Clinical trial NCT03443973
Conditions: Alzheimer Disease
Sponsor: Hoffmann-La Roche
Start date: 2018-08-22; Completion date: 2022-11-28
Enrollment: 975 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, double-blind, placebo-controlled, parallel group study will evaluate the efficacy and safety of gantenerumab versus placebo in participants with early (prodromal to mild) AD. All participants must show evidence of beta-amyloid pathology. Eligible participants will be randomized 1:1 to receive either subcutaneous (SC) injection of gantenerumab or placebo. The primary efficacy assessment will be performed at the end of the double blind period at week 116. Participants will then be offered to enter into an open-label extension (OLE). Participants not willing to go to the OLE will participate in a long term follow-up period for up to 50 weeks after the last gantenerumab dose.

Detailed description:

Arms: arm 1: Gantenerumab will be administered as SC injections with gradual uptitration. arm 2: Placebo will be administered as SC injections with gradual uptitration.
Interventions: intervention 1: Gantenerumab intervention 2: Placebo
Intervention descriptions: intervention 1: Gantenerumab will be administered as per the schedule specified in the respective arm. intervention 2: Placebo matching to gantenerumab will be administered as per the schedule specified in the respective arm.

Protocol documents:
Prot_002.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel,
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates,
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Gantenerumab—F. Hoffmann-La Roche Ltd
Protocol WN39658, Version 5
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED,
DOUBLE-BLIND, PLACEBO-CONTROLLED,
PARALLEL-GROUP EFFICACY AND SAFETY 
STUDY OF GANTENERUMAB IN PATIENTS WITH 
EARLY (PRODROMAL TO MILD) ALZHEIMER’S 
DISEASE
PROTOCOL NUMBER:
WN39658
VERSION NUMBER:
5
EUDRACT NUMBER:
2017-001365-24
IND NUMBER:
NCT NUMBER:
TEST PRODUCT:
MEDICAL MONITOR:
SPONSOR:
APPROVAL DATE:
102,266
NCT03443973
Gantenerumab (RO4909832)
, MBBS, PhD 
F. Hoffmann-La Roche Ltd
See electronic date stamp below.
Company Signatory
Approver's Name
Title
Date and Time (UTC)
04-Aug-2021 07:47:21


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PROTOCOL HISTORY
Protocol
Version
Date Final
4
23 May 2020
3
21 January 2020
2
11 February 2018
1
21 July 2017


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PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
The changes to the protocol, along with a rationale for each change, are summarized 
below:

Section 1.3.5 Overall Benefit-Risk Summary has been updated to address the 
COVID-19 pandemic impact on the Benefit-Risk assessment for Study WN39658, 
as per the MHRA requirement

Objectives and endpoints of the Double-Blind Treatment Period (Table 2) have been 
updated in the following manner:
–
Corresponding endpoints for the ‘exploratory efficacy’ objective have been revised 
to remove ‘in global outcome’ as a criteria for the measurement of change from 
baseline to Week 116, which was added in error.
–
The exploratory endpoint ‘Time to clinically evident decline, defined as an increase 
of in CDR-SOB subscore or 1 in at least four items of the FAQ’ has been 
removed from Table 2, as it is not considered relevant anymore based on new 
available data.
–
The exploratory endpoint ‘Change from baseline to Week 116 measured by 
‘Function as assessed by the CDR function subscore” has been removed as it is no 
longer considered relevant based on new available data.
–
The exploratory endpoint ’clinically evident decline as measured using the CDR’ has 
been added to Table 2.
–
The pharmacokinetic (PK) objective of the study has been changed to an 
exploratory PK objective to be consistent with the sparse PK sampling design and 
population modeling used to analyse the dose concentration–time data of 
gantenerumab. In addition, the protocol has been amended to enable early access 
PK, anti-drug antibodies (ADA) and pharmacodynamic (PD) biomarker samples. 
Early access will only be applied if there are sufficient sample data available to 
make an adequate assessment.
–
The corresponding endpoints for the pharmacodynamic (PD) biomarker objective 
have been revised to clarify the duration of change as a measurement from baseline 
to Week 116 when assessing brain amyloid load, brain tau load and cerebral spinal 
fluid markers.
–
The PD biomarker objective endpoint ‘MRI-derived measurements over time, such 
as volumetric changes in whole brain, ventricles, hippocampus, or other structures, 
in all participants ' has been reclassified as exploratory as it is no longer considered 
secondary based on new available data.

