating scales as above for 
the baseline visit should be followed (omitting those that are not conducted per the 
schedule of activities; see Appendix 1).  The home administration questionnaire should 
be performed after the cognition and function assessments. 
Vital sign measurements, ECGs, blood draws for clinical laboratory assessments, PK, 
ADA, plasma biomarkers, and urine samples are recommended to be conducted 
following scale assessments and must be performed prior to study drug administration. 
If assessments are split over 2 days, all safety assessments must be done on same day 
as the treatment administration. 
On each dosing day, after all assessments prior to dosing have been completed (see the 
schedule of activities in Appendix 1), gantenerumab will be administered subcutaneously 
at room temperature.  For the first four doses, participants should be observed for a 


 
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minimum of 2 hours after dosing and then for a minimum of 1 hour after all remaining 
doses (i.e., Doses 5 and beyond).  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. 
Rescue medications to treat anaphylactic and anaphylactoid reactions must be available 
at the site.  Participants and their study partners (non-professional caregivers) 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. 
Refer to Appendix 1 for the schedule of activities during the treatment period. 
4.6.4 
Procedures for New Magnetic Resonance Imaging Findings 
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 4.5.8). 
Refer to Section 5.1.3 for instructions in the event of new MRI findings (ARIA-E and 
ARIA-H). 
4.6.5 
Assessments at Study Completion or Early Termination Visit 
and at Follow-Up 
Participants who opt for the 2-year extension and complete the treatment period 
(defined as completion of 207 weeks of study drug treatment) have to complete the final 
PD and efficacy assessments 1 week after the final dose (Week 208).  Subsequently, 
participants are asked to come back for the follow-up safety assessments 16 weeks after 
Week 208 (Week 224), unless they are transitioning to a further gantenerumab OLE 
study.  
Participants who do not opt for the 2-year extension of Study WN29722 will receive the 
final dose of study drug at Week 103, and Week 104 final PD and efficacy assessments 
will be performed 1 week later.  Participants who do not enter an extension study will 
have an additional follow-up visit 16 weeks after the Week 104 visit for safety 
assessments (Week 120 follow-up visit). 
All participants who withdraw from treatment or discontinue from the study early (during 
the treatment period) will be asked to return 1 week after the final dose of study drug in 
order to complete the early termination visit.  


 
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In addition, participants who withdraw from treatment will be asked to return for 
collection of safety (except MRI) and PD data (i.e., the primary endpoints as well 
as assessments of cognition and function) at visits that have the assessments 
(e.g., Weeks 24, 52, and 76) per the schedule of activities until the end of the treatment 
period (including Weeks 104 and 120 for participants who do not opt into the 2-year 
extension and Weeks 208 and 224 for participants who opt for the 2-year extension).  If 
participants who withdraw from treatment are not willing to return for collection of safety 
(except MRI) and PD data, then they will be asked to come back for the follow-up 
assessments 16 weeks after the early termination visit. 
Autopsy reports, including cause of death, for all participants who die during the study 
should be requested. 
Refer to the schedule of activities to be performed at the study completion (either 
Week 104, 208 or early termination visit) in Appendix 1. 
4.6.6 
Unscheduled Assessments 
Assessments at unscheduled visits should be determined by the investigator based on 
clinical relevance and appropriateness to the cause of the unscheduled visit.  The 
schedule of activities in Appendix 1 allows for all assessments to be performed at 
unscheduled visits. 
4.7 
TREATMENT, PARTICIPANT, STUDY, AND SITE 
DISCONTINUATION 
4.7.1 
Study Treatment Discontinuation 
Participants must permanently discontinue study treatment if they experience any of the 
following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the participant's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant 
 
Pregnancy 
 
Upon evidence of more than 15 ARIA-H, cumulatively 
 
Any disseminated leptomeningeal hemosiderosis 
 
All participants who withdraw from treatment will be asked to return 1 week after final 
dose of study drug in order to complete the early termination visit.  In addition, 
participants who withdraw from treatment will be asked to return for collection of safety 
(except MRI) and PD data (i.e., the primary endpoints as well as assessments of 
cognition and function) at visits that have the assessments (e.g., Weeks 24, 52, and 76) 


 
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per the schedule of activities until the end of the treatment period (including Weeks 208 
and 224). 
 
If study drug 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 study treatment prematurely will not be 
replaced. 
4.7.2 
Participant Discontinuation from the Study 
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.  In addition, the investigator has the right to withdraw a participant from the 
study at any time. 
Reasons for participant discontinuation from the study may include, but are not limited 
to, the following: 
 
Participant withdrawal of consent  
 
Study termination or site closure 
 
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 three consecutive dose administrations (with Q4W dosing 
regimen), more than six consecutive dose administrations (with Q2W dosing 
regimen), or more than twelve 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.  
 
All participants who discontinue from the study early will be asked to return 1 week after 
final dose of study drug to complete the early termination 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.   
Participants who withdraw from the study will not be replaced. 


 
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4.7.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants 
 
Participant enrollment is unsatisfactory 
 
Sponsor determines it is the best interest of the participants 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.7.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all participants have completed the study and all obligations 
have been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Gantenerumab is not yet approved, and clinical development is ongoing.  The safety 
plan for participants in this study is based on clinical experience with gantenerumab in 
completed and ongoing studies.  The identified risks for gantenerumab are outlined 
below.  Please refer to the Gantenerumab Investigator’s Brochure for a complete 
summary of safety information.  
Several measures will be taken to ensure the safety of participants participating in this 
study.  Eligibility criteria have been designed to exclude participants at higher risk for 
imaging related abnormalities.  Participants will undergo safety monitoring during the 
study, including assessment of the nature, frequency, and severity of adverse events.  In 
addition, guidelines for managing adverse events, including criteria for dosage 
modification and treatment interruption or discontinuation, are provided below. 
5.1.1 
Risks Associated with Gantenerumab 
5.1.1.1 
Amyloid-Related Imaging Abnormalities  
The ARIAs are one of the most significant adverse events reported in therapies against 
aggregated forms of A.  These findings appear to be dependent on dose, time, and 
APOE 4 status (Piazza and Winblad 2016).  


 
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The mechanism underlying the development of ARIA-E and 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 is consistent with experiences in previous and ongoing 
studies and with reported data from the long-term extension study of aducanumab 
treatment (Haeberlein 2019). 
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 (prodromal AD), ARIA events were time, 
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 year of treatment (incidence of up to 2.3% in the 225-mg 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 arm and 6 participants (2.3%) from the 225-mg 
gantenerumab arm 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 one 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 OLE.  


 
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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:  one participant (0.5%) in the placebo group reported irritability that 
was mild in intensity and non-serious, and one participant (0.5%) in the gantenerumab 
group reported headache that was moderate in intensity and non-serious. 
The WN25203 and WN28745 OLE studies have been completed.  In the OLE phase of 
Study WN25203, all 154 participants dosed with gantenerumab in the WN25203 OLE 
study had a post-baseline MRI scan.  Of 154 participants, 47 participants (30.5%) had 
new ARIA-E (median maximum BGTS of 7.0), and 20 participants (13.0%) had new 
ARIA-H without ARIA-E.  The majority of ARIA-E findings were asymptomatic, with 19 of 
47 participants with new ARIA-E MRI findings reporting associated CNS adverse events.  
The CNS adverse events were mostly mild to moderate in intensity, non-serious, and did 
not require permanent cessation of study treatment (with the exception of the SAE of 
cerebral hematoma).  Most symptomatic ARIA-E cases resolved with protocol-defined 
ARIA management rules.  In 4 of the 19 participants with ARIA-E MRI findings who 
reported associated CNS adverse events, the events were reported as serious.  Three 
participants reported events of seizure (n=2) and cerebral haematoma which was severe 
in intensity and one participant reported confusion that was moderate in intensity. 
In the OLE phase of Study WN28745, as of 11 January 2021 (snapshot date) 219 of 225 
participants dosed with gantenerumab had a post-baseline MRI scan.  Seventy-one of 
219 participants (32.4%) had new ARIA-E (median maximum BGTS of 9.0), and 26 of 
219 participants (11.9%) had ARIA-H without ARIA-E.  The majority of ARIA-E events 
were asymptomatic, with 22 of 71 participants with ARIA-E MRI findings 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 the 22 
participants with symptomatic ARIA-E, the events were reported as serious (ischemic 
stroke, generalized tonic-clonic seizure, epilepsy, and hemiplegia). 
Study WN29722 will require an MRI scan documenting the absence of ARIA-E, more 
than five ARIA-H, or disseminated leptomeningeal hemosiderosis prior to the first 
gantenerumab dose.  If ARIA findings occur during the study, MRI monitoring, temporary 
dose holding, or permanent study drug discontinuation will be implemented according to 
an ARIA management plan, as described in Appendix 2.  
Safety findings, including individual participant and aggregate data, will be reviewed on a 
regular basis by the Sponsor’s IMC. 


 
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To date, clinical experience with gantenerumab reveals that ARIA events are dose 
dependent 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 
Appendix 2. 
5.1.1.2 
Injection Reactions and Hypersensitivity 
Gantenerumab may cause a local 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, 
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 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 ISR. 
In the OLE phase of Study WN25203, ISRs have been reported in 56 of 154 participants 
(36.4%) dosed with gantenerumab in the WN25203 OLE study.  All ISRs were non-
serious and mild except one 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. 
In the OLE phase of Study WN28745, as of 11 January 2021, ISRs have been reported 
in 90 of 225 participants (40.0%) treated with gantenerumab.  All ISRs were non-
serious, with the majority being mild and resolving without treatment.  Overall, 10 of 90 
participants (11.1%) who had an ISR received treatment, which included topical 
steroids and antihistamines.  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., uptitration was delayed]); this ISR resolved within 24 hours. 
Regular reviews of ISR data from the OLE Studies WN25203 and WN28745, and the 
pivotal Studies WN29922 and WN39658 have not identified any new or unexpected 
safety findings.   


 
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Detailed information on the characteristic signs and symptoms of ISRs (e.g., erythema, 
pruritus) will be recorded on the dedicated eCRF page (see Section 5.3.5.2 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 
indistinguishable from hypersensitivity reactions, including anaphylaxis. In comparison to 
hypersensitivity reactions, systemic injection reactions could occur on first exposure to 
gantenerumab 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 Appendix 1), gantenerumab will be administered subcutaneously 
at room temperature.  For the first 4 doses, participants should be observed for a 
minimum of 2 hours after dosing and then for a minimum of 1 hour after all remaining 
doses (i.e., Doses 5 and beyond).  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.  
Rescue medications to treat anaphylactic and anaphylactoid reactions must be available 
at the site.  Participants and their study partners (non-professional caregivers) 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 
ADA test, in the event any hypersensitivity reaction occurs. 
If anaphylaxis or a serious hypersensitivity reaction occurs, 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 ADA and PK-PD will be 
obtained. 
5.1.1.3 
Immunogenicity 
As with administration of any exogenous protein, there is the potential for the 
development of ADAs, which can be neutralizing and/or sensitizing and which can 
potentially lead to febrile or allergic reactions, including anaphylaxis.  The immunogenic 
risk of gantenerumab is considered low since it is a fully human antibody. 


 
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For the management of suspected immunogenicity-associated 
hypersensitivity/anaphylaxis, see section above.  
5.1.2 
Risks Associated with Amyloid PET Tracer 
5.1.2.1 
Risks Associated with Radiation 
The risks associated with radiation in Study WN29722 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 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.  To date, the most frequently 
reported adverse events with amyloid radioligands are ISRs, increased blood pressure, 
headache, dizziness, and nausea (see Sections 5.1.2.2 and 5.1.2.3 for specific details 
about each tracer). 
Radiation Exposure 
The dose of whole body effect radiation resulting from the recommended injected 
radioactivity is similar for florbetaben and flutemetamol and is well below the maximum 
annual effective dose limitations recommended in the United States, the European 
Union, and other countries where amyloid PET imaging will be used.  The recommended 
300-MBq dose of florbetaben results in a 5.8-mSv absorbed dose, and the 185-MBq 
dose of flutemetamol results in 5.9 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 amyloid tracers.  In dedicated PET scanners 
without CT scans, the transmission scan adds only a negligible amount of radiation 
dose.   
Radiation exposure for florbetaben and flutemetamol 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).  Amyloid 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. 
5.1.2.2 
Florbetaben 
The most commonly reported adverse reactions after injection of florbetaben are 
injection-site pain (3.9%), injection-site irritation (1.2%), and injection or application-site 
erythema (1.7%).  Florbetaben contains up to 1.5 mol of sodium (i.e., 33 mg) per dose.  


 
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This should be taken into account for participants on a sodium-controlled diet.  
Florbetaben contains up to 118 mg of ethanol (alcohol), which is equivalent to 30 mL of 
beer or 12.5 mL of wine per dose.  This can be harmful for those suffering from 
alcoholism and is also to be taken into account in pregnant or breastfeeding women and 
high-risk groups such as participants with liver disease or epilepsy. 
In countries where florbetaben PET radioligand is approved for marketing, for more 
information see the approved local product information.  In countries where the 
florbetaben PET radioligand is not approved for marketing, the Investigator’s Brochure 
will be provided. 
5.1.2.3 
Flutemetamol 
The most commonly reported adverse reactions after injection of flutemetamol are 
flushing (2%), increased blood pressure (1%), headache (1%), dizziness (1%), nausea 
(1%), and hypertension (1%).  Flutemetamol contains up to 9.0 mg of sodium and 70 L 
of ethanol. 
In countries where flutemetamol PET radioligand is approved for marketing, for more 
information see the approved local product information.  In countries where the 
flutemetamol PET radioligand is not approved for marketing, the Investigator’s Brochure 
will be provided. 
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 florbetaben and 
flutemetamol. 
5.1.3 
Management of Participants Who Experience Adverse Events 
5.1.3.1 
Dose Modifications and Treatment Interruption 
Participants will undergo brain MRI examinations prior to every dose increase 
(pre-uptitration MRI scans) and according to the schedule of activities once the target 
dose is achieved.  The pre-uptitration MRI scans will determine eligibility for the next 
uptitration dose.  Before reaching the maximum target dose (i.e., 255 mg Q1W), a 
minimum of three doses during 120-mg Q4W and 255-mg Q4W dosing periods, and a 
minimum of six doses during the 255-mg Q2W dosing period must be administered prior 
to uptitration. 
Participants will be eligible for uptitration if there is no new ARIA-E, if the ARIA-E is 
resolved (BGTS  0, asymptomatic), and if the criteria for permanent treatment 
discontinuation because of ARIA-H have not been met.   


 
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In addition, the following dose adjustment and discontinuation rules for MRI findings will 
apply: 
 
In case of asymptomatic ARIA-E  and BGTS  1 and  4:  Continue study drug at 
the same dose level (i.e., do not uptitrate) and repeat MRI scan 4 weeks later (for 
participants on Q1W dosing frequency, this can be after the third or fourth dose). 
As long as BGTS is  4 and  1, continue study drug at the same dose level 
and repeat MRI scan 4 weeks later until the event resolves (for participants on 
Q1W dosing frequency, this can be after the third or fourth dose).  Once ARIA-
E resolves, resume dosing including uptitration.  For participants in the 
uptitration phase, obtain a MRI scan per the titration schedule.  For participants 
on the target dose, perform another MRI scan 3 months after study drug 
reintroduction. 
 
Additional measures for nonclinical administration by study partner (non-
professional caregiver):  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/or study partner (non-professional caregiver) 
to elicit, in a non-leading way, information on medication errors and adverse events 
that may have occurred in the home setting.  Therefore, there will be frequent 
contact between the study staff and the participant/study partner (non-professional 
caregiver).  In addition, participants/study partners (non-professional caregivers) will 
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.  These requirements will aid symptomatic ARIA-E detection and dose 
intervention, as described below, in the case of an asymptomatic ARIA-E that 
becomes symptomatic at a later date.  
 
If BGTS  4 or symptoms develop, refer to the rule below. 
 
In case of occurrence of symptoms in the presence of ARIA-E (any size) or 
asymptomatic ARIA-E with BGTS  4:  Temporarily interrupt study drug (but 
continue all assessments per schedule of activities) and perform MRI monitoring at 
4-week intervals until symptoms and ARIA resolve.   
When symptoms and ARIA-E resolve, reintroduce study drug at the next 
scheduled dosing visit, at the same dose given at the time the event was 
detected.  
Perform an MRI scan after the first dose while participants are on a 
Q4W dosing frequency, or after the second dose while participants are on a 
Q2W dosing frequency, or after the third or fourth dose while participants are on 
a Q1W dosing frequency. 
If no new ARIA-E is detected, resume uptitration and obtain an MRI per the 
titration schedule.  For participants on the Q1W dosing frequency, perform 
another MRI scan 3 months after study drug reintroduction. 


 
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 
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 temporally associated with ARIA-E MRI findings. 
 
Any recurrence of ARIA-E:  Treat using the same procedures as for the first event 
(based on symptoms and BGTS). 
 
Participants who develop ARIA-H  15 cumulatively will be discontinued from study 
drug (the cumulative number should not include any disseminated leptomeningeal 
hemosiderosis, i.e., more than 3 focal leptomeningeal hemosiderosis cumulatively.  
A focal leptomeningeal hemosiderosis is counted as one ARIA-H). 
 
In cases where both ARIA-E and ARIA-H occur, the most conservative approach 
should be followed. 
 
In exceptional cases, as determined by the Sponsor and investigator: 
Q4W monitoring may no longer be necessary in case of an ARIA-E that is 
asymptomatic with BGTS  4 and considered stable over consecutive MRI 
images; or symptomatic ARIA-E for which the imaging evidence of ARIA-E 
has resolved but the CNS symptoms continue. 
The study drug can be either reintroduced or uptitrated, as applicable, in case of 
an asymptomatic ARIA-E that has stabilized at BGTS  4; or a symptomatic 
ARIA-E for which the imaging evidence of ARIA-E has resolved but the CNS 
symptoms continue.  
 
An additional plasma and blood 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); following new 
or worsened ARIA-E. 
 
A PK sample will be obtained as soon as practical (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). 
 
Any other new significant findings will be reviewed by the Medical Monitor and 
appropriate dose action will be proposed. 
 
The Sponsor’s IMC will review the incidence and other characteristics of ARIA and may 
recommend adjustment of dosing regimen and/or ARIA management for the overall 
study population or for a specific APOE 4 genotype. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 


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


 
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 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.12) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the participant's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
participant or may require medical/surgical intervention to prevent one of the 
outcomes listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows: 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.8) 
 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a participant exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
 


 
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5.2.4 
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 refer also to Section 5.3.5.1 for further details how to report ARIA events. 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.45.6.  The 
investigator is also responsible for reporting medical device complaints (see 
Section 5.4.4). 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
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 
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. 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each participant contact.  All 
adverse events, whether reported by the participant, the study partner (non-professional 
caregiver), or noted by study personnel, will be recorded in the participant's medical 
record and on the Adverse Event eCRF. 


 
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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported (see 
Section 5.4.2 for instructions for reporting serious adverse events). 
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, see Section 5.4.2 for instructions.  For 
non-serious PET ligand adverse events, a PET ligand specific non-serious adverse 
event reporting paper form should be completed and submitted to the Sponsor or its 
designee by scanning and emailing the form using the email address provided on the 
form. 
After initiation of study drug, all adverse events will be reported until the participant’s last 
follow-up visit, as defined in the Schedule of Assessments. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6. 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation timepoints.  Examples of 
non-directive questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.3.3 
Assessment of Severity of Adverse Events 
Table 2 provides guidance for assessing adverse event severity. 
Table 2 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  Refer to 
definition of a serious adverse event (see Section 5.2.2). 
 


 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether an adverse event is considered to be related to the study drug, 
indicating "yes" or "no" accordingly.  The following guidance should be taken into 
consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
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 
temporally associated with ARIA-E MRI findings), 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 5.3.5.5 for details on recording persistent 
adverse events). 


 
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5.3.5.2 
Injection Reactions 
Injection reactions (local and systemic) are defined as adverse events that occur during 
or within 24 hours after study drug administration that are judged to be related to the 
study drug injection.  
For local reactions, the diagnosis of injection site reaction should be captured on the 
Adverse Event eCRF, and associated signs and symptoms (e.g., erythema at injection 
site) should be recorded on the dedicated Injection Site Reaction eCRF.  
Systemic reactions should be recorded as a single diagnosis on the Adverse Event 
eCRF (e.g., anaphylactic reaction).  If possible, avoid ambiguous terms such as 
“systemic reaction.”  
5.3.5.3 
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, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.4 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 
 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 


 
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5.3.5.5 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious", providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between participant evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 
5.3.5.6 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
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., alkaline phosphatase and bilirubin 5  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". 


 
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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.5 for 
details on recording persistent adverse events). 
5.3.5.8 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an elevated 
total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total 
bilirubin  2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.6) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 


 
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5.3.5.9 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of AD. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of AD, "Alzheimer’s disease progression" 
should be recorded on the Adverse Event eCRF.   
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6. 
5.3.5.10 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for 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"). 
5.3.5.11 
Lack of Efficacy or Worsening of Alzheimer’s Disease 
 Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  If there is any uncertainty as to whether an 
event is due to disease progression, it should be reported as an adverse event. 
5.3.5.12 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  


 
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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 
 
Hospitalization due to expected progression of underlying disease 
 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The participant has not experienced an adverse event 
 
5.3.5.13 
Cases of Overdose, Medication Error, Drug Abuse, or Drug 
Misuse 
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm 
 
Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse 
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.} 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, the event should 
be reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).  For gantenerumab (or matching placebo), adverse events 
associated with special situations should be recorded as described below for each 
situation: 


 
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 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box. 
 
Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes. 
 
Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes. 
In addition, all special situations associated with gantenerumab (or matching placebo), 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
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. 


 
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 
Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box. 
 
Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes. 
 
Drug administered to someone other than the participant:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.3.5.14 
Clinical Outcome Assessment Data  
Adverse event reports will not be derived from clinical outcome data by the Sponsor, and 
safety analyses will not be performed using clinical outcome assessment (COA) data.  
Sites are not expected to review the COA data for adverse events. 
5.3.5.15 
Safety Biomarker Data 
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on participant 
management. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.4.3 for details on reporting requirements) 
 
Medical device complaints (see Section 5.4.4 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 


 
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than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Medical Monitors and Emergency Medical Contacts 
 
To ensure the safety of study participants, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week.  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 country-specific 
toll-free numbers for the Emergency Medical Call Center have been distributed to 
investigators and are filed in the investigator site file.  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
In addition, the following serious adverse events should be reported after administration 
of a PET ligand and prior to initiation of study drug: 
 
All serious adverse events believed to be related to the PET ligand 
 
All serious adverse events occurring within 48 hours of the PET ligand 
administration, regardless of relatedness to the PET ligand. 
 
The paper Clinical Trial Adverse Event/Special Situations Form provided to investigators 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the event), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until the participant’s last visit (including long-term follow-up 
visits).  Investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours after learning of the event) on the Adverse Event eCRF and submit 


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


 
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All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.4.3.3 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
study drug should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.4.4 
Reporting Requirements for Medical Device Complaints  
In this study, the vial adapter ReadyPack (FDA registration number K963583) 
manufactured by the company West Pharma will be provided to the study partner 
(non-professional caregiver) to aid study drug administration to the participant.  The vial 
adapter is considered a medical device.  The investigator must report all medical device 
complaints to the Sponsor.  The investigator should document as much information as 
possible on the IMP Deviation Form, including the vial adapter batch number, as 
reported on the blister, and forward the form to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event) (refer to the pharmacy manual for further 
details).  If the medical device results in an adverse event to the study participant, the 
event must be reported on the Adverse Event eCRF and submitted through the 
EDC system. If the event is serious, the Adverse Event eCRF must be completed 
immediately (i.e., no more than 24 hours after learning of the event), as outlined in 
Section 5.4.2. 
In this study, gantenerumab, in an autoinjector, may be provided to the study partner 
(non-professional caregiver), home nurse or site staff to administer study drug to the 
participant. The investigator must report all complaints to the Sponsor whether they 
pertain to the study drug or to the autoinjector part of the product. The investigator 
should document as much information as possible on the IMP Deviation Form, 
including the batch number, as reported on the label, and forward the form to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event) (refer to 
the pharmacy manual for further details). If use of the gantenerumab autoinjector 
results in an adverse event to the study participant, the event must be reported on the 
Adverse Event eCRF and submitted through the EDC system. If the event is serious, 
the Adverse Event eCRF must be completed immediately (i.e., no more than 24 hours 
after learning of the event), as outlined in Section 5.4.2.   
5.5 
FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the participant is lost to 
follow-up, or the participant withdraws consent.  Every effort should be made to follow all 


 
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serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the participant's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.6 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
per the Schedule of Assessments), if the event is believed to be related to prior study 
drug treatment.  These events should be reported through use of the Adverse Event 
eCRF.  However, if the EDC system is not available, the investigator should report these 
events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Adverse Event/Special Situations Form using the fax 
number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below: 
Drug 
Document 
Gantenerumab 
Gantenerumab Investigator's Brochure  
Florbetaben [18F] (Neuraceq)  
Florbetaben [18F] Investigator’s Brochure 
Flutemetamol [18F] (Vizamyl) 
Flutemetamol [18F] Investigator's Brochure  
 


 
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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
6.1 
DETERMINATION OF SAMPLE SIZE 
Determination of sample size is relative to the sample of participants assessed by 
amyloid PET imaging using florbetaben.  The sample size for this study is determined as 
the number of participants needed for the estimated change from baseline to Week 104 
in amyloid PET load to fall into a 10 CL confidence interval around its true value.  With a 
standard deviation of 25.67 CL (see below), 192 participants are sufficient to fulfill this 
criterion.  
The standard deviation of amyloid reduction was estimated using amyloid PET data from 
the ongoing Studies WN25203 and WN28745 OLEs (based on a cutoff date of 
14 October 2019), yielding a value of 25.67 CL. 
Uncertainties of the parameters affecting the estimation (e.g., drop-out rate, study drug 
discontinuation rate, and standard deviation) were assumed to be equivalent to a 
decrease in sample size of up to around 35% and were corrected for accordingly.  This 
drop-out rate is calculated based on the ongoing Study WN28745 OLE at Week 104.  
A sample size increase may be considered if factors external to the study would warrant 
a change to the sample size assumption. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of participants who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study discontinuation 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. 
6.3 
SUMMARIES OF DEMOGRAPHICS AND BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics (e.g., age, sex, race, disease stage, APOE 4 
status, use and non-use of background therapy for AD) will be summarized descriptively.  
Descriptive summaries of continuous data will present the mean, standard deviation, 
median, and minimum and maximum.  Descriptive summaries of discrete data will 
include frequencies expressed in terms of number and percentage of participants. 


 
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6.4 
PRIMARY AND SECONDARY ENDPOINT ANALYSES 
6.4.1 
Primary Endpoint 
The primary endpoint for this study is the change from baseline to Week 104 in brain 
amyloid load, as assessed by amyloid PET imaging using florbetaben as ligand and 
quantified on the CL conversion scale, in participants exposed to a Q1W administration 
regimen of SC gantenerumab.  For the purposes of analysis, the screening amyloid PET 
scan may be considered the baseline evaluation. 
Details about the primary estimand definition and corresponding statistical model 
specification, including handling of missing data will be described in the Statistical 
Analysis Plan (SAP).  For example, a linear mixed-effects model with change from 
baseline as dependent variable, and baseline value and visit as covariate may be used. 
Descriptive summary statistics of the change from baseline to Week 104 in brain amyloid 
CL load will also be produced.  Descriptive summaries of the primary endpoint will 
present the mean, standard deviation, median, and minimum and maximum.  
To evaluate the impact of different amyloid PET radioligands on the quantification of the 
PD effect of gantenerumab, a supplementary analysis will be performed similarly to the 
primary endpoint on the sample of participants scanned with florbetaben or flutemetamol 
in this study (if applicable). 
6.4.2 
Secondary Endpoint 
The secondary objective for this study is the caregiver’s confidence in his or her ability to 
perform the injection and his or her perception of the ease of injection, as well as the 
caregiver’s satisfaction with and convenience of home administration.  The 
corresponding endpoint consists of the responses to the caregiver part of the home 
administration questionnaire; these responses at various timepoints during study 
conduct will be summarized using descriptive statistics.  
6.5 
SAFETY ANALYSES 
All participants who have received at least one dose of the study drug, whether 
prematurely withdrawn from the study or not, and who completed the associated 
assessments and sample collection will be included in the safety analysis. 


 
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Safety will be assessed through descriptive summaries of the following endpoints:  
 
Incidence, nature, and severity of MRI safety findings:  ARIA-E and ARIA-H 
 
Incidence, nature, severity, and timing of ISRs 
 
Incidence, nature, and severity of serious adverse events 
 
Incidence, nature, and severity of adverse events 
 
Incidence of adverse events of special interest 
 
Incidence of treatment discontinuations due to adverse events 
 
Mean changes in clinical laboratory tests from baseline over time; incidence of 
treatment-emergent abnormal laboratory values and abnormal laboratory values 
reported as adverse events 
 
Mean change in ECG assessments from baseline over time and incidence of 
abnormal ECG assessments 
 
Physical and neurologic examination abnormalities 
 
Mean change in vital signs (blood pressure, pulse rate) from baseline over time and 
incidence of abnormal vital sign measurements 
 
Changes in C-SSRS scores from baseline over time 
 
Number and proportion of participants with ADAs during the study relative to the 
number and proportion of participants with ADAs at baseline 
 
The incidence, severity, and nature of adverse events, serious adverse events, ARIA-E 
and ARIA-H, and laboratory abnormalities will be assessed on a regular basis by the 
Sponsor’s IMC, as documented in the IMC Charter.   
6.6 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES  
Details of the PK analyses will be described in a separate analysis plan, and the results 
will be reported in a separate document from the Clinical Study Report. 
Observed plasma concentration data for gantenerumab will be tabulated and 
summarized.  Descriptive summary statistics will include the arithmetic mean, median, 
range, standard deviation, and coefficient of variation, as appropriate.   
Because a sparse PK sampling design is being used, population (non-linear 
mixed-effects) modeling will be used to analyze the dose concentrationtime data of 
gantenerumab.  Information from other clinical studies will be incorporated to establish 
the population PK model.  The selection of parameters and the derivation of individual 
measures of exposure, such as AUC, Cmax, and trough serum concentration, will depend 
on the final PK model used for this analysis.  
Where applicable, the relationships between drug PK exposure and the efficacy and 
safety endpoints of gantenerumab will be explored.  The previously developed PK-PET 
models will be initially used to compare the expected PET reduction under Q1W regimen 


 
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with the observed PET reduction to provide supporting evidence for the independence of 
frequency of administration and plaque clearance.  If needed, the PK-PET model will be 
updated by adding the data collected in this study.  The influence of the gantenerumab 
dosing regimens (Q1W, Q2W, and Q4W) on the relationships between exposure and 
amyloid reduction will then be specifically assessed.   
6.7 
BIOMARKER ANALYSES  
The exploratory biomarker analysis will quantify the change from baseline, using MRI at 
baseline and follow-up at Weeks 52 and 104, in the following imaging biomarkers: 
 
Whole brain volume 
 
Regional brain volumes 
 
Ventricular volume 
 
In addition, exploratory biomarker analysis will be performed to assess functional brain 
connectivity and fiber tract integrity at baseline and Week 104.  Additional statistical 
modeling and subgroup analysis may be considered and will eventually be specified in 
the SAP.   
Exploratory fluid biomarkers will be assessed for tau and amyloid pathology as well as 
neurodegeneration, including, but not limited to, the following: 
 
p-tau 
 
A1-42 
 
Neurofilament light chain 
 
The plasma concentration of these biomarkers will be assessed and analyzed using 
descriptive statistics, subgroup analysis, or statistical models if appropriate.  The change 
from baseline in these biomarkers will also be estimated.  Exploratory biomarkers may 
be reported separately.  
6.8 
EXPLORATORY ANALYSES 
The change from baseline in the continuous, exploratory endpoints listed in Table 1 
(including cognition and function endpoints, and endpoints measuring other AD 
symptoms and effects) will be analyzed using descriptive statistics or statistical models if 
appropriate.  Further details will be given in the SAP. 
Additionally, the feasibility of using amyloid PET data from the ongoing 
Studies WN29922 and WN39658 as an external control group will be explored for a 
comparison of measured amyloid reduction between dosing regimens.  Additional details 
will be given in the SAP. 


 
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6.9 
INTERIM ANALYSIS  
6.9.1 
Planned Interim Analysis  
An interim analysis will be conducted on the latest data cut available at the time of the 
primary analysis for Studies WN29922 and WN39658.  The maximum sample available 
at this timepoint with valid screening and Week 52 PET scans will be included in the 
analysis. 
Change from baseline in amyloid PET load with the Q1W regimen will be assessed at 
Week 52.  This may be compared with the predictions of the PK-PET model for this 
timepoint.  At the time of the interim analysis, all available PK and safety data, 
responses to the Caregiver part of the home administration questionnaire, and 
exploratory endpoints may be reported descriptively as supporting evidence.  The 
interim analysis will not impact the conduct of the study, i.e., early termination for futility 
or efficacy will not be considered. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  All electronic data from external vendors 
will be sent directly to the Sponsor, using the Sponsor's standard procedures to handle 
and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
The eCRFs are to be completed through use of a Sponsor-designated EDC system.  
Sites will receive training and have access to a manual for appropriate eCRF 
completion.  The eCRFs will be submitted electronically to the Sponsor and should be 
handled in accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  The eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 


 
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At the end of the study, the investigator will receive participant data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 
7.3 
ELECTRONIC CLINICAL OUTCOME DATA 
An electronic device will be used by participants, caregivers, and appropriate site staff to 
capture COA data.  The device is designed for entry of data in a way that is attributable, 
secure, and accurate, in compliance with FDA regulations for electronic records 
(21 CFR Part 11).  The data will be transmitted to a centralized database maintained by 
the electronic device vendor. 
The electronic data will be available for view access only, via a secure online web portal.  
Only identified and trained users may view the data, and their actions will become part of 
the audit trail.  The Sponsor will have view access only.  System backups for data stored 
by the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive participant data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participant-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
participant files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 


 
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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper COA data, Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 15 years after completion or discontinuation of the study or for 
the length of time required by relevant national or local health authorities, whichever is 
longer.  After that period of time, the documents may be destroyed, subject to local 
regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 


 
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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 
8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Home Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each participant the 
objectives, methods, and potential risks associated with each optional procedure.  
Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a participant's agreement to participate in optional procedures.  Participants 
who decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the participant or the participant's 
legally authorized representative before his or her participation in the study.  The case 
history or clinical records for each participant shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while a 
participant is participating in the study, the participant or a legally authorized 
representative must re-consent by signing the most current version of the Consent 
Forms or the addendum, in accordance with applicable laws and IRB/EC policy.  For any 
updated or revised Consent Forms, the case history or clinical records for each 
participant shall document the informed consent process and that written informed 
consent was obtained using the updated/revised Consent Forms for continued 
participation in the study. 


 
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A copy of each signed Consent Form must be provided to the participant or the 
participant's legally authorized representative.  All signed and dated Consent Forms 
must remain in each participant's study file or in the site file and must be available for 
verification by study monitors at any time. 
For sites in the United States, each Consent Form may also include participant 
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the 
site utilizes a separate Authorization Form for participant authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review, 
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the 
participant, and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated.  In addition, any participant recruitment materials must be approved by the 
IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments 
(seeSection 9.7). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each participant enrolled in 
the study through assignment of a unique participant identification number.  This means 
that participant names are not included in data sets that are transmitted to any Sponsor 
location. 
Participant medical information obtained by this study is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
participant, unless permitted or required by law. 


 
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Medical information may be given to a participant's personal physician or other 
appropriate medical personnel responsible for the participant's welfare, for treatment 
purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication (see Section 9.6). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.6). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the participant data, including an audit trail containing a complete record of all changes 
to data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on participant safety 


 
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and data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol deviations and 
assess whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities.  As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed. 
9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity.  
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks.  Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
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 40 sites globally will participate to enroll 192 participants.  Enrollment will 
occur through an IxRS.   
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected. 
An IMC will be employed to monitor and evaluate participant safety throughout the study.   
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to health care professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 


 
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comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Study Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in participants involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective Clinical Study Report.  In addition, for all clinical trials in 
participants involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and statistically 
sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 


 
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eliminate an immediate hazard to participants or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Gantenerumab—F. Hoffmann-La Roche Ltd 
128/Protocol WN29722, Version 3 
Appendix 1  
Schedule of Activities 
Table 1 
Screening up to Week 34 for All Participants   
Assessment/Procedure 
Screen 
BL a 
Dose-Escalation Period 
UV 
Wk 8 to  
Wk 1 
Day 1 
Day 4 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 b 
Wk 26 
Wk 28 
Wk 30 
Wk 32 
Wk 34 
Visit type c 
 
I 
I 
I 
I 
I 
I 
I 
I 
- 
T 
- 
T 
- 
I 
Informed consent(s) d 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of 
inclusion/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history, personal 
status, and demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical genotyping 
sample e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis f 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine sample for drugs of 
abuse g 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation (PT and aPTT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral serology (HIV, 
hepatitis B, and hepatitis C) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG h 
x 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
x 
Plasma PK sample i 
 
x 
x 
 
 
 
 
 
x 
 
 
 
 
 
x j 
Plasma ADA sample 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Serum chemistry k and 
hematology l 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Plasma biomarker sample 
x 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x j 


Appendix 1:  Schedule of Activities (cont.) 
  
Table 1  
Screening up to Week 34 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
129/Protocol WN29722, Version 3 
Assessment/Procedure 
Screen 
BL a 
Dose-Escalation Period 
UV 
Wk 8 to  
Wk 1 
Day 1 
Day 4 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 b 
Wk 26 
Wk 28 
Wk 30 
Wk 32 
Wk 34 
Clinical RNA samples 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x j 
Complete physical and 
neurologic exams m 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Limited physical exams n 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
Weight and height o 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
MRI e, p 
x q 
 
 
 
 
x 
 
 
x 
 
 
 
 
 
x r 
PET scan e 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Dementia Rating 
P&CG 
P&CG 
 
 
 
 
 
 
P&CG 
 
 
 
 
 
P&CG 
MMSE 
P 
P 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
ADAS-Cog 13 
 
P 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
Verbal Fluency Task 
 
P 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
Coding 
 
P 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
ADCS-ADL 
 
CG 
 
 
 
 
 
 
CG 
 
 
 
 
 
CG 
C-SSRS BL/SLV 
 
P 
 
 
 
 
 
 
P 
 
 
 
 
 
P 
Home administration 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P&C
G 
Vital signs s 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
Adverse events t 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
Urine pregnancy test u 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 


Appendix 1:  Schedule of Activities (cont.) 
  
Table 1  
Screening up to Week 34 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
130/Protocol WN29722, Version 3 
Assessment/Procedure 
Screen 
BL a 
Dose-Escalation Period 
UV 
Wk 8 to  
Wk 1 
Day 1 
Day 4 
Wk 4 
Wk 8 
Wk 12 
Wk 16 
Wk 20 
Wk 24 b 
Wk 26 
Wk 28 
Wk 30 
Wk 32 
Wk 34 
Study drug administration 
(dose level [mg])  v 
 
C 
(120) 
 
C 
(120) 
C 
(120) 
S 
(255) 
S 
(255) 
S 
(255) 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
- 
Caregiver diary w 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; BL  baseline; APOE  apolipoprotein E; ARIA  amyloid-related imaging abnormality; 
ARIA-E  amyloid-related imaging abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; C  clinic 
administration by study staff; CG  caregiver completion; C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion tensor imaging; 
ET  early termination; H  visit appropriate for home/nonclinical administration, where applicable; I  in-clinic visit; MMA  methylmalonic acid; 
MMSE  Mini-Mental State Examination; MRI  magnetic resonance imaging; P  participant completion; P&CG  participant and caregiver completion; 
PET  positron emission tomography; PK  pharmacokinetic; Q1W  once a week; Q2W  every 2 weeks; Q4W  every 4 weeks; S  supervised at-clinic 
administration, where applicable; Screen  screening; SLV  since last visit; T  telephone visit; UV  unscheduled visit; Wk  week. 
Notes:  For Q4W injections, the dosing window is  7 days, and the recommended minimum time between doses is 3 weeks.  The maximum 
recommended time between doses should not exceed 6 weeks.  For Q2W and Q1W injections, the dosing window is  3 days.  The time window is 
 3 days for non-dosing Day 4. 
Participants should use the actual Day 1 visit to calculate the timing of all subsequent visits, regardless of whether out-of-window visits may have 
occurred.  
For participants who terminate early, assessments listed in the ET visit should be completed.  
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed within 1 week prior to the first dose.  All safety 
assessments (e.g., vital signs, blood tests, and ECGs) should be completed on the day of dosing, prior to dosing. 
b Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital 
signs, blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functional and PET 
assessments should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, for visits 
after start of study treatment, if the study partner (non-professional caregiver), the primary rater, or even the participant cannot perform these 
assessments as per schedule of activities, they may be performed up to 4 weeks out of window. 


Appendix 1:  Schedule of Activities (cont.) 
  
Table 1  
Screening up to Week 34 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
131/Protocol WN29722, Version 3 
c 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/or study partner (non-professional caregiver) to collect adverse event information and any other updates 
regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular participant/study partner 
(non-professional caregiver) if considered appropriate by the investigator. 
d Informed consent must be documented before any study-specific screening procedure is performed. 
e PET and MRI scans at screening should be performed once all other screening results are available and none exclude the participant from the 
trial.  In case of re-screening a participant, all screening assessments must be repeated other than the amyloid PET testing if performed within the 
previous 6 months for this study and within eligible ranges.  Given that APOE status will not change over time, there is no need to repeat clinical 
genotyping in case of re-screening. 
f Performed at the site by dipstick for blood, protein, glucose, and pH. 
g Urine samples will be analyzed for the presence of the following drugs: amphetamine, benzodiazepines, cannabinoids, opiates, cocaine, 
barbiturates, and methadone. 
h Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be obtained 
prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI scans).  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. 
i Accurate recording of the time of study drug administration and PK sample is necessary. 
j An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, worsened, 
stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that meets the 
discontinuation criteria (e.g., during an unscheduled visit). 
k Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, BUN, 
and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the screening period, Week 52, and Week 104, 
hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, MMA, T4, free T4, and TSH 
levels will also be assessed and should ideally be collected at least 4 hours after meals. 
l Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 


Appendix 1:  Schedule of Activities (cont.) 
  
Table 1  
Screening up to Week 34 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
132/Protocol WN29722, Version 3 
m A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be 
performed if clinically indicated.  
n Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
o Height measured at screening only. 
p During the uptitration period, MRIs must be performed after the third dose of current dose level whilst on the Q4W schedule, or after the sixth dose 
of current dose level whilst on the Q2W schedule.  MRIs should be performed at least 7 days prior to dose uptitration to the next dose level and 
the results must be available for review by the investigator or their qualified designee before the dosing can proceed.  It is not recommended that 
the MRI is performed on the same day as the investigational medicinal product administration.  During the Q4W schedule, it is recommended to do 
the MRI at least 10 days after the third dose of the current dose level.  
q Includes resting-state functional MRI and DTI outcome measures where available. 
r Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context of ARIA or to 
follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
s Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate should be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should be 
used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obtained manually, the 
pulse rate should be counted for a minimum of 20 seconds at each assessment. 
t Adverse event information should be collected either at clinic visits or via a telephone call during at-home administration. 
u Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test at screening, within 24 hours 
before a PET scan, after the last study drug dose, and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents.  
v Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  Study 
drug will be administered to participants by SC injection.  Participants should be observed for a minimum of 2 hours after dosing for the first four 
doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised administration by study partner (non-
professional caregiver), additional training may be given as per the investigator’s judgment. 
w If applicable, study partners (non-professional caregivers) will confirm completed administration in the home (nonclinical) setting using a caregiver 
diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary to each visit to the clinic. 


Appendix 1:  Schedule of Activities (cont.) 
  
Gantenerumab—F. Hoffmann-La Roche Ltd 
133/Protocol WN29722, Version 3 
Table 2 
Weeks 3659 for All Participants 
Assessment/Procedure 
Target Dose 
UV 
Wk 36 
Wk 
3739 
Wk 40 
Wk 
4143 
Wk 44 
Wk 
4547 
Wk 48 
Wk 
4951 
Wk 52 a 
Wk 
5355 
Wk 56 
Wk 
5759 
Visit type b 
I 
- 
T 
- 
T 
- 
T 
- 
I 
- 
T 
- 
I 
12-lead ECG c 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Plasma PK sample d 
x 
 
 
 
 
 
 
 
x 
 
 
 
x e 
Plasma ADA sample 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
Serum chemistry f and 
hematology g 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Plasma biomarker samples 
x 
 
 
 
 
 
 
 
x 
 
 
 
x e 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Limited physical exams h 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Weight 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
MRI i 
x 
 
 
 
 
 
x j 
 
 
 
 
 
x k 
PET scan  
 
 
 
 
 
 
 
 
x 
 
 
 
 
Clinical Dementia Rating  
 
 
 
 
 
 
 
 
P&CG 
 
 
 
P&CG 
MMSE 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
ADAS-Cog 13 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
Verbal Fluency Task 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
Coding 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
ADCS-ADL 
 
 
 
 
 
 
 
 
CG 
 
 
 
CG 
C-SSRS BL/SLV 
 
 
 
 
 
 
 
 
P 
 
 
 
P 


Appendix 1:  Schedule of Activities (cont.) 
  
Table 2  
Weeks 3659 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
134/Protocol WN29722, Version 3 
Assessment/Procedure 
Target Dose 
UV 
Wk 36 
Wk 
3739 
Wk 40 
Wk 
4143 
Wk 44 
Wk 
4547 
Wk 48 
Wk 
4951 
Wk 52 a 
Wk 
5355 
Wk 56 
Wk 
5759 
Home administration 
questionnaire 
P&CG 
 
 
 
 
 
 
 
P&CG 
 
 
 
P&CG 
Vital signs l 
x 
 
 
 
 
 
 
 
x 
 
 
 
x 
Concomitant medications 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Adverse events m 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Urine pregnancy test n 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Study drug administration 
(dose level [mg])  o 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
- 
Caregiver diary p 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging 
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion tensor imaging; ET  early termination; H  visit appropriate for home/nonclinical 
administration, where applicable; I  in-clinic visit; MMA  methylmalonic acid; MMSE  Mini-Mental State Examination; MRI  magnetic resonance 
imaging; P  participant completion; P&CG  participant and caregiver completion; PET  positron emission tomography; PK  pharmacokinetic; 
Q1W  once a week; S  supervised at-clinic administration, where applicable; SLV  since last visit; T  telephone visit; UV  unscheduled visit; 
Wk  week. 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  
For participants who terminate early, assessments listed in the ET visit should be completed. 
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functional assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, if the study 
partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of activities, 
they may be performed up to 4 weeks out of window. 


Appendix 1:  Schedule of Activities (cont.) 
  
Table 2  
Weeks 3659 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
135/Protocol WN29722, Version 3 
b 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/or study partner (non-professional caregiver) to collect adverse event information and any other updates 
regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular participant/study partner 
(non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be obtained 
prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI scans).  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. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, worsened, 
stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that meets the 
discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, 
BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the screening period, Week 52, and 
Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, MMA, T4, free 
T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals. 
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i During the target dose period, MRIs should be performed at least 7 days but not 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 the dosing at the visit that requires a safety 
MRI can proceed. 
j Includes resting-state functional MRI and DTI outcome measures, where available. 
k Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context of ARIA or to 
follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
l Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate should be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should 


Appendix 1:  Schedule of Activities (cont.) 
  
Table 2  
Weeks 3659 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
136/Protocol WN29722, Version 3 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obtained manually, the 
pulse rate should be counted for a minimum of 20 seconds at each assessment. 
m Adverse event information should be collected either at clinic visits or via a telephone call during at-home administration. 
n Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, within 24 hours 
before a PET scan, after the last study drug dose, and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents. 
o Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  Study 
drug will be administered to participants by SC injection.  Participants should be observed for a minimum of 2 hours after dosing for the first four 
doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised administration by study partner 
(non-professional caregiver), additional training may be given as per the investigator’s judgment. 
p If applicable, study partners (non-professional caregivers) will confirm completed administration in the home (nonclinical) setting using a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary to each visit to the clinic. 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
137/Protocol WN29722, Version 3 
Table 3 
Weeks 6083 for All Participants 
Assessment/Procedure 
Target Dose 
UV 
Wk 
60 
Wk 
6163 
Wk 
64 
Wk 
6567 
Wk 
68 
Wk 
6971 
Wk 
72 
Wk 
7375 
Wk 
76 a 
Wk 
7779 
Wk 
80 
Wk 
8183 
Visit type b 
T 
- 
I 
- 
T 
- 
T 
- 
I 
- 
T 
- 
 
12-lead ECG c 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Plasma PK sample d 
 
 
 
 
 
 
 
 
x 
 
 
 
x e 
Plasma ADA sample 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Serum chemistry f and 
hematology g 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Plasma biomarker samples 
 
 
 
 
 
 
 
 
x 
 
 
 
x e 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Limited physical exams h 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
Weight 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
MRI i  
x 
 
 
 
 
 
 
 
x 
 
 
 
x j 
PET scan  
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Dementia Rating 
 
 
 
 
 
 
 
 
P&CG 
 
 
 
P&CG 
MMSE 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
ADAS-Cog 13 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
Verbal Fluency Task 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
Coding 
 
 
 
 
 
 
 
 
P 
 
 
 
P 
ADCS-ADL 
 
 
 
 
 
 
 
 
CG 
 
 
 
CG 
C-SSRS BL/SLV 
 
 
 
 
 
 
 
 
P 
 
 
 
P 


 
Appendix 1: Schedule of Activities (cont.) 
Table 3 
Weeks 6083 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
138/Protocol WN29722, Version 3 
Assessment/Procedure 
Target Dose 
UV 
Wk 
60 
Wk 
6163 
Wk 
64 
Wk 
6567 
Wk 
68 
Wk 
6971 
Wk 
72 
Wk 
7375 
Wk 
76 a 
Wk 
7779 
Wk 
80 
Wk 
8183 
Home administration 
questionnaire 
 
 
 
 
 
 
 
 
P&C
G 
 
 
 
P&C
G 
Vital signs k 
 
 
x 
 
 
 
 
 
x 
 
 
 
x 
Concomitant medications 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Adverse events l 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Urine pregnancy test m 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Study drug administration 
(dose level [mg])  n 
H 
(255) 
H 
(255) 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
 
Caregiver diary o 
x 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging 
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; ET  early termination; H  visit appropriate for home/nonclinical administration, where 
applicable; I  in-clinic visit; MMA  methylmalonic acid; MMSE  Mini-Mental State Examination; MRI  magnetic resonance imaging; P  participant 
completion; P&CG  participant and caregiver completion; PET  positron emission tomography; PK  pharmacokinetic; Q1W  once a week; 
S  supervised at-clinic administration, where applicable; SLV  since last visit; T  telephone visit; UV  unscheduled visit; Wk  week. 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  
For participants who terminate early, assessments listed in the ET visit should be completed. 
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functional assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, if the study 
partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of activities, 
they may be performed up to 4 weeks out of window. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 3 
Weeks 6083 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
139/Protocol WN29722, Version 3 
b 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/or study partner (non-professional caregiver) to collect adverse event information and any other updates 
regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular participant/study partner 
(non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be obtained 
prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI scans).  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. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, worsened, 
stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that meets the 
discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, 
BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the screening period, Week 52, and 
Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, MMA, T4, free 
T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals. 
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i During the target dose period, MRIs should be performed at least 7 days but not 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 can proceed. 
j Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context of ARIA or to 
follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
k Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate should be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obtained manually, the 
pulse rate should be counted for a minimum of 20 seconds at each assessment. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 3 
Weeks 6083 for All Participants (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
140/Protocol WN29722, Version 3 
l Adverse event information should be collected either at clinic visits or via a telephone call during at-home administration. 
m Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test at screening, within 24 hours 
before a PET scan, after the last study drug dose, and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents. 
n Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  Study 
drug will be administered to participants by SC injection.  Participants should be observed for a minimum of 2 hours after dosing for the first four 
doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised administration by study partner 
(non-professional caregiver), additional training may be given as per the investigator’s judgment. 
o If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting using a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary to each visit to the clinic. 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
141/Protocol WN29722, Version 3 
Table 4 
Weeks 84104, Early Termination Visit, and Follow-Up for Participants Who Do Not Take Part in 2-
Year Extension 
Assessment/ Procedure 
Target Dose 
ET a 
FU 
UV 
Wk 
84 
Wk 
8587 
Wk 
88 
Wk 
8991 
Wk 
92 
Wk 
9395 
Wk 
96 
Wk 
9799 
Wk 
100 a 
Wk 
101103 
Wk 
104 a 
 
Wk 
120 
 
Visit type b 
T 
- 
I 
- 
T 
- 
T 
- 
T 
- 
I 
I 
I 
 
12-lead ECG c 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Plasma PK sample d 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x e 
Plasma ADA sample  
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Serum chemistry f and 
hematology g 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
Plasma biomarker sample 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
x e 
Clinical RNA sample 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
x e 
Complete physical and 
neurologic exams h 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
 
Limited physical exams i 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
x 
Weight 
 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
MRI j 
 
 
 
 
 
 
 
 
 
 
x k 
x k 
 
x l 
PET scan  
 
 
 
 
 
 
 
 
 
 
x 
x m 
 
 
Clinical Dementia Rating 
 
 
 
 
 
 
 
 
 
 
P&CG 
P&CG 
 
P&CG 
MMSE 
 
 
 
 
 
 
 
 
 
 
P 
P 
 
P 
ADAS-Cog 13 
 
 
 
 
 
 
 
 
 
 
P 
P 
 
P 
Verbal Fluency Task 
 
 
 
 
 
 
 
 
 
 
P 
P 
 
P 
Coding 
 
 
 
 
 
 
 
 
 
 
P 
P 
 
P 


 
Appendix 1: Schedule of Activities (cont.) 
Table 4 
Weeks 84104, Early Termination Visit, and Follow-Up for Participants Who Do Not Take Part in 2-
Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
142/Protocol WN29722, Version 3 
Assessment/ Procedure 
Target Dose 
ET a 
FU 
UV 
Wk 
84 
Wk 
8587 
Wk 
88 
Wk 
8991 
Wk 
92 
Wk 
9395 
Wk 
96 
Wk 
9799 
Wk 
100 a 
Wk 
101103 
Wk 
104 a 
 
Wk 
120 
 
ADCS-ADL 
 
 
 
 
 
 
 
 
 
 
CG 
CG 
 
CG 
C-SSRS BL/SLV 
 
 
 
 
 
 
 
 
 
 
P 
P 
 
P 
Home administration  
questionnaire 
 
 
 
 
 
 
 
 
 
 
P&CG 
P&CG 
 
P&CG 
Vital signs n 
 
 
x 
 
 
 
 
 
 
 
x 
x 
x 
x 
Concomitant medications 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Adverse events o 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
x 
Urine pregnancy test p 
 
 
 
 
 
 
 
 
 
 
x 
x 
 
x 
Study drug administration 
(dose level [mg])  q 
H 
(255) 
H 
(255) 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
 
 
- 
 
Caregiver diary r 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging 
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion tensor imaging; ET  early termination; FU  follow-up; H  visit appropriate for 
home/nonclinical administration, where applicable; I  in-clinic visit; MMA  methylmalonic acid; MMSE  Mini-Mental State Examination; 
MRI  magnetic resonance imaging; P  participant completion; P&CG  participant and caregiver completion; PET  positron emission tomography; 
PK  pharmacokinetic; S  supervised at-clinic administration, where applicable; Q1W  once a week; SLV  since last visit; T  telephone visit; 
UV  unscheduled visit. 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  
For participants who terminate early, assessments listed in the ET visit should be completed. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 4 
Weeks 84104, Early Termination Visit, and Follow-Up for Participants Who Do Not Take Part in 2-
Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
143/Protocol WN29722, Version 3 
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functional assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances, if the study 
partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of activities, 
they may be performed up to 4 weeks out of window. 
b 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/or study partner (non-professional caregiver) to collect adverse events information and any other updates 
regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular participant/study partner 
(non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be obtained 
prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI scans).  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. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, worsened, 
stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that meets the 
discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, 
potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the screening period, 
Week 52, and Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, 
MMA, T4, free T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals. 
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 
h A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be 
performed if clinically indicated. 
i Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  


 
Appendix 1: Schedule of Activities (cont.) 
Table 4 
Weeks 84104, Early Termination Visit, and Follow-Up for Participants Who Do Not Take Part in 2-
Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
144/Protocol WN29722, Version 3 
j During the target dose period, MRIs should be performed at least 7 days but not 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 can proceed. 
k Includes resting-state functional MRI and DTI outcome measures, where available. 
l Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context of ARIA or to 
follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
m In the event a participant terminates early, an amyloid PET scan should only be collected if at least 6 months have elapsed since the previous 
amyloid PET scan and if compatible with local/national regulation for annual radiation exposure limit. 
n Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate should be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obtained manually, the 
pulse rate should be counted for a minimum of 20 seconds at each assessment. 
o Adverse event information should be collected either at clinic visits or via a telephone call during at-home administration. 
p Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, within 24 hours 
before a PET scan, after the last study drug dose and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents. 
q Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  Study 
drug will be administered to participants by SC injection.  Participants should be observed a minimum of 2 hours after dosing for the first four 
doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised administration by study partner 
(non-professional caregiver), additional training may be given as per the investigator’s judgment. 
r If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting using a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary to each visit to the clinic. 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
145/Protocol WN29722, Version 3 
Table 5 
Weeks 84107 for Participants Who Take Part in 2-Year Extension 
Assessment/ Procedure 
Target Dose 
UV 
Wk 
84 
Wk 
8587 
Wk 
88 
Wk 
8991 
Wk 
92 
Wk 
9395 
Wk 
96 
Wk 
9799 
Wk 
100  
Wk 
10110
3 
Wk 
104 a 
Wk 
105
107 
Visit type b 
T 
- 
I 
- 
T 
- 
T 
- 
T 
- 
I 
- 
 
12-lead ECG c 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Plasma PK sample d 
 
 
 
 
 
 
 
 
 
 
x  
 
x e 
Plasma ADA sample  
 
 
 
 
 
 
 
 
 
 
x  
 
x 
Serum chemistry f and 
hematology g 
 
 
 
 
 
 
 
 
 
 
x  
 
x 
Plasma biomarker sample 
 
 
 
 
 
 
 
 
 
 
x  
 
x e 
Clinical RNA sample 
 
 
 
 
 
 
 
 
 
 
x 
 
x e 
Complete physical and 
neurologic exams h 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Limited physical exams i 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Weight 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
MRI j 
 
 
 
 
 
 
 
 
 
 
x k 
 
x l 
PET scan  
 
 
 
 
 
 
 
 
 
 
x 
  
 
Clinical Dementia Rating 
 
 
 
 
 
 
 
 
 
 
P&C
G 
 
P&C
G 
MMSE 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
ADAS-Cog 13 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
Verbal Fluency Task 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
 


 
Appendix 1: Schedule of Activities (cont.) 
Table 5 
Weeks 84107 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
146/Protocol WN29722, Version 3 
Assessment/Procedure 
Target Dose 
UV 
Wk 
84 
Wk 
8587 
Wk 
88 
Wk 
8991 
Wk 
92 
Wk 
9395 
Wk 
96 
Wk 
9799 
Wk 
100  
Wk 
10110
3 
Wk 
104 a 
Wk 
105
107 
Coding 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
ADCS-ADL 
 
 
 
 
 
 
 
 
 
 
CG 
 
CG 
C-SSRS BL/SLV 
 
 
 
 
 
 
 
 
 
 
P 
 
P 
Home administration 
questionnaire 
 
 
 
 
 
 
 
 
 
 
P&C
G 
 
P&C
G 
Vital signs m 
 
 
x 
 
 
 
 
 
 
 
x 
 
x 
Concomitant medications 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Adverse events n 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Urine pregnancy test o 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
Study drug 
administration (dose level 
[mg]) p 
H 
(255) 
H 
(255) 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255) 
S 
(255) 
H 
(255) 
 
Caregiver diary q 
x 
x 
 
x 
x 
X 
x 
x 
x 
x 
 
x 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging 
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI   diffusion tensor imaging; ET   early termination; FU  follow-up; H  visit 
appropriate for home/nonclinical administration, where applicable; I   in-clinic visit; MMA  methylmalonic acid; MMSE   Mini-Mental State 
Examination; MRI  magnetic resonance imaging; P  participant completion; P&CG   participant and caregiver completion; PET  positron 
emission tomography; PK  pharmacokinetic; S  supervised at-clinic administration, where applicable; Q1W  once a week; SLV  since last 
visit; T  telephone visit; UV  unscheduled visit. 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  


 
Appendix 1: Schedule of Activities (cont.) 
Table 5 
Weeks 84107 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
147/Protocol WN29722, Version 3 
For participants who terminate early, assessments listed in the ET visit should be completed. 
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functional assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances,  if the 
study partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of 
activities, they may be performed up to 4 weeks out of window. 
b 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/or study partner (non-professional caregiver) to collect adverse events information and any other 
updates regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular participant/study 
partner (non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECG s are to be 
obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI scans).  
Circumstances that may induce changes in heart rate, including environmental distractions (e.g., television, radio, conversat ion), should be 
avoided during the pre-ECG resting period and during ECG recording. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e .g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA -E or ARIA-H that 
meets the discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, 
potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the sc reening period, 
Week 52, and Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin 
B-12, MMA, T4, free T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals.  
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocyt es, 
monocytes, and neutrophils. 
h A complete physical examination, performed at specified visits, should include an evaluation of t he head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinati ons may be 
performed if clinically indicated. 
i Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  


 
Appendix 1: Schedule of Activities (cont.) 
Table 5 
Weeks 84107 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
148/Protocol WN29722, Version 3 
j During the target dose period, MRIs should be performed at least 7 days but not more than 13 days before the dosing visit tha t 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 can proceed. 
k Includes resting-state functional MRI and DTI outcome measures, where available. 
l Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context of ARIA or 
to follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
m Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate shou ld be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obt ained manually, 
the pulse rate should be counted for a minimum of 20 seconds at each assessment. 
n Adverse event information should be collected either at clinic visits or via a telephone call during at -home administration. 
o Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, within 24 hours 
before a PET scan, after the last study drug dose and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents.  
p Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by SC injection.  Participants should be observed a minimum of 2 hours after dosing for the 
first four doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised admini stration by 
study partner (non-professional caregiver), additional training may be given as per the investigator’s judgment.  
q If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting usin g a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary t o each visit to the 
clinic. 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
149/Protocol WN29722, Version 3 
Table 6 
Weeks 108131 for Participants Who Take Part in 2-Year Extension 
Assessment/Procedure 
Target Dose 
UV 
Wk 
108 
Wk 
1091
11 
Wk 
112 
Wk 
11311
5 
Wk 
116 
Wk 
117
119 
Wk 
120 
Wk 
12112
3 
Wk 
124  
Wk 
12512
7 
Wk 
128 
Wk 
129 
Wk 
130 a  
Visit type b 
T 
- 
T 
- 
I 
- 
T 
- 
T 
- 
T 
- 
I 
 
12-lead ECG c 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Plasma PK sample d 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Plasma ADA sample 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Serum chemistry f and 
hematology g 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Plasma biomarker 
samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Limited physical exams h 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
MRI i  
 
 
 
 
 
 
 
 
 
 
 
 
x 
x j 
PET scan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Dementia 
Rating 
 
 
 
 
 
 
 
 
 
 
 
 
P&C
G 
P&C
G 
MMSE 
 
 
 
 
 
 
 
 
 
 
 
 
P 
P 
ADAS-Cog 13 
 
 
 
 
 
 
 
 
 
 
 
 
P 
P 
Verbal Fluency Task 
 
 
 
 
 
 
 
 
 
 
 
 
P 
P 
Coding 
 
 
 
 
 
 
 
 
 
 
 
 
P 
P 
 


 
Appendix 1: Schedule of Activities (cont.) 
Table 6 
Weeks 108131 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
150/Protocol WN29722, Version 3 
Assessment/Procedure 
Target Dose 
UV 
Wk 
108 
Wk 
109 
111 
Wk 
112 
Wk 
11311
5 
Wk 
116 
Wk 
117
119 
Wk 
120 
Wk 
12112
3 
Wk 
124  
Wk 
12512
7 
Wk 
128 
Wk 
129 
Wk 
130 a  
ADCS-ADL 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
CG 
C-SSRS BL/SLV 
 
 
 
 
 
 
 
 
 
 
 
 
P 
P 
Home administration 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
P&C
G 
P&C
G 
Vital signs k 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
x 
Concomitant medications 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Adverse events l 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Urine pregnancy test m 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Study drug 
administration (dose 
level [mg]) n 
H 
(255
) 
H 
(255) 
H 
(255
) 
H 
(255) 
S 
(255
) 
H 
(255) 
H 
(255
) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255
) 
H 
(255) 
S 
(255) 
 
Caregiver diary o 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging 
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI   diffusion tensor imaging; ET   early termination; FU  follow-up; H  visit 
appropriate for home/nonclinical administration, where applicable; I   in-clinic visit; MMA  methylmalonic acid; MMSE   Mini-Mental State 
Examination; MRI  magnetic resonance imaging; P  participant completion; P&CG   participant and caregiver completion; PET  positron 
emission tomography; PK  pharmacokinetic; S  supervised at-clinic administration, where applicable; Q1W   once a week; SLV  since last 
visit; T  telephone visit; UV  unscheduled visit. 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  
For participants who terminate early, assessments listed in the ET visit should be completed.  


 
Appendix 1: Schedule of Activities (cont.) 
Table 6 
Weeks 108131 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
151/Protocol WN29722, Version 3 
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functio nal assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances,  if the 
study partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of 
activities, they may be performed up to 4 weeks out of window. 
b 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/or study partner (non-professional caregiver) to collect adverse events information and any other 
updates regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular part icipant/study 
partner (non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be 
obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI sca ns).  
Circumstances that may induce changes in heart rate, including environmental distractions (e.g., television, radio, conversation), should b e 
avoided during the pre-ECG resting period and during ECG recording. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e .g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokin ase, sodium, 
potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the sc reening period, 
Week 52, and Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin 
B-12, MMA, T4, free T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals.  
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i During the target dose period, MRIs should be performed at least 7 days but not 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 can proceed. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 6 
Weeks 108131 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
152/Protocol WN29722, Version 3 
j Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context o f ARIA or 
to follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
k Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate shou ld be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obt ained manually, 
the pulse rate should be counted for a minimum of 20 seconds at each assessment. 
l Adverse event information should be collected either at clinic visits or via a telephone call during at -home administration. 
m Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, within 24 hours 
before a PET scan, after the last study drug dose and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents.  
n Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by SC injection.  Participants should be observed a minimum of 2 hours after dosing for the 
first four doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised admini stration by 
study partner (non-professional caregiver), additional training may be given as per the investigator’s judgment.  
o  If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting usi ng a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary t o each visit to the 
clinic. 
 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
153/Protocol WN29722, Version 3 
Table 7 
Weeks 132155 for Participants Who Take Part in 2-Year Extension 
Assessment/Procedure 
Target Dose 
 
UV 
Wk 
131
133 
Wk 
134 
Wk 
135
137 
Wk 138 
Wk 
139
141 
Wk 
142 
Wk 
143
145 
Wk 146 
Wk 
1471
49  
Wk 150 
Wk 
151-
153 
Wk 
154 
Wk 
155 
Visit type a 
- 
T 
- 
T 
- 
I 
- 
T 
- 
T 
- 
T 
- 
 
12-lead ECG b 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Plasma PK sample c 
 
 
 
 
 
 
 
 
 
 
 
 
 
x d 
Plasma ADA sample 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Serum chemistry e and 
hematology f 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Plasma biomarker 
samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
x d 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
x d 
Limited physical exams g 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
MRI h 
 
 
 
 
 
 
 
 
 
 
 
 
 
x i 
PET scan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Dementia 
Rating 
 
 
 
 
 
 
 
 
 
 
 
 
 
P&C
G 
MMSE 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
ADAS-Cog 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
Verbal Fluency Task 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
Coding 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
 


 
Appendix 1: Schedule of Activities (cont.) 
Table 7 
Weeks 132155 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
154/Protocol WN29722, Version 3 
Assessment/Procedure 
Target Dose 
UV 
Wk 
131
133 
Wk 
134 
Wk 
135
137 
Wk 138 
Wk 
139
141 
Wk 
142 
Wk 
143
145 
Wk 146 
Wk 
1471
49  
Wk 150 
Wk 
151
153 
Wk 
154 
Wk 
155 
ADCS-ADL 
 
 
 
 
 
 
 
 
 
 
 
 
 
CG 
C-SSRS BL/SLV 
 
 
 
 
 
 
 
 
 
 
 
 
 
P 
Home administration 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
P&C
G 
Vital signs j 
 
 
 
 
 
x 
 
 
 
 
 
 
 
x 
Concomitant medications 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Adverse events k 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
Urine pregnancy test l 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Study drug 
administration (dose 
level [mg]) m 
H 
(255
) 
H 
(255) 
H 
(255
) 
H 
(255) 
H 
(255
) 
S 
(255) 
H 
(255
) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255
) 
H 
(255) 
H 
(255) 
 
Caregiver diary n 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging 
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI   diffusion tensor imaging; ET   early termination; FU  follow-up; H  visit 
appropriate for home/nonclinical administration, where applicable; I   in-clinic visit; MMA  methylmalonic acid; MMSE   Mini-Mental State 
Examination; MRI  magnetic resonance imaging; P  participant completion; P&CG   participant and caregiver completion; PET  positron 
emission tomography; PK  pharmacokinetic; S  supervised at-clinic administration, where applicable; Q1W   once a week; SLV  since last 
visit; T  telephone visit; UV  unscheduled visit. 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  
For participants who terminate early, assessments listed in the ET visit should be completed.  


 
Appendix 1: Schedule of Activities (cont.) 
Table 7 
Weeks 132155 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
155/Protocol WN29722, Version 3 
a 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/or study partner (non-professional caregiver) to collect adverse events information and any other 
updates regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular part icipant/study 
partner (non-professional caregiver) if considered appropriate by the investigator. 
b Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECG s are to be 
obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI scans).  
Circumstances that may induce changes in heart rate, including environmental distractions (e.g., television, radio, conversat ion), should be 
avoided during the pre-ECG resting period and during ECG recording. 
c Accurate recording of the time of study drug administration and PK sample is necessary. 
d An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA -E or ARIA-H that 
meets the discontinuation criteria (e.g., during an unscheduled visit). 
e Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinas e, sodium, 
potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central labora tory).  During the screening period, 
Week 52, and Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin 
B-12, MMA, T4, free T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals. 
f Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymph ocytes, 
monocytes, and neutrophils. 
g Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
h During the target dose period, MRIs should be performed at least 7 days but not more than 13 days before the dosing visit tha t 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 can proceed. 
i Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context of ARIA or 
to follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
j Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and p ulse rate should be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The  same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obtained manually, 
the pulse rate should be counted for a minimum of 20 seconds at each assessment. 
k Adverse event information should be collected either at clinic visits or via a telephone call during at -home administration. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 7 
Weeks 132155 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
156/Protocol WN29722, Version 3 
l Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, w ithin 24 hours 
before a PET scan, after the last study drug dose and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source docu ments. 
m Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by SC injection.  Participants should be observed a minimum of 2 hours after dosing for the 
first four doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised administration by 
study partner (non-professional caregiver), additional training may be given as per the investigator’s judgment.  
n   If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting using a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary t o each visit to the 
clinic. 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
157/Protocol WN29722, Version 3 
Table 8 
Weeks 156179 for Participants Who Take Part in 2-Year Extension 
Assessment/Procedure 
Target Dose 
UV 
Wk 
156 a 
Wk 
1571
59 
Wk 
160 
Wk 
16116
3 
Wk 
164 
Wk 
165
167 
Wk 
168 
Wk169
171 
Wk 
172  
Wk 
17317
5 
Wk 
176 
Wk 
1771
79 
Visit type b 
I 
- 
T 
- 
T 
- 
I 
- 
T 
- 
T 
- 
 
12-lead ECG c 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Plasma PK sample d 
x 
 
 
 
 
 
 
 
 
 
 
 
x e 
Plasma ADA sample 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Serum chemistry f and 
hematology g 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Plasma biomarker 
samples 
x 
 
 
 
 
 
 
 
 
 
 
 
x e 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Limited physical exams h 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
Weight 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
MRI i  
x j 
 
 
 
 
 
 
 
 
 
 
 
x k 
PET scan  
x 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Dementia 
Rating 
P&C
G 
 
 
 
 
 
 
 
 
 
 
 
P&C
G 
MMSE 
P 
 
 
 
 
 
 
 
 
 
 
 
P 
ADAS-Cog 13 
P 
 
 
 
 
 
 
 
 
 
 
 
P 
Verbal Fluency Task 
P 
 
 
 
 
 
 
 
 
 
 
 
P 
Coding 
P 
 
 
 
 
 
 
 
 
 
 
 
P 
 


Appendix 1: Schedule of Activities (cont.) 
Table 8 
Weeks 156179 for Participants Who Take Part in 2-Year Extension (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd 
158/Protocol WN29722, Version 3 
Assessment/Procedure 
Target Dose 
UV 
Wk 
156 a 
Wk15
7159
Wk 
160 
Wk 
16116
3 
Wk 
164 
Wk 
165
167 
Wk 
168 
Wk169
171
Wk 
172 
Wk 
17317
5 
Wk 
176 
Wk 
1771
79 
ADCS-ADL 
CG 
CG 
C-SSRS BL/SLV
P 
P 
Home administration 
questionnaire 
P&C
G 
P&C
G 
Vital signs l 
x 
x 
x 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
Adverse events m 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test n 
x 
x 
Study drug 
administration (dose 
level [mg]) o 
S 
(255
) 
H 
(255) 
H 
(255
) 
H 
(255) 
H 
(255
) 
H 
(255) 
S 
(255
) 
H 
(255) 
H 
(255) 
H 
(255) 
H 
(255
) 
H 
(255) 
Caregiver diary p 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion;
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI   diffusion tensor imaging; ET   early termination; FU  follow-up; H  visit
appropriate for home/nonclinical administration, where applicable; I   in-clinic visit; MMA  methylmalonic acid; MMSE   Mini-Mental State
Examination; MRI  magnetic resonance imaging; P  participant completion; P&CG  participant and caregiver completion; PET  positron
emission tomography; PK  pharmacokinetic; S  supervised at-clinic administration, where applicable; Q1W   once a week; SLV  since last
visit; T  telephone visit; UV  unscheduled visit.
Notes:  For Q1W injections, the dosing window is  3 days.
Participants should return to initial planned schedule per Day 1 for subsequent visits. 
For participants who terminate early, assessments listed in the ET visit should be completed.  


 
Appendix 1: Schedule of Activities (cont.) 
Table 8 
Weeks 156179 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
159/Protocol WN29722, Version 3 
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functio nal assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances,  if the 
study partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of 
activities, they may be performed up to 4 weeks out of window. 
b 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/or study partner (non-professional caregiver) to collect adverse events information and any other 
updates regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular part icipant/study 
partner (non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be 
obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI sca ns).  
Circumstances that may induce changes in heart rate, including environmental distractions (e.g., television, radio, conversation), should b e 
avoided during the pre-ECG resting period and during ECG recording. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e .g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokin ase, sodium, 
potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the sc reening period, 
Week 52, and Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin 
B-12, MMA, T4, free T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals.  
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i During the target dose period, MRIs should be performed at least 7 days but not 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 can proceed. 
j Includes resting-state functional MRI and DTI outcome measures, where available. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 8 
Weeks 156179 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
160/Protocol WN29722, Version 3 
k Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context o f ARIA or 
to follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
l Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate shou ld be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obt ained manually, 
the pulse rate should be counted for a minimum of 20 seconds at each assessment. 
m Adverse event information should be collected either at clinic visits or via a telephone call during at -home administration. 
n Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, within 24 hours 
before a PET scan, after the last study drug dose and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents.  
o Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by SC injection.  Participants should be observed a minimum of 2 hours after dosing for the 
first four doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised admini stration by 
study partner (non-professional caregiver), additional training may be given as per the investigator’s judgment.  
p   If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting us ing a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary t o each visit to the 
clinic. 
 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
161/Protocol WN29722, Version 3 
Table 9 
Weeks 180203 for Participants Who Take Part in 2-Year Extension 
Assessment/Procedure 
Target Dose 
UV 
Wk 
180 
Wk 
181 
Wk 
182 a 
Wk 
183
185 
Wk 186 
Wk 
187
189 
Wk 
190 
Wk 
191
193 
Wk 194 
Wk 
1951
97  
Wk 198 
Wk 
199
201 
Wk 
202 
Visit type b 
T 
- 
I 
- 
T 
- 
T 
- 
I 
- 
T 
- 
T 
 
12-lead ECG c 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Plasma PK sample d 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Plasma ADA sample 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Serum chemistry f and 
hematology g 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Plasma biomarker 
samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Clinical RNA samples 
 
 
 
 
 
 
 
 
 
 
 
 
 
x e 
Limited physical exams h 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
Weight 
 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
MRI i  
 
 
x 
 
 
 
 
 
 
 
 
 
 
x j 
PET scan  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Dementia 
Rating 
 
 
P&C
G 
 
 
 
 
 
 
 
 
 
 
P&C
G 
MMSE 
 
 
P 
 
 
 
 
 
 
 
 
 
 
P 
ADAS-Cog 13 
 
 
P 
 
 
 
 
 
 
 
 
 
 
P 
Verbal Fluency Task 
 
 
P 
 
 
 
 
 
 
 
 
 
 
P 
Coding 
 
 
P 
 
 
 
 
 
 
 
 
 
 
P 
 


 
Appendix 1: Schedule of Activities (cont.) 
Table 9 
Weeks 180203 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
162/Protocol WN29722, Version 3 
Assessment/Procedure 
Target Dose 
UV 
Wk 
180 
Wk 
181 
Wk 
182a 
Wk 
183
185 
Wk 186 
Wk 
187
189 
Wk 
190 
Wk 
191
193 
Wk 194 
Wk 
1951
97  
Wk 198 
Wk 
199
201 
Wk 
202 
ADCS-ADL 
 
 
CG 
 
 
 
 
 
 
 
 
 
 
CG 
C-SSRS BL/SLV 
 
 
P 
 
 
 
 
 
 
 
 
 
 
P 
Home administration 
questionnaire 
 
 
P&C
G 
 
 
 
 
 
 
 
 
 
 
P&C
G 
Vital signs k 
 
 
x 
 
 
 
 
 
x 
 
 
 
 
x 
Concomitant medications 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Adverse events l 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
Urine pregnancy test m 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
Study drug 
administration (dose 
level [mg]) n 
H 
(255
) 
H 
(255) 
S 
(255) 
H 
(255
) 
H 
(255) 
H 
(255
) 
H 
(255) 
H 
(255
) 
S 
(255) 
H 
(255) 
H 
(255) 
H 
(255
) 
H 
(255) 
 
Caregiver diary o 
x 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 
 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease 
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging 
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion; 
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI   diffusion tensor imaging; ET   early termination; FU  follow-up; H  visit 
appropriate for home/nonclinical administration, where applicable; I   in-clinic visit; MMA  methylmalonic acid; MMSE   Mini-Mental State 
Examination; MRI  magnetic resonance imaging; P  participant completion; P&CG   participant and caregiver completion; PET  positron 
emission tomography; PK  pharmacokinetic; S  supervised at-clinic administration, where applicable; Q1W   once a week; SLV  since last 
visit; T  telephone visit; UV  unscheduled visit. 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  
For participants who terminate early, assessments listed in the ET visit should be completed.  


 
Appendix 1: Schedule of Activities (cont.) 
Table 9 
Weeks 180203 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
163/Protocol WN29722, Version 3 
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functio nal assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circumstances,  if the 
study partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of 
activities, they may be performed up to 4 weeks out of window. 
b 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/or study partner (non-professional caregiver) to collect adverse events information and any other 
updates regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular part icipant/study 
partner (non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be 
obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI sca ns).  
Circumstances that may induce changes in heart rate, including environmental distractions (e.g., television, radio, conversation), should b e 
avoided during the pre-ECG resting period and during ECG recording. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e .g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokin ase, sodium, 
potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the sc reening period, 
Week 52, and Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin 
B-12, MMA, T4, free T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals.  
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 
h Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i During the target dose period, MRIs should be performed at least 7 days but not 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 can proceed. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 9 
Weeks 180203 for Participants Who Take Part in 2-Year Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
164/Protocol WN29722, Version 3 
j Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring in the context o f ARIA or 
to follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
k Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate shou ld be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obt ained manually, 
the pulse rate should be counted for a minimum of 20 seconds at each assessment. 
l Adverse event information should be collected either at clinic visits or via a telephone call during at -home administration. 
m Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, within 24 hours 
before a PET scan, after the last study drug dose and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source documents.  
n Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by SC injection.  Participants should be observed a minimum of 2 hours after dosing for the 
first four doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised admini stration by 
study partner (non-professional caregiver), additional training may be given as per the investigator’s judgment.  
o   If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting us ing a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bring the diary t o each visit to the 
clinic. 
 


Appendix 1:  Schedule of Activities (cont.) 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
165/Protocol WN29722, Version 3 
Table 10 Weeks 204207, Early Termination Visit, and Follow-up for Participants Who Take Part in 2-Year 
Extension 
Assessment/ Procedure 
Target Dose 
ET a 
FU 
UV 
Wk 
203205 
Wk 206 
Wk 207 
Wk 208 a 
 
Wk 224 
 
Visit type b 
- 
T 
- 
I 
I 
I 
 
12-lead ECG c 
 
 
 
x 
x 
x 
x 
Plasma PK sample d 
 
 
 
x 
x 
x 
x e 
Plasma ADA sample  
 
 
 
x 
x 
x 
x 
Serum chemistry f and 
hematology g 
 
 
 
x 
x 
x 
x 
Plasma biomarker 
sample 
 
 
 
x 
x 
 
x e 
Clinical RNA sample 
 
 
 
x 
x 
 
x e 
Complete physical and 
neurologic exams h 
 
 
 
x 
x 
 
 
Limited physical exams 
i 
 
 
 
 
 
 
x 
Weight 
 
 
 
x 
x 
x 
x 
MRI j 
 
 
 
x k 
x k 
 
x l 
PET scan  
 
 
 
x 
x m 
 
 
Clinical Dementia 
Rating 
 
 
 
P&CG 
P&CG 
 
P&CG 
MMSE 
 
 
 
P 
P 
 
P 
ADAS-Cog 13 
 
 
 
P 
P 
 
P 
 


Appendix 1: Schedule of Activities (cont.) 
Table 10 Weeks 204207, Early Termination Visit, and Follow-up for Participants Who Take Part in 2-Year
Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
166/Protocol WN29722, Version 3 
Assessment/ Procedure 
Target Dose 
ET a 
FU 
UV 
Wk 
203205
Wk 206 
Wk 207 
Wk 208 a 
Wk 224 
Verbal Fluency Task 
P 
P 
P 
Coding 
P 
P 
P 
ADCS-ADL 
CG 
CG 
CG 
C-SSRS BL/SLV
P 
P 
P 
Home administration 
questionnaire 
P&CG 
P&CG 
P&CG 
Vital signs n 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
Adverse events o 
x 
x 
x 
x 
x 
Urine pregnancy test p 
x 
x 
x 
Study drug 
administration (dose 
level [mg]) q 
H (255) 
H (255) 
H (255) 
- 
Caregiver diary r 
x 
x 
x 
ADA  anti-drug antibody; ADAS-Cog13  Alzheimer's Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer’s Disease
Cooperative Study GroupActivities of Daily Living; ARIA  amyloid-related imaging abnormality; ARIA-E  amyloid-related imaging
abnormality-edema/effusion; ARIA-H  amyloid-related imaging abnormality-hemosiderin deposition; BL  baseline; CG  caregiver completion;
C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI   diffusion tensor imaging; ET   early termination; FU  follow-up; H  visit
appropriate for home/nonclinical administration, where applicable; I   in-clinic visit; MMA  methylmalonic acid; MMSE   Mini-Mental State
Examination; MRI  magnetic resonance imaging; P  participant completion; P&CG   participant and caregiver completion; PET  positron
emission tomography; PK  pharmacokinetic; S  supervised at-clinic administration, where applicable; Q1W   once a week; SLV  since last
visit; T  telephone visit; UV  unscheduled visit.


 
Appendix 1: Schedule of Activities (cont.) 
Table 10 Weeks 204207, Early Termination Visit, and Follow-up for Participants Who Take Part in 2-Year 
Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
167/Protocol WN29722, Version 3 
Notes:  For Q1W injections, the dosing window is  3 days. 
Participants should return to initial planned schedule per Day 1 for subsequent visits.  
For participants who terminate early, assessments listed in the ET visit should be completed.  
a Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vital signs, 
blood tests, and ECGs) should be completed on the day of dosing, prior to dosing.  Whenever possible, cognitive and functio nal assessments 
and PET should be performed at the visit timepoints stipulated in the schedule of activities.  However, in exceptional circum stances, if the 
study partner (non-professional caregiver), the primary rater, or even the participant cannot perform these assessments as per schedule of 
activities, they may be performed up to 4 weeks out of window. 
b 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/or study partner (non-professional caregiver) to collect adverse events information and any other 
updates regarding the participant’s health.  The study staff is encouraged to have more frequent calls with a particular part icipant/study 
partner (non-professional caregiver) if considered appropriate by the investigator. 
c Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  The 
ECG recordings must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be 
obtained prior to other procedures scheduled at that same time (e.g., vital sign measurements, blood draws, and brain MRI sca ns).  
Circumstances that may induce changes in heart rate, including environmental distractions (e.g., television, radio, conversation), shoul d be 
avoided during the pre-ECG resting period and during ECG recording. 
d Accurate recording of the time of study drug administration and PK sample is necessary. 
e An additional plasma and blood sample for the assessment of exploratory biomarkers will be obtained as soon as practicable (e .g., at an 
unscheduled visit or the next study visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution (i.e., new, 
worsened, stable, improved, resolved ARIA-E); following new or worsened ARIA-E.  A PK sample will be obtained as soon as practicable 
(e.g., at an unscheduled visit or the next study visit) following a MRI scan showing new occurrence or worsening of ARIA-E or ARIA-H that 
meets the discontinuation criteria (e.g., during an unscheduled visit). 
f Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphok inase, sodium, 
potassium, calcium, BUN, and serum creatinine (and creatinine clearance calculated by the central laboratory).  During the sc reening period, 
Week 52, and Week 104, hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin 
B-12, MMA, T4, free T4, and TSH levels will also be assessed and should ideally be collected at least 4 hours after meals.  
g Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, plate lets, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils. 


 
Appendix 1: Schedule of Activities (cont.) 
Table 10 Weeks 204207, Early Termination Visit, and Follow-up for Participants Who Take Part in 2-Year 
Extension (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
168/Protocol WN29722, Version 3 
h A complete physical examination, performed at specified visits, should include an evaluation of the head, eyes, ears, nose, a nd throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems; genitourinary examinations may be 
performed if clinically indicated. 
i Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant not es.  
j During the target dose period, MRIs should be performed at least 7 days but not more than 13 days before the dosing visit tha t 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 can proceed. 
k Includes resting-state functional MRI and DTI outcome measures, where available. 
l Additional unscheduled MRI scans may be performed to better understand relevant CNS adverse events occurring i n the context of ARIA or 
to follow a sign that emerges at a scheduled scan as described in Sections 4.5.8 and 5.1.3.1. 
m In the event a participant terminates early, an amyloid PET scan should only be collected if at least 6 months have elapsed since the previous 
amyloid PET scan and if compatible with local/national regulation for annual radiation exposure limit.  
n Vital signs include measurements of pulse rate and systolic and diastolic blood pressure.  Blood pressure and pulse rate should be taken when 
the participant is at rest and should not be measured unless at least 15 minutes have elapsed since the last blood draw.  The  same arm should 
be used for all blood pressure measurements.  Pulse rate will be determined and will be recorded as beats per minute.  If obtained manually, 
the pulse rate should be counted for a minimum of 20 seconds at each assessment. 
o Adverse event information should be collected either at clinic visits or via a telephone call during at-home administration. 
p Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy at screening, w ithin 24 hours 
before a PET scan, after the last study drug dose and if a woman is suspected to have become pregnant.  If a urine pregnancy test is positive, 
it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in the source docu ments. 
q Study drug administration should be performed only after all assessments for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by SC injection.  Participants should be observed a minimum of 2 hours after dosing for the 
first four doses.  From the fifth dose, the observation time may be reduced to a minimum of 1 hour.  At any supervised admini stration by 
study partner (non-professional caregiver), additional training may be given as per the investigator’s judgmen t. 
r If applicable, non-professional caregivers (study partners) will confirm completed administration in the home (nonclinical) setting using a 
caregiver diary (including date, time, correct injection location, and amount).  They will also be asked to bri ng the diary to each visit to the 
clinic. 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
169/Protocol WN29722, Version 3 
Appendix 2  
Management Rules for Amyloid-Related Imaging Abnormalities 
Event 
Characteristics 
Action to Be Taken 
ARIA-E 
Asymptomatic ARIA-E 
and BGTS  4 
 
Continue study drug at the same dose level 
(i.e., do not uptitrate) and repeat MRI scan 
4 weeks later (for participants on Q1W dosing 
frequency, this can be after the third or fourth 
dose). 
 
As long as BGTS is  4 and  1, continue study 
drug at the same dose level and repeat MRI 
4 weeks later (for participants on Q1W dosing 
frequency, this can be after the third or fourth 
dose). 
 
Once ARIA-E resolves, resume dosing including 
uptitration.  For participants in the uptitration 
phase, obtain a MRI scan per the titration 
schedule.  For participants on the target dose, 
perform another MRI scan 3 months after study 
drug reintroduction.  
Symptomatic ARIA-E (of 
any size) or  
asymptomatic ARIA-E 
and BGTS  4 
 
Temporarily interrupt study drug and perform 
MRI scans at 4-week intervals until symptoms 
and ARIA-E resolve. 
 
When symptoms and ARIA-E resolve, 
reintroduce study drug at dose given at the time 
the event was detected.  
 
Perform a MRI scan after the first dose while 
participants are on a Q4W dosing frequency, or 
after the second dose while participants are on a 
Q2W dosing frequency or after the third or fourth 
dose for participants on a Q1W dosing 
frequency. 
 
If no new ARIA-E is detected, resume uptitration 
and obtain an MRI per the titration schedule.  For 
participants on the Q1W dosing frequency, 
perform another MRI scan 3 months after study 
drug reintroduction.  
Any recurrence of 
ARIA-E 
 
Treat the same as the first event (based on 
symptoms and BGTS). 
ARIA-H 
ARIA-H  15 
cumulatively (should not 
include any 
disseminated LH) 
 
Permanently discontinue study drug. 
ARIA-E  amyloid-related imaging abnormalityedema/effusion; ARIA-H  amyloid-related imaging 
abnormalityhemosiderin deposition; BGTS  Barkhof grand total score; LH  leptomeningeal 
hemosiderosis; MRI  magnetic resonance imaging; Q1W  once a week; Q2W  every 2 weeks; 
Q4W  every 4 weeks. 
 
The investigator may choose to perform additional magnetic resonance imaging (MRI) 
monitoring for amyloid-related imaging abnormality (ARIA) at any time. 


 
Appendix 2: Management Rules for Amyloid Related Imaging Abnormalities 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
170/Protocol WN29722, Version 3 
Symptomatic amyloid-related imaging abnormality-edema/effusion (ARIA-E) is defined as 
onset or worsening of CNS symptom(s) that is/are temporally associated with ARIA-
E MRI findings. 
Any recurrence of ARIA-E:  Treat using the same procedures as for the first event (based 
on symptoms and Barkhof grand total score [BGTS]). 
Participants who develop amyloid-related imaging abnormalityhemosiderin deposition 
(ARIA-H)  15 cumulatively will be discontinued from study drug (the cumulative 
number should not include any disseminated leptomeningeal hemosiderosis, i.e., 
more than 3 focal leptomeningeal hemosiderosis cumulatively.  A focal 
leptomeningeal hemosiderosis is counted as one ARIA-H). 
In cases where both ARIA-E and ARIA-H occur, the most conservative approach should 
be followed. 
In exceptional cases, as determined by the Sponsor and investigator: 
Q4W monitoring may no longer be necessary in case of an ARIA-E that is 
asymptomatic with BGTS  4 and considered stable over consecutive MRI 
images; or symptomatic ARIA-E for which the imaging evidence of ARIA-E 
has resolved but the CNS symptoms continue. 
The study drug can be either reintroduced or uptitrated, as applicable, in case of 
an asymptomatic ARIA-E that has stabilized at BGTS  4; or a symptomatic 
ARIA-E for which the imaging evidence of ARIA-E has resolved but the CNS 
symptoms continue.  
A pharmacokinetic sample will be obtained as soon as practicable (e.g., at an 
unscheduled visit or the next study visit) following a MRI scan showing new 
occurrence or worsening of ARIA-E or ARIA-H that meets the discontinuation criteria 
(e.g., during an unscheduled visit).  
An additional plasma and blood sample for the assessment of exploratory biomarkers will 
be obtained as soon as practicable (e.g., at an unscheduled visit or the next study 
visit) following each MRI scan showing ARIA-E until and including ARIA-E resolution 
(i.e., new, worsened, stable, improved, or resolved ARIA-E). 
Any other new significant findings will be reviewed by the Medical Monitor and 
appropriate dose action will be proposed. 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
171/Protocol WN29722, Version 3 
Appendix 3  
National Institute on Aging-Alzheimer’s Association Criteria for Mild Alzheimer’s Disease 
NIA-AA Category 
Description 
Probable dementia: 
core clinical criteria 
Meets criteria for 
dementia described 
earlier in the text, 
and, in addition, has 
the following 
characteristics: 
A. Insidious onset:  Symptoms have a gradual onset over months to years, not sudden over hours or days. 
B. Clear-cut history of worsening of cognition by report or observation; and 
C. The initial and most prominent cognitive deficits are evident on history and examination in one of the following 
categories: 
1. 
Amnestic presentation 
 
It is the most common syndromic presentation of AD dementia.  The deficits should include 
impairment in learning and recall of recently learned information.  There should also be evidence of 
cognitive dysfunction in at least one other cognitive domain, as defined earlier in the text. 
2. 
Non-amnestic presentations 
 
Language presentation:  The most prominent deficits are in word finding, but deficits in other 
cognitive domains should be present. 
 
Visuospatial presentation:  The most prominent deficits are in spatial cognition, including object 
agnosia, impaired face recognition, simultanagnosia, and alexia.  Deficits in other cognitive domains 
should be present. 
 
Executive dysfunction:  The most prominent deficits are impaired reasoning, judgment, and problem 
solving.  Deficits in other cognitive domains should be present. 
D. The diagnosis of probable AD dementia should not be applied when there is evidence of (a) substantial 
concomitant cerebrovascular disease, defined by a history of a stroke temporally related to the onset or 
worsening of cognitive impairment; or the presence of multiple or extensive infarcts or severe white matter 
hyperintensity burden; or (b) core features of dementia with Lewy bodies other than dementia itself; or 
(c) prominent features of behavioral variant frontotemporal dementia; or (d) prominent features of semantic 
variant primary progressive aphasia or non-fluent/agrammatic variant primary progressive aphasia; or 
(e) evidence for another concurrent, active neurologic disease, or a non-neurologic medical comorbidity or use 
of medication that could have a substantial effect on cognition. 
 


Appendix 3:  National Institute on Aging-Alzheimer’s Association Criteria for Mild Alzheimer’s Disease 
 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
172/Protocol WN29722, Version 3 
NIA-AA Category 
Description 
Probable AD 
dementia with 
increased level of 
certainty 
Probable AD dementia with documented decline 
In persons who meet the core clinical criteria for probable AD dementia, documented cognitive decline increases 
the certainty that the condition represents an active, evolving pathologic process, but it does not specifically 
increase the certainty that the process is that of AD pathophysiology. 
Probable AD dementia with documented decline is defined as follows: evidence of progressive cognitive decline 
on subsequent evaluations based on information from informants and cognitive testing in the context of either 
formal neuropsychological evaluation or standardized mental status examinations. 
Probable AD dementia in a carrier of a causative AD genetic mutation 
In persons who meet the core clinical criteria for probable AD dementia, evidence of a causative genetic mutation 
(in APP, PSEN1, or PSEN2) increases the certainty that the condition is caused by AD pathology.  The working 
group noted that carriage of the ɛ4 allele of the APOE gene was not sufficiently specific to be considered in this 
category. 
Probable AD 
dementia with 
evidence of the AD 
pathophysiological 
process 
AD dementia is part of a continuum of clinical and biological phenomena. AD dementia is fundamentally a clinical 
diagnosis.  To make a diagnosis of AD dementia with biomarker support, the core clinical diagnosis of AD 
dementia must first be satisfied. 
Relevant biomarkers include amyloid- (CSF or PET) and tau (CSF or PET). 
AD  Alzheimer’s disease; APOE  apolipoprotein E; CSF  cerebral spinal fluid; NIA-AA  National Institute on Aging-Alzheimer’s 
Association; PET  positron emission tomography. 
 
REFERENCE 
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the 
National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement 2011;7:2639. 
 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
173/Protocol WN29722, Version 3 
Appendix 4  
National Institute on Aging-Alzheimer’s Association Criteria for 
Prodromal Alzheimer’s Disease (Mild Cognitive Impairment due 
to Alzheimer’s Disease 
NIA-AA Category 
Clinical and Cognitive Criteria 
Clinical criteria 
 
Cognitive concern reflecting a change in cognition reported by 
participant or informant or clinician (i.e., historical or observed 
evidence of decline over time) 
 
Objective evidence of impairment in one or more cognitive 
domains, typically including memory (i.e., formal or bedside 
testing to establish level of cognitive function in multiple domains) 
 
Preservation of independence in functional abilities 
 
Not demented 
Etiology of MCI 
consistent with AD 
pathophysiological 
process 
 
Rule out vascular, traumatic, medical causes of cognitive decline, 
when possible. 
 
Provide evidence of longitudinal decline in cognition, when 
feasible. 
 
Report history consistent with AD genetic factors, when relevant. 
Prodromal AD 
dementia with 
evidence of the AD 
pathophysiological 
process 
Prodromal AD is part of a continuum of clinical and biological 
phenomena.  Prodromal AD is fundamentally a clinical diagnosis.  To 
make a diagnosis of prodromal AD with biomarker support, the core 
clinical diagnosis of prodromal AD must first be satisfied. 
Relevant biomarkers include amyloid- (CSF or PET) and tau (CSF 
or PET).  
AD  Alzheimer’s disease; CSF  cerebral spinal fluid; MCI  mild cognitive impairment; 
NIA-AA  National Institute on Aging-Alzheimer’s Association; PET  positron emission 
tomography. 
 
REFERENCES 
Albert MS, DeKosky ST, Dickson B, et al. The diagnosis of mild cognitive impairment 
due to Alzheimer’s disease: recommendations from the National Institute on 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer's disease. Alzheimers Dement 2011;7:2709. 
 
 


Signature Page for: System identifier:RIM-CLIN-439968
Protocol - WN29722 - GANTENERUMAB - v3 - Global/Core - Published
Approval Task
Company Signatory
16-May-2022 09:55:36 GMT+0000

SAP_001.pdf: 
 
Official Title: 
A Phase II, Multicenter, Open-Label, Single Arm Study to Evaluate 
the Pharmacodynamic Effects of Once Weekly Administration of 
Gantenerumab in Participants with Early (Prodromal to Mild) 
Alzheimer’s Disease 
NCT Number: 
NCT04592341 
Document Date: 
SAP Version 1: 20-Jun-2023 
 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL 
 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the last page of this 
document  
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Gantenerumab— F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan: WN29722 (GRADUATION) 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: A PHASE II, MULTICENTER, OPEN-LABEL, SINGLE ARM STUDY 
TO EVALUATE THE PHARMACODYNAMIC EFFECTS OF ONCE 
WEEKLY ADMINISTRATION OF GANTENERUMAB IN 
PARTICIPANTS WITH EARLY (PRODROMAL TO MILD) 
ALZHEIMER’S DISEASE 
STUDY NUMBER: 
WN29722 
STUDY NAME:  
GRADUATION 
VERSION NUMBER: 
1.0 
ROCHE COMPOUND(S): 
Gantenerumab (RO4909832)  
EUDRACT NUMBER: 
2020-001384-87 
IND NUMBER: 
102,266 
NCT NUMBER: 
NCT04592341 
PLAN PREPARED BY: 
, MSc; 
, Ph.D 
Protocol Number: 
 Report Number: 
Clinical Study Report: gantenerumab - F. Hoffmann-La Roche Ltd
WN29722
1117435
1


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan: WN29722 (GRADUATION) 
2 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This SAP was developed based on Roche SAP model document v2.0, revised 
26 October 2020. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
see electronic date stamp 
on the last page of this 
document 
Version 3.0, 16 May 2022 
Protocol Number: 
 Report Number: 
Clinical Study Report: gantenerumab - F. Hoffmann-La Roche Ltd
WN29722
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Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan: WN29722 (GRADUATION) 
3 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 8 
1.1 
Objectives, Endpoints and Estimands ....................................... 8 
1.2 
Study Design ........................................................................... 13 
1.2.1 
Treatment Assignment ............................................................. 16 
1.2.2 
Independent Review Facility .................................................... 16 
1.2.3 
Data Monitoring ....................................................................... 16 
2. 
STATISTICAL HYPOTHESES ...................................................... 16 
3. 
SAMPLE SIZE DETERMINATION ................................................ 17 
4. 
ANALYSIS SETS .......................................................................... 17 
5. 
STATISTICAL ANALYSES ........................................................... 18 
5.1 
General Consideration ............................................................. 18 
5.1.1 
Visit Windowing ....................................................................... 19 
5.2 
Participant Disposition ............................................................. 20 
5.3 
Primary Endpoint Analysis ....................................................... 20 
5.3.1 
Definition of Primary Endpoint ................................................. 20 
5.3.2 
Definition of Primary Estimand ................................................. 21 
5.3.3 
Main Analytical Approach for Primary Endpoint ....................... 22 
5.3.4 
Sensitivity Analyses for Primary Endpoint ............................... 22 
5.3.5 
Supplementary Analyses for Primary Endpoint........................ 23 
5.3.5.1 
Subgroup Analyses for Primary Endpoint ................................ 23 
5.4 
Secondary Endpoint(s) Analysis(ses) ...................................... 23 
5.5 
Exploratory Endpoint(s) Analysis(ses) ..................................... 24 
5.5.1 
Amyloid PET Comparison to Data from GRADUATE I and 
GRADUATE II .......................................................................... 24 
5.5.2 
Clinical Efficacy Outcomes ...................................................... 24 
5.5.2.1 
CDR ......................................................................................... 24 
5.5.2.2 
MMSE ...................................................................................... 25 
5.5.2.3 
ADAS-Cog11 and ADAS-Cog13 .............................................. 25 
5.5.2.4 
Verbal Fluency Task ................................................................ 25 
5.5.2.5 
Coding ..................................................................................... 25 
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Statistical Analysis Plan: WN29722 (GRADUATION) 
4 
5.5.2.6 
ADCS-ADL............................................................................... 26 
5.5.3 
Home Administration Questionnaire (Patient) .......................... 26 
5.5.4 
Biomarker Analyses ................................................................. 26 
5.5.4.1 
Volumetric MRI Analyses ......................................................... 26 
5.5.4.2 
Plasma Biomarker Analyses .................................................... 27 
5.6 
Safety Analyses ....................................................................... 27 
5.6.1 
Extent of Exposure .................................................................. 28 
5.6.2 
Adverse Events ........................................................................ 28 
5.6.3 
MRI Safety Findings ................................................................ 29 
5.6.3.1 
CNS Symptoms Temporally Associated with ARIA-E MRI 
Findings ................................................................................... 30 
5.6.4 
Laboratory Data ....................................................................... 31 
5.6.5 
Vital Signs ................................................................................ 31 
5.6.6 
ECGs ....................................................................................... 31 
5.6.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) ................. 31 
5.6.8 
Safety of Home Administration by the Study Partner ............... 31 
5.7 
Other Analyses ........................................................................ 33 
5.7.1 
Summaries of Conduct of Study .............................................. 33 
5.7.2 
Summaries of Demographics and Baseline Characteristics .... 33 
5.7.3 
Concomitant Medications ........................................................ 33 
5.7.4 
Summaries of COVID-19 Impact on the Trials ......................... 34 
5.7.5 
Immunogenicity Analyses ........................................................ 34 
5.7.6 
Biomarker Analyses ................................................................. 34 
5.7.7 
Pharmacokinetic and Pharmacodynamic Endpoint 
Analyses .................................................................................. 34 
5.8 
Interim Analyses ...................................................................... 35 
5.8.1 
Planned Interim Analyses ........................................................ 35 
6. 
SUPPORTING DOCUMENTATION .............................................. 35 
7. 
REFERENCES.............................................................................. 36 
 
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Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan: WN29722 (GRADUATION) 
5 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints/Estimands for the 
Interim and Primary Analyses ....................................................... 9 
Table 2 
Time Windows for Amyloid PET Endpoints ................................. 19 
Table 3 
Time Windows for Home Administration Questionnaire 
Endpoints .................................................................................... 19 
Table 4 
Time Windows for Cognitive and Functional Endpoints .............. 20 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 15 
 
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Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan: WN29722 (GRADUATION) 
6 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
AD 
Alzheimer’s Disease 
ADA 
anti-drug antibody 
AE 
adverse event 
APOE ε4 
apolipoprotein E allele ε4 
ARIA-E 
amyloid-related imaging abnormalities – edema/effusion 
ARIA-H 
amyloid-related imaging abnormalities – hemosiderin deposition 
BGTS 
Barkhof Grand Total Score 
CDR 
Clinical Dementia Rating 
CDR-GS 
Clinical Dementia Rating global score 
CI 
confidence interval 
CL 
centiloid 
CSR 
Clinical Study Report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
HAQ 
Home Administration Questionnaire 
HCP 
health care professional 
HN 
home nursing 
IA 
interim analysis 
ICE 
intercurrent event 
ICH 
International Council on Harmonization 
IMC 
Internal Monitoring Committee 
IND 
investigational new drug 
ITT 
intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model for repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
M-SE 
MRI safety evaluable 
NIA-AA 
National Institute on Aging/Alzheimer’s Association 
OLE 
open label extension 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PK 
pharmacokinetic 
 
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Statistical Analysis Plan: WN29722 (GRADUATION) 
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Abbreviation or Term 
Description 
Q1W 
once a week 
Q2W 
every two weeks 
Q4W 
every four weeks 
ROI 
region of interest 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SE 
safety-evaluable 
SUVR 
standardized uptake value ratio 
 
 
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Statistical Analysis Plan: WN29722 (GRADUATION) 
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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) document is to describe the data 
handling rules, derivation rules, and statistical analysis methodologies, tables and/or 
graphical displays for the interim analysis (IA) and primary analysis of the data from 
Study WN29722 (hereafter referred to as “GRADUATION”).  This document will focus on 
the statistical methodology underlying the interim and primary Clinical Study Reports 
(CSR).  
The description of layouts for the CSR outputs, the details about the underlying analysis 
datasets and programs, and the linking of production outputs to sections in the CSR, are 
not within the scope of this document and will be covered in separate documents. 
The language used in this SAP supersedes that in the protocol and protocol synopsis.  
This SAP document has been developed based on the study protocol (version 3) issued 
on 16 May 2022.  The final analyses planned for the optional two-year extension of the 
study until Week 208 will be described in a subsequent version of this SAP or in a 
separate document. 
1.1 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
This study will evaluate the pharmacodynamics, pharmacokinetics, and safety of 
gantenerumab in participants with early (prodromal to mild) AD.  Specific objectives and 
corresponding endpoints for the first 104 weeks of the study are outlined in Table 1 
below.  Details of endpoints pertaining to the optional two-year extension of the study 
can be found in Protocol Section 2. 
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Statistical Analysis Plan: WN29722 (GRADUATION) 
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Table 1 
Objectives and Corresponding Endpoints/Estimands for the Interim and Primary Analyses 
 
Interim Analyses 
Primary Analyses 
Primary Objective 
Corresponding Endpoint and Estimand  
Corresponding Endpoint and Estimand 
 
To evaluate the PD effect of a Q1W dosing 
regimen of gantenerumab on brain amyloid 
load as determined by PET imaging in 
participants with early (prodromal to mild) 
AD 
 
The change from baseline to Week 52 in 
deposited amyloid as measured by brain 
amyloid PET CL levels 
Estimand: 
 
Target Population: 
Early (prodromal to mild) AD population 
as identified by the inclusion and 
exclusion criteria, see Protocol Sections 
4.1.1 and 4.1.2 
 
Variable: 
Change from baseline to Week 52 in 
amyloid PET Centiloid 
 
Treatment: 
Prescribed study drug including up-
titration to the target dose 
 
Population-level summary: 
Variable mean within the treatment arm 
 
Intercurrent Event (ICE): Substantial 
reduction in drug exposure due to the 
COVID-19 pandemic (defined as  4 
missed dose-months).  Treatment 
discontinuation due to any reason.  These 
ICEs will be handled by hypothetical 
strategy. 
 
The change from baseline to Week 104 in 
deposited amyloid as measured by brain 
amyloid PET CL levels 
Estimand: 
 
Target Population: 
Early (prodromal to mild) AD population 
as identified by the inclusion and 
exclusion criteria, see Protocol Sections 
4.1.1 and 4.1.2 
 
Variable: 
Change from baseline to Week 104 in 
amyloid PET Centiloid 
 
Treatment: 
Prescribed study drug including up-
titration to the target dose 
 
Population-level summary: 
Variable mean within the treatment arm 
 
Intercurrent Event (ICE): Substantial 
reduction in drug exposure due to the 
COVID-19 pandemic (defined as  4 missed 
dose-months).  Treatment discontinuation 
due to any reason.  These ICEs will be 
handled by hypothetical strategy. 
Secondary Objective 
Corresponding Endpoint 
Corresponding Endpoint 
 
To evaluate caregiver overall satisfaction 
and confidence with home administration 
 
Responses to home administration 
questionnaire (Caregiver) up to Week 52 
 
Responses to home administration 
questionnaire (Caregiver) up to Week 104 
 
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Table 1 
Objectives and Corresponding Endpoints/Estimands (cont.)  
 
Interim Analyses 
Primary Analyses 
Safety Objective 
Corresponding Endpoints 
Corresponding Endpoints 
 
To assess the safety of gantenerumab in 
participants with early (prodromal to mild) 
AD 
 
Nature, frequency, severity, and timing of 
adverse events and serious adverse 
events 
 
Physical examinations (including 
neurologic 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 
injection-site reactions 
 
Presence of ADAs during the study 
relative to the presence of ADAs at 
baseline 
 
Nature, frequency, severity, and timing of 
adverse events and serious adverse 
events 
 
Physical examinations (including 
neurologic 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 
injection-site reactions 
 
Presence of ADAs during the study 
relative to the presence of ADAs at 
baseline 
PK/PD Objectives 
Corresponding Endpoints 
Corresponding Endpoints 
 
To characterize the PK profile of 
gantenerumab using a new titration 
scheme and especially at the Q1W dosing 
frequency 
 
To assess the PD effect of the dosing 
frequency (e.g., Q1W, Q2W) on brain 
amyloid 
 
Plasma concentration of gantenerumab 
(administered subcutaneously) at 
specified timepoints 
 
 
The influence of dosing frequency 
information on the performance of a 
quantitative PK-PD model developed 
based on PK and PET from this and 
previous studies (e.g., GRADUATE I and 
GRADUATE II) 
 
Plasma concentration of gantenerumab 
(administered subcutaneously) at 
specified timepoints 
 
 
The influence of dosing frequency 
information on the performance of a 
quantitative PK-PD model developed 
based on PK and PET from this and 
previous studies (e.g., GRADUATE I and 
GRADUATE II) 
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Statistical Analysis Plan: WN29722 (GRADUATION) 
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Table 1 
Objectives and Corresponding Endpoints/Estimands (cont.)  
 
Interim Analyses 
Primary Analyses 
Exploratory Biomarker Objective 
Corresponding Endpoints 
Corresponding Endpoints 
 
To evaluate the pharmacodynamic effect 
of gantenerumab at the Q1W dosing 
regimen on plasma and MRI biomarkers 
N/A 
 
Change from baseline in plasma 
biomarkers (including, but not limited to, 
phosphorylated tau and NFL) to 
Week 104 
 
Change from baseline to Week 104 in 
functional brain connectivity, as measured 
by resting-state functional MRI (where 
available) 
 
Change from baseline to Week 104 in 
integrity of white matter, as measured by 
DTI-MRI (where available) 
 
MRI-derived measurements over time, 
such as volumetric changes in whole 
brain, ventricles, hippocampus, or other 
structures, in all participants. 
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Table 1 
Objectives and Corresponding Endpoints/Estimands (cont.)  
 
Interim Analyses 
Primary Analyses 
Exploratory Objectives 
Corresponding Endpoints 
Corresponding Endpoints 
 
To compare the effect of a Q1W to a Q2W 
dosing regimen on amyloid reduction 
using external controlsa 
 
To evaluate the effects of gantenerumab 
at the Q1W dosing on cognitive and 
functional endpoints 
 
 
 
 
 
 
 
 
 
 
To evaluate patient overall satisfaction 
with at home administration 
 
N/A 
 
 
N/A 
 
 
 
Responses to home administration 
questionnaire (Patient) up to Week 52 
 
The change from baseline to Week 52 
and Week 104 in deposited amyloid as 
measured by brain amyloid PET 
compared with the change in the pivotal 
GRADUATE I and GRADUATE II studiesa 
 
The change from baseline to Week 104 in 
the following: 
− 
The CDR-SOB 
− 
MMSE total score 
− 
ADAS-Cog11 and ADAS-Cog13 
− 
Verbal Fluency Task 
− 
Coding 
− 
ADCS-ADL 
 
Responses to home administration 
questionnaire (Patient) up to Week 104 
AD  Alzheimer's disease; ADA  anti-drug antibody; ADAS-Cog11  Alzheimer Disease Assessment ScaleCognition, Subscale 11; ADAS-
Cog13  Alzheimer Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL  Alzheimer Disease Cooperative Study Group- Activities of 
Daily Living; ARIA-E  amyloid-related imaging abnormalitiesedema/effusion; ARIA-H  amyloid-related imaging abnormalitieshemosiderin 
deposition; CDR-SOB  Clinical Dementia RatingSum of Boxes; CL  Centiloid; C-SSRS  ColumbiaSuicide Severity Rating Scale; DTI  diffusion 
tensor imaging; MMSE  Mini-Mental State Examination; MRI  magnetic resonance imaging; NFL  neurofilament light chain; 
PD  pharmacodynamic; PET  positron emission tomography; PK  pharmacokinetic; Q1W  once a week; Q2W  every 2 weeks; Q4W  every 4 
weeks. 
a Pooled analyses with data from the pivotal Studies WN29922 (GRADUATE I) and WN39658 (GRADUATE II) will be described in a separate SAP 
and provided in a separate report. 
  
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1.2 
STUDY DESIGN 
GRADUATION is a Phase II, multicenter, open-label, single arm, pharmacodynamics 
(PD) study in participants with early (prodromal to mild) Alzheimer’s Disease (AD) to 
evaluate the effect of a Q1W dosing regimen on deposited amyloid as measured by 
change from baseline to Weeks 52 and 104 in brain amyloid positron emission 
tomography (PET).  The dosing regimen being evaluated in current Phase III studies 
(WN29922 [hereafter referred to as “GRADUATE I”] and WN39658 [hereafter referred to 
as “GRADUATE II”]) is gantenerumab 120 mg subcutaneous (SC) injection every 4 
weeks (Q4W) for 12 weeks, followed by 255 mg SC Q4W for 12 weeks, and 510 mg SC 
Q4W for 12 weeks, prior to reaching the target dose of 510 mg SC every two weeks 
(Q2W).  As an alternative to administering two 255-mg injections Q2W at the target 
dose, the administration of gantenerumab as a single injection of 255 mg once a week 
(Q1W) will be investigated in this study, to simplify the dosing regimen for patients and 
caregivers and to provide additional flexibility and convenience depending on individual 
patient's needs and preferences.  In addition, GRADUATION will evaluate the feasibility 
of home administration by study partners (non-professional caregivers), which is 
particularly relevant in conjunction with a Q1W dosing regimen. 
A total of approximately 150 participants were planned to be enrolled in participating 
countries in protocol Version 1.  Approximately 40 centers in approximately 8 countries 
worldwide were planned to participate in this study.  Due to a lower than expected 
screen failure rate at the end of the enrollment period, a total of 192 participants have 
been enrolled in a total of 38 centers in 8 countries worldwide that participate in this 
study.  
Participants will be selected on the basis of a clinical diagnosis of probable AD 
(consistent with the National Institute on Aging/Alzheimer’s Association [NIA-AA] 
Diagnostic Criteria and Guidelines for probable AD; McKhann et al. 2011) or prodromal 
AD (consistent with the NIA-AA diagnostic criteria and guidelines for mild cognitive 
decline due to AD; Albert et al. 2011). 
Eligible participants will be 5090 years old, inclusive, and must have increased brain 
amyloid as indicated by positive amyloid PET scan by visual read.  At the time of 
screening, participants must have a Mini-Mental State Examination (MMSE) score 
 22 points and a Clinical Dementia Rating global score (CDR-GS) of 0.5 or 1.0.  To 
confirm objective memory impairment, participants must have a Clinical Dementia Rating 
(CDR) memory domain score  0.5. 
In addition, all eligible participants should have a study partner (non-professional 
caregiver) who is willing and judged as capable of administering SC injections 
(exceptions can be made for participants who are able to attend weekly clinic visits or 
who are able to have weekly home nursing [HN]/site staff visits). 
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Neuroradiologic evaluation will use a standard magnetic resonance imaging (MRI) 
protocol (including T2*-weighted gradient−recalled echo and fluid−attenuated inversion 
recovery).  Screening MRIs will be read by a central reader who will exclude participants 
with other structural causes of dementia, significant cerebral vascular pathology, more 
than five microbleeds, disseminated leptomeningeal hemosiderosis, or evidence of a 
prior cerebral macrohemorrhage.  
Participants will be eligible for the study whether or not they are receiving 
standard-of-care symptomatic medications for AD (e.g., cholinesterase inhibitors or 
memantine, combination, or an approved medical food supplement).  Intake of these 
medications must have been stable for  3 months prior to screening and until start of 
study treatment.  All eligible participants have to meet eligibility criteria as detailed in the 
Protocol (version 3.0), Section 4.1.   
The study will consist of a screening period of up to 8 weeks for each participant who 
agrees to participate, signs the Informed Consent Form, and is eligible for the study.  
Eligible participants will then undergo the baseline visit (Day 1), when they will receive 
the first dose following completion of all relevant assessments.  Participants will be 
enrolled in an open-label treatment period of up to 208 weeks.  The PET scans will be 
performed at screening (will be considered as baseline evaluation), Weeks 52, 104, 156, 
and 208 using florbetaben as the tracer at all sites (in exceptional circumstances, the 
use of flutemetamol may be acceptable at sites where florbetaben is not available, but 
only after prior written approval from the Sponsor).  Participants will be treated according 
to the following dosing regimen:  120 mg Q4W (Day 1, Week 4, and Week 8), then 
255 mg Q4W (Weeks 12, 16, and 20), and then 255 mg Q2W for 12 weeks (Weeks 24, 
26, 28, 30, 32, and 34), followed by the target dose 255 mg Q1W (Weeks 36207).  
Before reaching the target dose (i.e., 255 mg Q1W), a minimum of three doses during 
the 120 mg Q4W and 255-mg Q4W dosing periods, and a minimum of six doses during 
255 mg Q2W dosing period must be administered prior to uptitration.  Participants who 
do not opt for the two-year extension of GRADUATION, will receive the final dose of 
study drug at Week 103.  Final PD and efficacy assessments will be performed 1 week 
later at Week 104.  Participants who do not enter an extension study will have an 
additional follow-up visit 16 weeks after the Week 104 visit for safety assessments 
(Week 120 follow-up visit).  Participants who opt for the two-year extension of 
GRADUATION will receive the final dose of study drug at Week 207.  Final PD and 
efficacy assessments will be performed one week later at Week 208.  Eligible 
participants may qualify for continued access or ongoing extension studies as outlined in 
the Protocol (version 3.0), Section 4.3.5.  Participants who do not enter an extension 
study will have an additional follow-up visit 16 weeks after the Week 208 visit for safety 
assessments (Week 224 follow-up visit). 
Depending on the site and individual participant/caregiver suitability, participants will 
have the option to receive SC injections of gantenerumab at the site or at home by study 
staff, a home nurse, or a study partner (non-professional caregiver) after a defined 
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period of appropriate training and supervision.  For more details on study treatment 
administration, see the Protocol (version 3.0), Section 4.3.2.1. 
Participants will undergo brain MRI examinations for safety monitoring and longitudinal 
changes in brain structure.  MRI scans will be read by a central MRI reader (for more 
details regarding imaging-related criteria, see the Protocol (version 3.0), Section 
4.1.2.2).  Participants will also undergo standard tests to monitor safety (blood tests and 
ECG), as well as the ColumbiaSuicide Severity Rating Scale (C-SSRS) to monitor for 
suicidality, tests for cognition, and function.  Blood samples for assessment of plasma 
biomarkers for AD and ARIA, pharmacokinetics, and exploratory genetic markers, and 
for the measurement of antibodies directed against gantenerumab will be obtained from 
all participants.  
Participants who do not meet the criteria for participation in this study (screen failure) 
may qualify for re-screening at the investigator's discretion as described in the Protocol 
(version 3.0), Section 4.6.  Participants must re-sign the consent form prior to 
re-screening.  The investigator will record reasons for screen failure in the screening log 
(see the Protocol [version 3.0], Section 4.5.1). 
An interim analysis will be conducted on the latest data cut available at the time of the 
primary analysis for GRADUATE I and GRADUATE II, and it will include descriptive 
analyses only.  The primary analysis will be performed after database lock when the last 
participant has completed the Week 104 assessment or discontinued the study. 
The study schema is shown in Figure 1. 
Figure 1 Study Schema 
 
D  day; Q1W  once a week; Q2W  every 2 weeks; Q4W  every 4 weeks; W  week. 
a Treatment period W104-207 is optional and only for participants who consent to the optional 
two-year extension. 
  
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1.2.1 
Treatment Assignment 
Since this is a single-arm study, all participants will be assigned to the same treatment 
and no randomization is performed. 
1.2.2 
Independent Review Facility 
MRI scans will be reviewed by a central MRI core laboratory, which will perform the 
diagnostic reads and assessment of MRI outcome measures.  MRI scans should 
preferably be transferred to the central MRI core laboratory electronically.  Data transfer 
from individual study sites to the central MRI core laboratory may take up to 7-10 days, if 
not done electronically.  Upon receipt of the MRI scans from the study sites, the central 
MRI core laboratory will provide the diagnostic reads.  MRI results must be made 
available to investigators prior to next dosing or prior to the Week 104 visit (refer to the 
Protocol (version 3.0), Section 5.1.3 for additional details on MRI safety management). 
MRI facility qualification and scan quality control will be performed by the central MRI 
core laboratory. 
Additional instructions regarding the procedures for MRI scan acquisition and transmittal 
to the central reading facility can be found in the MRI Manual.  
1.2.3 
Data Monitoring 
An Internal Monitoring Committee (IMC) will be employed to monitor and evaluate 
participant safety throughout the study. 
The incidence, severity, and nature of adverse events (AEs), serious adverse events 
(SAEs), amyloid-related imaging abnormalities (ARIA) – edema/effusion (ARIA-E) and 
amyloid-related imaging abnormalities – hemosiderin deposition (ARIA-H), and 
laboratory abnormalities will be assessed on a regular basis by the Sponsor’s IMC, as 
documented in the IMC Charter. 
The Sponsor Safety Scientist and the Study Clinical Scientist will review the SAEs 
periodically and submit IND safety reports to the regulatory agencies, Institutional 
Review Boards / Independent Ethics Committees, and the IMC for any unexpected or 
serious events (as well as to the iDMC for GRADUATE I/II if deemed necessary).  The 
main scope of the IMC is to review accumulating safety data for gantenerumab under 
the Q1W dosing regimen.  Through summary and review of study data, the IMC will help 
the study Clinical Scientist minimize subject exposure to undue risk.  Starting from 8 
months after first-patient-in, the IMC will meet approximately every 3 to 6 months to 
review summaries of overall rates of death, ARIAs, AEs, and SAEs. 
2. 
STATISTICAL HYPOTHESES 
No statistical hypotheses will be tested in this study.  All analyses are descriptive or 
purely exploratory. 
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3. 
SAMPLE SIZE DETERMINATION 
Determination of sample size is relative to the sample of participants assessed by 
amyloid PET imaging using florbetaben.  The sample size for this study is determined as 
the number of participants needed for the estimated change from baseline to Week 104 
in amyloid PET load to fall into a 10 CL confidence interval (CI) around its true value.  
With a standard deviation of 25.67 CL (see below), 150 participants are required to 
fulfill this criterion.  However, due to a lower than expected screen failure rate at the end 
of the enrollment period, a total of 192 participants have been enrolled. 
The standard deviation of amyloid reduction was estimated using amyloid PET data from 
the ongoing Studies WN25203 (hereafter referred to as “SCarlet RoAD”) and WN28745 
(hereafter referred to as “Marguerite RoAD”) open label extension (OLE) periods (based 
on a cutoff date of 14 October 2019), yielding a value of 25.67 CL. 
Uncertainties of the parameters affecting the estimation (e.g., drop-out rate, study drug 
discontinuation rate, and standard deviation) were assumed to be equivalent to a 
decrease in sample size of up to around 35% and were corrected for accordingly.  This 
drop-out rate is calculated based on Marguerite RoAD OLE at Week 104 that was 
ongoing at the time the study protocol was written.  A sample size increase may be 
considered if factors external to the study would warrant a change to the sample size 
assumption. 
4. 
ANALYSIS SETS 
The following analysis sets are defined: 
Analysis Set 
Definition 
Intent to treat (ITT) 
All enrolled participants (i.e., who gave informed consent, did not 
fail screening, and had at least one Amyloid PET scan with a valid 
quantitative measurement performed with either florbetaben or 
flutemetamol), whether or not the participant received the assigned 
treatment. 
Safety-evaluable (SE) 
All participants enrolled who received at least one dose of study 
treatment, whether prematurely withdrawn from the study or not.   
MRI safety-evaluable 
(M-SE) 
All participants of the SE analysis set who had at least one 
post-baseline MRI assessment. 
Amyloid-PET-
longitudinal 
All participants in the ITT analysis set with a valid post-baseline 
quantitative amyloid PET measurement performed with either 
florbetaben or flutemetamol. 
MRI modified intent-to-
treat (MRI-mITT) 
All participants in the ITT analysis set who had at least one valid 
volumetric MRI quantitative measurement. 
MRI-longitudinal 
All participants in the MRI-mITT with at least one valid post-
baseline volumetric MRI quantitative measurement. 
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Opportunity for home 
dosing safety-
evaluable (OH-SE) 
All participants of the SE analysis set who did not discontinue 
study drug before week 26. 
Home dosing by study 
partner safety-
evaluable (H-SE) 
All participants of the SE analysis set who received at least one 
dose of study treatment administered at home by caregiver / study 
partner. 
ITT  intent to treat; H-SE  safety-evaluable with home dosing by study partner; 
M-SE  safety-evaluable with post-baseline MRI; MRI  magnetic resonance imaging; MRI-
mITT  modified intent-to-treat with at least one valid vMRI measurement; OH-SE  safety 
evaluable with opportunity for home dosing by study partner; SE  safety-evaluable;. 
  
5. 
STATISTICAL ANALYSES 
Details of the interim and primary statistical analysis to be conducted on data collected 
from Day 1 through Week 104 are detailed in Section 5.1 through Section 5.8.  Details of 
the final analyses planned for the optional two-year extension of the study until Week 
208 will be described in a subsequent version of this SAP or in a separate document. 
5.1 
GENERAL CONSIDERATION 
In the following sections, for all continuous variables for which descriptive statistics are 
indicated, the following statistics will be reported:  the number of observations, the mean, 
median, standard deviation, and minimum and maximum.  The 25th and 75th percentiles 
(Q1 and Q3) will also be reported for selected tables.  Descriptive summaries of discrete 
data will include frequencies expressed in terms of number and percentage of 
participants. 
For safety endpoints, the baseline is defined as the last available assessment prior to 
first study drug intake. For all other assessments, the baseline is defined as the last 
available assessment before or on the day of first study drug intake, unless specified 
otherwise.  
All PD analyses and all clinical efficacy analyses will be performed on the ITT analysis 
set, unless specified otherwise.  Safety analyses will be performed on the SE analysis 
set, except for analyses of MRI findings which will be performed on the M-SE analysis 
set and analyses of home administrations by study partner that will be performed on the 
SE, OH-SE, or H-SE analysis sets, as appropriate. 
All analyses will be purely descriptive or exploratory without any formal hypothesis 
testing.  For exploratory tests, a two-sided significance level of 5% will be used. 
In general, missing outcome data will not be replaced or imputed unless specified 
otherwise.  Number and percentage of missing data points will be reported for each visit 
for key endpoints of interest. 
In statistical models using change from baseline of a given outcome measure as the 
dependent variable, participants with missing baseline outcome measure will be 
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Table 4 
Time Windows for Cognitive and Functional Endpoints 
Visit 
Target study day 
Time window 
Baseline 
1 
Up to Day 1 
Week 24 
169 
2, 266 
Week 52 
365 
267, 448 
Week 76 
533 
449, 630 
Week 104 
729 
631, 770 
  
5.2 
PARTICIPANT DISPOSITION 
The analysis of participant disposition will be based on the ITT analysis set.  The number 
of enrolled participants will be tabulated by geographical region, country, and site. 
The number of participants enrolled, treated with study drug, discontinued study drug, 
discontinued study, and completed study will be tabulated.  Reasons for study drug 
discontinuations and for study discontinuations will be listed and summarized.  
Major protocol deviations, including major deviations with regard to the inclusion and 
exclusion criteria, will be summarized.  Separate tables will be provided for 
COVID-19-related major protocol deviations and reasons for COVID-19-related major 
protocol deviations. 
5.3 
PRIMARY ENDPOINT ANALYSIS 
5.3.1 
Definition of Primary Endpoint 
The primary endpoint for this study is the change from baseline to Week 104 in brain 
amyloid load, as assessed by amyloid PET imaging using florbetaben as ligand and 
quantified on the centiloid (CL) conversion scale.  For the purposes of analysis, the 
screening amyloid PET scan may be considered the baseline evaluation. 
Brain amyloid load will be quantified in terms of Standardized Uptake Value Ratio 
(SUVR), defined as the ratio of the tracer uptake in a target region of interest (ROI) to 
the tracer uptake in a reference ROI.  The target ROI is a weighted composite of the 
following regions (left and right), where each region is weighted by its own volume: 
frontal, temporal, parietal lobes, anterior and posterior cingulate gyri.  The reference ROI 
is the whole cerebellum.  The whole cerebellum region is represented by a weighted 
average of Cerebellum Ventral, Cerebellum Dorsal (left and right), and Cerebellar White 
Matter. 
For each participant at each visit, SUVR will be linearly transformed to the standardized 
CL scale using the following formula: 
𝐶𝐿= 175.6 × 𝑆𝑈𝑉𝑅𝑊𝐶
𝐹𝐵𝐵−174.2 
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The CL variable is the current common standard in the scientific community. 
 
5.3.2 
Definition of Primary Estimand 
The scientific question of interest is to assess the effect of the intended study treatment 
on the PD endpoint, change from baseline to Week 104 in brain amyloid load, in 
participants treated with SC gantenerumab, in the absence of a substantial impact of the 
COVID-19 pandemic and as if treatment discontinuation would not have occurred. 
In alignment with the Addendum to ICH E9, the primary Amyloid PET estimand is thus 
described by the following attributes: 
 
Target Population: 
Early (prodromal to mild) AD population as identified by the inclusion and exclusion 
criteria, see the Protocol (version 3.0), Sections 4.1.1 and 4.1.2 
 
Variable: 
Change from baseline to Week 104 in amyloid PET CL 
 
Treatment: 
Prescribed study drug in a Q1W regimen, including up-titration to the target dose 
 
Population-level summary: 
Variable mean in the ITT analysis set 
 
Intercurrent events (ICEs): 
o Substantial reduction in drug exposure due to the COVID-19 pandemic 
(defined as 4 missed dose-months) 
o Treatment discontinuation due to any reason 
Considering that amyloid PET primarily aims at estimating the Pharmacodynamic effect 
of the drug, rather than a direct measure of clinical efficacy, reporting treatment effect 
estimated "as if there were no treatment discontinuations and no substantial reduction in 
exposure due to COVID-19 pandemic" (thus using a hypothetical strategy) addresses 
the scientific question of interest. 
 
The ICE of substantial reduction in drug exposure due to the COVID-19 pandemic is 
defined as 4 or more dose-months (i.e., 16 weeks) of treatment missed due to 
COVID-19-related reason.  One dose-month is defined as 4 weeks of dosing, i.e., one 
dose with a Q4W dosing frequency or two doses with a Q2W dosing frequency or four 
doses with a Q1W dosing frequency (at target dose).  The threshold (4) on the number 
of missed dose-months was determined based on the following reasons: 
 
Based on the half-life of approximately 24 days of gantenerumab, plasma 
concentrations after 4 months’ interruption at the target dose are expected to 
be below the concentration with the dose of 225 mg Q4W which was shown to be 
ineffective in SCarlet RoAD and Marguerite RoAD 
 
Comparability to the GRADUATE I and GRADUATE II studies which use the same 
cut-off. 
 
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5.3.3 
Main Analytical Approach for Primary Endpoint 
Descriptive summary statistics for the brain amyloid CL load at baseline, Week 52 and 
Week 104 as well as the change from baseline to Week 52 and to Week 104 will be 
produced on both the ITT and Amyloid-PET-longitudinal analysis sets.  Descriptive 
summaries of the primary endpoint will present the mean, standard deviation, median, 
and minimum and maximum.  
A Mixed Model for Repeated Measures (MMRM) analysis will be used to estimate the 
mean change in CL from baseline to Week 52 and to Week 104 on the ITT analysis set.  
The model will include the change from baseline in CL as the dependent variable, while 
adjusting for visit (as categorical), apolipoprotein E allele ε4 (APOE ε4) status (as 
categorical; carrier vs non-carrier), baseline CL, and baseline CL-by-visit.  Visit will be 
treated as the repeated variable within a participant.  An unstructured variance-
covariance matrix will be applied to model the within-participant errors; in the case of 
non-convergence, compound symmetry will be used, together with a robust estimator of 
standard error (“sandwich” estimator).  
In line with the primary estimand definition, data acquired after the ICE “Substantial 
reduction in drug exposure due to the COVID-19 pandemic” (as defined above) or more 
than 56 days from date of last dose will be excluded from the analysis and treated as 
missing for the primary analysis purposes.  
There will be no data imputation for missing data.  However, the MMRM model provides 
unbiased estimates and valid inference in the presence of missing data, under the MAR 
(missing at random) assumption.  
The least squares means at Week 52 and at Week 104 will be estimated and presented 
with a 95% CI. 
5.3.4 
Sensitivity Analyses for Primary Endpoint 
Impact of COVID-19 
The following sensitivity analyses will be performed to evaluate the impact of the 
COVID-19 pandemic: 
 
Vary threshold on the number of missed doses due to the pandemic in the definition 
of “substantial reduction in drug exposure” ICE.  The “substantial reduction in drug 
exposure” ICE is defined with a threshold of  4 dose- months.  A sensitivity 
analysis will be performed using different thresholds: 1, 2, 3, 5, and 6 dose-months.  
All other aspects of the primary estimator remain the same. 
 
Ignore COVID-19 impact on missed doses.  A sensitivity analysis will be performed 
where all available data points will be used, irrespective of whether or not a 
“substantial reduction in drug exposure” ICE occurred or not. 
 
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5.3.5 
Supplementary Analyses for Primary Endpoint 
The number and proportion of participants with values below or equal to the positivity 
threshold will be summarized for each assessment time point.  CL zero is the mean 
amyloid burden for a typical population of young healthy controls, and 100 CL is the 
typical mean of a population with AD.  The CL value of 24 is consistent with the 
diagnostic amyloid positivity threshold (Klunk et al. 2015; Navitsky et al. 2018) and will 
be used for the CL variable as defined for the primary analysis (see Section 5.3.2).   
In order to account for the potential impact of missing values, a completers analysis will 
be performed, i.e., restricting the analysis at each visit to participants who completed the 
visit with non-missing data. 
5.3.5.1 
Subgroup Analyses for Primary Endpoint 
The analysis of the primary endpoint will be repeated for subgroups of participants who 
received no home administrations of study drug by their study partner vs participants 
who received at least 1 home administrations by their study partner.  The threshold of 1 
administration may be varied for additional exploratory, data-driven analyses. 
5.4 
SECONDARY ENDPOINT(S) ANALYSIS(SES) 
The secondary objective for this study is the study partner’s confidence in his or her 
ability to perform the injection and their perception of the ease of injection, as well as the 
study partner’s satisfaction with and convenience of home administration.  The 
corresponding endpoints consist of the responses to the caregiver part of the home 
administration questionnaire (HAQ) up to Week 52 (for the interim analysis) and up to 
Week 104 (for the primary analysis). 
The home administration questionnaire is to be completed as per Schedule of 
Assessments at site visits on Weeks 36, 52, 76, 104, early termination and unscheduled 
visits, and comprises a caregiver and a participant portion.  The Caregiver portion of the 
HAQ is the secondary endpoint of the study.  The participant portion of the HAQ will be 
analyzed as an exploratory endpoint (Section 5.5.3). 
The home administration questionnaire comprises 4 items to be completed by study 
partner and 2 items to be completed by participants.  The Caregiver portion of the 
questionnaire includes confidence with administration, convenience, ease of use, and 
overall satisfaction.  Each item is rated on a 4-point verbal Likert scale and respondents 
will be asked to consider their most recent at home administration.  Participants will 
complete satisfaction and convenience items with the same response options and recall 
period.  Responses to this questionnaire may be captured electronically and transferred 
to the database directly from the core laboratory. 
Descriptive summaries will be reported separately for each of the 4 items of the 
caregiver portion of the HAQ on the H-SE analysis set.  Responses to each item are 
considered ordinal data: for each item and at each visit, the number of available 
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responses as well as the number and percentage for each response category will be 
reported.  No imputation of missing data will be performed for this endpoint.  
Descriptive tables will summarize the number of home administrations by study partner 
per participant as well as the reasons for the study partner not performing home-
administrations.  Reasons for switches in the person administering the study drug will be 
summarized as well.  Graphical representations may be used to show the proportion of 
participants receiving administrations at home by study partner over time or to visualize 
the administrations by their study partner vs by a healthcare professional at home or at 
the site over time.  The change from baseline in amyloid burden will be summarized as 
described in Sections 5.3.5.1 and 5.3.3 for participants who have had at least one home 
administration by their study partner vs those who have had none.  These tables and 
figures will be based on the SE analysis set. 
5.5 
EXPLORATORY ENDPOINT(S) ANALYSIS(SES) 
The change from baseline in the continuous, exploratory endpoints listed below. 
5.5.1 
Amyloid PET Comparison to Data from GRADUATE I and 
GRADUATE II 
The feasibility of using amyloid PET data from the pivotal ongoing GRADUATE I and 
GRADUATE II as an external control group will be explored for a comparison of 
measured amyloid reduction between dosing regimens.  Such an analysis may be 
performed at the primary analysis of this study. 
In case that it is feasible to compare the change from baseline to Week 52 and to 
Week 104 in deposited amyloid as measured by brain amyloid PET within this study with 
the change measured in GRADUATE I and GRADUATE II as external control, then this 
analysis will be reported separately.  Pertinent descriptions of the planned analysis will 
be appended to this SAP as a separate document. 
5.5.2 
Clinical Efficacy Outcomes 
Clinical efficacy outcomes of CDR-SOB, MMSE, ADAS-Cog, Verbal Fluency Task, 
Coding, and ADCS-ADL will be assessed and collected via electronic tablets.  The 
number of participants with available results at each visit will be presented.  For all these 
outcomes, the total score, the change and percent change from baseline (if applicable) 
will be summarized descriptively for all participants at each visit. 
5.5.2.1 
CDR 
Clinical Dementia Rating Sum of Boxes (CDR-SOB) is a global scale covering both 
functional and cognitive domains. 
The CDR-GS characterizes a participant’s level of impairment according to the following 
categories: 0 (normal), 0.5 (very mild dementia), 1 (mild dementia), 2 (moderate 
dementia), and 3 (severe dementia).  The Sum of Boxes score is a detailed quantitative 
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general index that provides more information than the CDR-GS in patients with mild 
dementia (Berg 1988; Morris et al. 2001; O'Bryant et al. 2010) and is scored from 0 to 18 
with higher scores indicating greater impairment.  The CDR characterizes six domains: 
memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care.  The necessary information to make each rating is obtained 
through a semi-structured interview with the participant and a reliable informant or 
collateral source (e.g., a study partner [non-professional caregiver]). 
5.5.2.2 
MMSE 
The MMSE is a set of standardized questions used to evaluate possible cognitive 
impairment and help stage the severity level of this impairment (Folstein et al. 1975).  
The questions target six areas: orientation, registration, attention, short-term recall, 
language, and constructional praxis/visuospatial abilities.  The MMSE is a participant-
based assessment. 
5.5.2.3 
ADAS-Cog11 and ADAS-Cog13 
The ADAS-Cog is the most frequently used scale to assess cognition in clinical trials for 
mild to moderate AD dementia (Rozzini et al. 2007; Connor and Sabbagh 2008; Ihl et al. 
2012).  More specifically, the ADAS-Cog is a patient-based assessment that measures 
learning and memory, language production, language comprehension, constructional 
praxis, ideational praxis, and orientation.  The modified version will be used; it has 
13 items and includes the addition of delayed word recall and a number of cancellation 
subtests, as well as use of only one trial for word recognition (Mohs et al. 1997).  
Equivalent alternate forms of the word recall, word recognition, and number cancellation 
subtests will be used in successive test administrations. 
The ADAS-Cog 11 and 13 will be used in this study.  Individual item scores are based on 
errors and generally range from 1 to 5, although some items have smaller or larger score 
ranges.  The ADAS-Cog 13 total score ranges from 0-85, with higher scores reflecting 
greater impairment.  It takes approximately 45 min to administer the ADAS-Cog 13. 
5.5.2.4 
Verbal Fluency Task 
The category verbal fluency (e.g., animals) is a participant-based assessment that 
measures speed and flexibility of verbal thought.  Verbal fluency tests are sensitive tools 
for detecting dementia (Pasquier et al. 1995; Lezak et al. 2004) and for monitoring 
decline over time (Clark et al. 2009). 
5.5.2.5 
Coding 
The Coding, also called Digit Symbol Substitution Test (or DSST), is a subtest from the 
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV; Wechsler 2008).  The 
Coding is a participant-based assessment that measures speed of processing and 
associative memory.  The test is known to be sensitive to disease progression (Lezak et 
al. 2004).  The 120-second version of the test will be used in this study. 
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5.5.2.6 
ADCS-ADL 
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in participants with AD (Vellas et al. 2008).  The ADCS-ADL is a 23-item 
informant-based questionnaire that covers both basic activities of daily living (ADL) (e.g., 
eating and toileting) and more complex ADL or instrumental ADL (e.g., using the 
telephone, managing finances, preparing a meal).  It has a 4-week recall period.  Total 
scores range from 0-78, with higher scores indicating better functioning. 
5.5.3 
Home Administration Questionnaire (Patient) 
As described in Section 5.4, the home administration questionnaire contains 2 items to 
be completed by participants.  Participants will complete satisfaction and convenience 
items on a 4-point verbal Likert scale and respondents will be asked to consider their 
most recent at home administration in answering these questions.  Responses to this 
questionnaire may be captured electronically and transferred to the database directly 
from the core laboratory. 
5.5.4 
Biomarker Analyses 
5.5.4.1 
Volumetric MRI Analyses 
Analysis of volumetric MRI will be based on the MRI-mITT analysis set. 
Volumetric MRI, for each brain region, will be summarized visit using descriptive 
statistics for the absolute volume at baseline and percent change from baseline at post-
baseline visits.  These summaries will be provided for both the MRI-mITT and the MRI-
longitudinal analysis sets. 
A MMRM analysis will be used to estimate the mean percent change from baseline to 
Week 104 (as well Week 48) in volumetric MRI for each brain region.  The model will 
include the percent change from baseline in volumetric MRI as the dependent variable, 
while adjusting for visit (as categorical), baseline age, gender (as categorical), APOE ε4 
status (as categorical; carrier vs. non-carrier) and disease stage (as categorical).  Visit 
will be treated as the repeated variable within a participant.  An unstructured variance-
covariance matrix will be applied to model the within-participant errors; in the case of 
non-convergence, compound symmetry will be used, together with a robust estimator of 
standard error (“sandwich” estimator). 
There will be no data imputation for missing data.  However, the MMRM provides 
unbiased estimates and valid inference in the presence of missing data, under the MAR 
(missing at random) assumption. 
The following brain regions will be considered: 
 
Whole brain volume 
 
Regional brain volumes 
 
Ventricular volume 
Other exploratory analyses based on other brain regions may be reported separately. 
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In addition, exploratory biomarker analysis will be performed to assess change from 
baseline to Week 104 in functional brain connectivity, fiber tract integrity, and cerebral 
blood perfusion.  
5.5.4.2 
Plasma Biomarker Analyses 
Exploratory fluid plasma biomarkers will be assessed at each visit for tau and amyloid 
pathology as well as neurodegeneration, including, but not limited to, the following: 
 
p-tau 
 
A1-42 
 
Neurofilament light chain (NFL) 
 
Glial fibrillary acidic protein (GFAP) 
 
The plasma concentration of these biomarkers will be assessed.  Analysis of plasma 
biomarkers will be based on the ITT analysis set. Biomarker data will be summarized for 
each assessment visit using descriptive statistics of absolute values as well as change 
from baseline values.  
An MMRM analysis will be used to estimate the mean change from baseline to Week 
104 (but also to Week 24, 36, 52, and 76) for each plasma biomarker. The model will 
include the change from baseline in the plasma biomarker as the dependent variable, 
while adjusting for visit (as categorical), APOE ε4 status (as categorical; carrier vs 
non‑carrier), baseline biomarker and baseline biomarker-by-visit. Visit will be treated as 
the repeated variable within a participant. An unstructured variance-covariance matrix 
will be applied to model the within-participant errors; in case of non-convergence, 
compound symmetry will be used, together with a robust estimator of standard error 
(“sandwich” estimator).  The MMRM model will be based on log-transformed biomarker 
data. 
There will be no data imputation for missing data. However, the MMRM provides 
unbiased estimates and valid inference in the presence of missing data, under the MAR 
(missing at random) assumption. 
 
Other exploratory plasma biomarkers may be reported separately. 
5.6 
SAFETY ANALYSES 
Descriptive statistics will be used to analyze all safety data collected in SE analysis set, 
unless otherwise specified.  Safety data collected during the safety follow-up will also be 
included but may be summarized in separate tables.  Safety analyses will be assessed 
through summaries of exposure to study treatment, adverse events, changes in 
laboratory test results, MRI findings, changes in vital signs and ECGs, changes in 
C-SSRS scores and immunogenicity. 
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5.6.1 
Extent of Exposure 
Exposure to study drug information will be descriptively summarized overall and by dose 
level as follows: 
 
Treatment duration (in weeks) 
 
Total cumulative study drug dose (mg) 
 
Total number of study drug administrations 
 
Medication errors 
 
5.6.2 
Adverse Events 
All verbatim Adverse Events (AE) terms will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) version that is current at the time of the analysis 
(Version 24.1 or higher), and AE intensity will be graded according to the scale defined 
in Table 2 in Section 5.3.3 of the study protocol (mild/moderate/severe).  The frequency 
of each AE preferred term will be defined as the number of participants experiencing at 
least one occurrence of the event.  Each table will present the overall number and 
percentage of participants experiencing at least one AE and the total number of AEs 
reported.  Percentages will be based on the number of participants in the SE analysis 
set.  In summary tables, AEs will be sorted by body system (also referred to as System 
Organ Class, in decreasing order of overall incidence), then by preferred term (in 
decreasing order of overall incidence).  The summary tables will be restricted to 
treatment-emergent AEs, i.e., AEs that occur on or after the day of first study drug, and 
to those AEs with onset no later than 17 weeks after last dose of study drug.  
Non-treatment-emergent AEs (with onset before the first dose) will be listed, and AEs 
occurring more than 17 weeks after the last dose will be summarized. 
The following safety information will be summarized for treatment-emergent AEs:   
 
AEs, AEs by greatest intensity, AEs related to study drug, AEs related to radioligand 
 
SAEs, SAEs by greatest intensity, SAEs related to study drug 
 
AEs leading to discontinuation of study drug  
 
AEs leading to dose modification (dose interruption, dose reduction, or delayed up-
titration). Delayed up-titration at any given visit is defined as the simultaneous 
occurrence of the following two tickboxes in the eCRF Adverse Events form: 
- Action taken with Gantenerumab due to AE/SAE: Dose Not Changed 
- Was dose regimen modified from protocol schedule? Yes 
 
AEs resulting in death 
 
Injection site reaction (ISR) signs and symptoms  
 
Systemic injection reactions (AEs with eCRF tickbox “systemic injection reaction” 
selected) 
 
Hypersensitivity AEs 
 
AEs associated with medication errors, AEs of medication errors 
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The impact of the COVID-19 pandemic on the safety data will be assessed by reviewing 
the following: 
 
Confirmed or suspected COVID-19 AEs 
 
AEs associated with COVID-19 
 
Potential long COVID-19 symptoms 
The following data handling rules will be applied for all AE summary tables: 
 
Events that are missing both at onset and at end dates will be considered to have 
started after the first dose of study drug and the duration will be set to missing.  
 
If the onset date is missing, and the end date is on or after the first dosing date or 
unresolved or missing, then the event will be considered to have started after the 
first dose of study drug. 
The following data handling rules will also be applied for specific tables: 
 
An AE will be included in the summary table of AEs leading to study drug 
discontinuation if the “action taken with Gantenerumab due to SAE/AE” drop-down 
menu on the AE eCRF is checked “drug withdrawn”. 
 
In the summary table of AEs by intensity, if a participant has more than one 
occurrence of an event, the event with the most severe intensity will be counted.  If 
the intensity of an AE is missing, then the AE will be included only in the total 
number of events column, and not in the count of participants with the event by 
intensity. 
 
In summary tables of AEs related to study drug, if a participant has more than one 
occurrence of an event, the related event will be counted if applicable.  If the 
relationship of an AE is missing, then the AE will not be included. 
5.6.3 
MRI Safety Findings 
ARIA-E and ARIA-H are identified risks associated with gantenerumab.  According to the 
study protocol, 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 
temporally associated with ARIA-E MRI findings), and/or 
 
ARIA findings that result in a change in study treatment (e.g., dose 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. 
Since not all ARIA MRI findings qualify as AE, ARIA analyses will be mainly based on 
ARIA MRI findings.  ARIA AEs will also be reported.  Based on MRI data, the incidence, 
severity (based on the Barkhof Grand Total Score [BGTS]), and timing of ARIA-E and 
the incidence and timing of ARIA-H will be summarized overall and also by APOE ε4 
genotype (by number of alleles) and by dose level.  The timing of ARIA-E and ARIA-H 
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may be summarized by descriptive statistics and Kaplan-Meier methods.  Recurrence of 
ARIA-E will be summarized overall and also by APOE ε4 genotype (by number of 
alleles).  ARIA-E associated with CNS symptoms (see Section 5.6.3.1) and with serious 
CNS symptoms will be summarized by APOE ε4 genotype.  Temporal co-occurrence of 
ARIA-E and ARIA-H will be summarized overall and also by APOE ε4 genotype.  
Temporal co-occurrence is defined as an MRI scan showing new ARIA-H that occurs 
between ARIA-E onset and resolution (inclusive), irrespective of the brain region. 
MRI findings other than ARIA will also be summarized. 
The summaries of MRI safety findings will be produced using the SE analysis set with at 
least one post-baseline MRI (M-SE, see Section 4). 
5.6.3.1 
CNS Symptoms Temporally Associated with ARIA-E MRI 
Findings 
CNS symptoms temporally associated with ARIA-E are defined as onset or worsening of 
CNS symptom(s) that is/are temporally associated with ARIA-E MRI findings.  CNS 
symptoms experienced by the participant that are new or worsened since the last MRI 
without ARIA-E are collected in a CNS Symptoms Request Form before the MRI takes 
place at a visit.  To identify CNS symptoms temporally associated with ARIA-E MRI 
findings, the following definitions will be used:  
NEW CNS symptoms: If there is any AE reported in the eCRF with “Reported on the 
MRI CNS symptoms request form”  Y that is [new since date of most recent MRI scan 
showing no ARIA-E findings] AND is [ongoing or ends between the date of most recent 
site visit prior to date of MRI scan showing new ARIA-E (MRI) and date of MRI scan 
showing ARIA-E resolution (MRI)] then ARIA-E should be classified as associated with 
CNS symptoms 
 
OR 
 
WORSENED CNS symptoms: If there is any AE reported in the eCRF with “Reported on 
the MRI CNS symptom request form” = Y that is [started before the date of most recent 
MRI scan showing no ARIA-E findings ] AND is [ongoing or ends between the date of 
most recent site visit prior to date of MRI scan showing new ARIA-E (MRI) and date of 
MRI scan showing ARIA-E resolution from MRI data] AND [there is an increase in 
severity grading] then ARIA-E should be classified as associated with CNS symptoms. 
The CNS symptoms temporally associated with ARIA-E MRI findings will be listed and 
summarized by treatment group and within this also by APOE ε4 genotype (by number 
of alleles). 
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5.6.4 
Laboratory Data 
Laboratory data will be summarized for each assessment visit using descriptive statistics 
of absolute values and change from baseline values.  In addition, the frequency of 
participants with abnormal laboratory values will be summarized.  
5.6.5 
Vital Signs 
Vital signs assessments include systolic blood pressure, diastolic blood pressure, and 
pulse rate measured throughout the study.  Vital sign measurements will be summarized 
for each assessment visit using descriptive statistics of absolute values and change from 
baseline values.  In addition, the frequency of participants with abnormal results will be 
summarized. 
5.6.6 
ECGs 
ECG data will be summarized for each assessment visit using descriptive statistics of 
absolute values and change from baseline values for the following parameters:  
 
Heart rate 
 
QRS duration 
 
RR interval 
 
PR interval 
 
QT interval 
 
QT corrected using Bazett’s formula (QTcB) and QT corrected using Fridericia’s 
formula (QTcF) 
 
In addition, ECG overall interpretations will be summarized by visit. 
5.6.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is an assessment tool used to assess the lifetime suicidality of a participant 
(C-SSRS at baseline) as well as any new instances of suicidality (C-SSRS since last 
visit).  The structured interview prompts recollection of suicidal ideation, including the 
intensity of the ideation, behavior, and attempts with actual or potential lethality. 
The highest post-baseline suicidal ideation, suicidal behavior, and self-injurious behavior 
without suicidal intent will be summarized.  In addition, change from baseline to worst 
post-baseline assessment in suicidality categories will be summarized. 
5.6.8 
Safety of Home Administration by the Study Partner 
Descriptive analyses will be performed to assess the safety of home administrations of 
study drug by the study partner.  These will compare data at a participant level and at an 
injection level. 
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On the participant level, a descriptive table will show: 
 
Number and frequency of participants with at least one home administration by 
study partner 
 
Number and frequency of participants who changed the study partner during the 
study (overall) 
 
Number and frequency of participants with different overall number of changes in 
study partner 
 
Total number of home administrations by study partner per participant (descriptive 
statistics) 
 
Percentage of possible home administrations by study partner (i.e., number of 
actual home administrations by study partner divided by maximum possible number) 
per participant (descriptive statistics) 
 
Percentage of participants who received home administration by study partner at 
each visit (starting from Week 26, excluding planned in-clinic visits; line plot) 
 
First week with home administration by study partner 
 
Heat map of administrations by study partner or HCP at home or at site 
The summaries above will be presented for the SE, OH-SE, and/or the H-SE analysis 
set as appropriate. 
Furthermore, participants will be grouped in the following way: 
 
Participants who have had no home administrations by their study partner  
 
Participants who have been dosed at home by their study partner at least once 
The threshold of 1 home administration by study partner may be varied for additional 
exploratory, data-driven analyses. 
For these two groups, demographic data and baseline characteristics will be 
summarized as described in Section 5.7.2.  Furthermore, demographics and 
characteristics of all study partners will be summarized.  
An AE overview table will summarize the AE profile by group.  Selected AE tables of 
ISRs, systemic injection reactions, and hypersensitivity will provide the frequency of 
these events by group.  Additionally, medication errors will also be summarized 
descriptively by group. 
Injection Level 
On the injection level, each single injection of study drug from Week 26 onwards (after 
the scheduled training of study partners at the site) will be grouped in the following way: 
 
Home administration by study partner 
Participant Level 
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 
Home administration by Health Care Professional (HCP) 
 
In clinic administration by study partner 
 
In clinic administration by HCP 
The frequency of medication errors, ISRs, systemic injection reactions, and 
hypersensitivity will be summarized descriptively for home administrations by study 
partner vs. the combined group of all other administrations.  The denominator in the 
calculations of percentages is here the number of administrations in each group (not the 
number of participants). 
Other comparisons between home administrations by the study partner and other groups 
may be added. 
5.7 
OTHER ANALYSES 
5.7.1 
Summaries of Conduct of Study 
The summary of study conduct will include a description of the following items: 
 
Number of participants enrolled  
 
Number of participants included in each analysis set 
 
Number and percentage of participants who prematurely withdrew from the study or 
from study treatment (including the reasons for discontinuation and the distribution 
of these discontinuations by time-windowed visit) 
 
Incidence of major protocol deviations – overall and by four main categories 
(inclusion criteria, exclusion criteria, medication and procedural) 
 
Number of participants with home nursing 
Major protocol deviations and premature withdrawals will be listed. 
5.7.2 
Summaries of Demographics and Baseline Characteristics 
Demographics and baseline characteristics (including age, sex, medical history) will be 
summarized descriptively for the ITT population. 
Exposure to AD concomitant medication (including post-baseline initiation or change in 
dose) will be summarized for the ITT population.   
Participants are eligible for study participation whether or not they are receiving 
approved medication for AD (i.e., acetylcholinesterase inhibitors, memantine, and/or 
medical food supplements, where approved) with the exception of GV-971. 
5.7.3 
Concomitant Medications 
The following medication concept of interest has been identified: 
 
Antiplatelet therapy 
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The Medication terms (based on WHO ATC-Coding standard) used to identify the 
medication of interest will be listed (by WHO ATC Coding class). 
In addition, medications administered to treat ARIA-Es, CNS symptoms associated with 
ARIA-E MRI findings and ISRs will be summarized separately by WHO ATC Coding 
class and preferred term.  Summaries and listings will be provided for all previous and all 
concomitant medications. 
5.7.4 
Summaries of COVID-19 Impact on the Trials 
GRADUATION is ongoing during the COVID-19 pandemic.  Consequently, to monitor 
the potential impact of the pandemic on the trials, we will provide a specific set of 
descriptive analyses related to COVID-19 for the ITT analysis set (see Section 4), 
including: 
 
Demographic and Baseline Characteristics in Participants with 
Confirmed/Suspected COVID-19  
 
COVID-19 AEs (see Section 5.6.2) 
 
COVID-19 related Protocol Deviations (see Section 5.2) 
 
Missed dose-months due to COVID-19 
 
Study discontinuations due to COVID-19 
 
Site actions 
 
5.7.5 
Immunogenicity Analyses 
Immunogenicity analyses include the evaluation for antibodies against gantenerumab 
(anti-drug antibody [ADA]), including the determination of antibody titers.  The results of 
the confirmatory assay will be presented as a frequency table summarizing baseline and 
post-baseline results.   
A listing of participants with positive ADA status per confirmatory assay and titer result 
will be provided. 
5.7.6 
Biomarker Analyses 
Please see Section 5.5.4. 
5.7.7 
Pharmacokinetic and Pharmacodynamic Endpoint Analyses 
Gantenerumab plasma concentration will be descriptively summarized by nominal 
time/visit.  
Population PK and PK-PD modeling analyses that include assessing the influence of 
dosing frequency on PK-PD model performance will be reported separately in a 
modeling and simulation report and are therefore not covered in this document. 
 
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5.8 
INTERIM ANALYSES 
5.8.1 
Planned Interim Analyses 
An interim analysis will be conducted at the time of the primary analysis for 
GRADUATE I and GRADUATE II, to support a potential filing of gantenerumab in case 
of positive read-out of the pivotal studies.  The analysis will be considered strictly 
descriptive and will not impact the conduct of the study, i.e., early termination for futility 
or efficacy will not be considered.  As this study is open-label and no formal hypothesis 
testing is planned, the interim analysis is considered of an administrative nature and will 
not have an impact on the final study results (e.g., in terms of alpha spending). 
The last patient last visit for GRADUATE I and GRADUATE II is expected for 
23 September 2022.  To allow for cleaning and other data management processes, the 
clinical cut-off date for GRADUATION will be set to 30 June 2022.  All participants who 
were enrolled in the study by the time of the cut-off date will be included in the interim 
analysis.  This is expected to comprise approximately 192 participants and of those 
approximately 180 participants are expected to have had the opportunity to complete the 
Week 52 assessment. 
The following will be included in the interim analysis and analyzed according to the 
methods specified in the pertinent sections: 
 
Participant disposition (see Section 5.2) 
 
Demographics and baseline characteristics (see Section 5.7.2) 
 
Change in amyloid burden from baseline to Week 52 (see Section 5.3) 
 
Caregiver portion of the home administration questionnaire (see Section 5.4) 
 
Extent of exposure (see Section 5.6.1) 
 
Adverse events (see Section 5.6.2) 
 
MRI safety findings (see Section 5.6.3) 
 
Laboratory data (see Section 5.6.4) 
 
Vital signs (see Section 5.6.5) 
 
ECG data (see Section 5.6.6) 
 
C-SSRS (see Section 5.6.7) 
 
Immunogenicity analyses (see Section 5.6.8 ) 
 
Pharmacokinetics analyses (see Section 5.7.7) 
 
Safety of Home Administration by study partner (see Section 5.6.8). 
The interim analysis will be performed by the Sponsor and reported in an interim CSR. 
6. 
SUPPORTING DOCUMENTATION 
This section is not applicable, since there is no additional supporting document. 
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 Report Number: 
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36 
7. 
REFERENCES 
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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. 
Connor DJ, Sabbagh MN. Administration and scoring variance on the ADAS-Cog. 
J Alzheimers Dis 2008;15:4614. 
Columbia-Suicide Severity Rating Scale (C-SSRS; Columbia Protocol). The Columbia 
Lighthouse Project [resource on the Internet]. 2016 [Accessed: 28 July 2022]. 
Available from: https://cssrs.columbia.edu/ 
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. 
Galasko D, Bennett D, Sano M, et al. An inventory to assess activities of daily living for 
clinical trials in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. 
Alzheimer Dis Assoc Disord 1997;11(Suppl 2):S33-9. 
Ihl R, Ferris S, Robert P, et al. Detecting treatment effects with combinations of the 
ADAS-Cog items in patients with mild and moderate Alzheimer’s disease. Int J 
Geriatr Psychiatry 2012;27:1521. 
Klunk WE, Koeppe RA, Price JC, et al. The Centiloid Project: standardizing quantitative 
amyloid plaque estimation by PET. Alzheimers Dement 2015;11(1):1-15 e11-14. 
Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment (4th revised 
edition). New York: Oxford University Press, 2004.  
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to 
Alzheimer’s disease: recommendations from the National Institute on 
AgingAlzheimer’s Association workgroups on diagnostic guidelines for 
Alzheimer’s disease. Alzheimers Dement 2011;7:2639. 
Mohs RC, Knopman D, Petersen RC, et al. Development of cognitive instruments for 
use in clinical trials of antidementia drugs: additions to the Alzheimer’s disease 
assessment scale that broaden its scope. The Alzheimer’s Disease Cooperative 
Study. Alzheimer Dis Assoc Disord 1997;11(Suppl 2):S13-21. 
Morris JC, Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage 
Alzheimer disease. Arch Neurol 2001;58:397405. 
Protocol Number: 
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Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan: WN29722 (GRADUATION) 
37 
Navitsky M, Joshi AD, Kennedy I, et al. Standardization of amyloid quantitation with 
florbetapir standardized uptake value ratios to the Centiloid scale. Alzheimer's & 
Dementia 2018, 14: 1565-71.  
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. 
Pasquier F, Lebert F, Grymonprez L, et al. Verbal fluency in dementia of frontal lobe 
type and dementia of Alzheimer type. J Neurol Neurosurg Psychiatry 
1995;58:814. 
Rozzini L, Chilovi BV, Conti M, et al. Conversion of amnestic mild cognitive impairment 
to dementia of Alzheimer type is independent to memory deterioration. Int J Geriatr 
Psychiatry 2007;22:121722. 
Vellas B, Andrieu S, Sampaio C, et al., for the European Task Force Group. Endpoints 
for trials in Alzheimer’s disease: a European Task Force Consensus. Lancet 
Neurol 2008;7:43650. 
Wechsler D. Wechsler adult intelligence scaleFourth Edition (WAISIV). San Antonio, 
TX: NCS Pearson, 2008. 
 
Protocol Number: 
 Report Number: 
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Signature Page for Published - Statistical Analysis Plan - WN29722
System identifier: RIM-CLIN-447398
Approval Task
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Protocol Number: 
 Report Number: 
Clinical Study Report: gantenerumab - F. Hoffmann-La Roche Ltd
WN29722
1117435
38


Signature Page for 1117435-csr-wn29722-1619
System identifier: RIM-CLIN-489692
Approval Task
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