Sections 3.1.1 and 4.1.3 have been updated to clarify that the open-label extension 
(OLE) of Study WN39658 is not applicable in countries that cannot run Study 
WN42171.

Sections 4.1.2.7, 4.4.1, 4.7.2, and Appendix 1 have been revised to clarify the 
Medical Monitor’s responsibility to review and support patient cohort management 


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and other protocol activities. Any reference to approval by the Medical Monitor with 
regards to medical decisions following enrollment has been removed from the 
protocol. The Principal Investigator (PI) may consult with the Medical 
Monitor/Sponsor for advice or clarification and may share risk factor information 
pertinent to the patient, but the medical decisions for the study participants are the 
responsibility of the PI.

Section 4.1.3 has been amended to replace Week 104 with Week 116 (or Week 
128, if applicable) which was omitted in the previous protocol amendment.

Section 4.6.3 and 4.6.4 have been amended to better clarify the order of 
assessments during the study visits.

Section 6.4.1 has been updated according to the estimand framework outlined in the 
ICH-E9 draft addendum with regards to the primary endpoint.

Section 6.4.2 has been updated to remove the reference to time to event, which was 
included in error.

Sections 6.4.4, 6.5 and 6.6 have been updated to clarify that a separate cut off may 
be necessary for PD biomarker, PK, and ADA samples to allow early access to PD
biomarker samples and ensure expedient data analyses.

Section 6.7.1 and 6.7.2 have been updated to include additional details surrounding 
the conduct of an interim analysis, should one be implemented.
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.


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TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND .......................................................................................... 36
1.1
Background on Alzheimer’s Disease..................................... 36
1.2
Background on Gantenerumab.............................................. 37
1.2.1
Nonclinical Studies ................................................................ 38
1.2.1.1
Nonclinical Pharmacology ..................................................... 38
1.2.1.2
Nonclinical Pharmacokinetics and Metabolism...................... 39
1.2.1.3
Toxicology and Safety Pharmacology ................................... 39
1.2.2
Clinical Studies...................................................................... 40
1.2.2.1
Study NN19866 ..................................................................... 41
1.2.2.2
Study WN25203 .................................................................... 41
1.2.2.3
Study WN28745 .................................................................... 42
1.2.2.4
OLE Studies WN25203 and WN28745.................................. 43
1.2.2.5
Study WP40052..................................................................... 43
1.2.3
Safety Overview .................................................................... 43
1.3
Study Rationale and BenefitRisk Assessment..................... 46
1.3.1
Study Rationale ..................................................................... 46
1.3.2
Rationale for Dosing Strategy................................................ 53
1.3.3
Risk-Mitigation Measures for ARIA Findings ......................... 55
1.3.4
Risk to Participants without Alzheimer’s Disease 
Pathology............................................................................... 56
1.3.5
Overall BenefitRisk Summary.............................................. 56
2.
OBJECTIVES AND ENDPOINTS ............................................................... 57
3.
STUDY DESIGN......................................................................................... 61
3.1
Description of the Study......................................................... 61
3.1.1
Overview of Study Design ..................................................... 61
3.1.2
Substudies............................................................................. 66
3.1.3
Data Monitoring Committee................................................... 66
3.2
End of Study and Length of Study......................................... 67


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3.3
Rationale for Study Design.................................................... 67
3.3.1
Rationale for Participant Population ...................................... 67
3.3.2
Rationale for Use of a Placebo Control Group....................... 69
3.3.3
Rationale for Gantenerumab Dosage and 
Titration Schedule.................................................................. 69
3.3.4
Rationale for Treatment Duration .......................................... 70
3.3.4.1
Rationale for Double-Blind Treatment Duration..................... 70
3.3.4.2
Rationale for OLE Treatment Duration .................................. 71
3.3.5
Rationale for Long-Term Follow-Up....................................... 71
3.3.5.1
Rationale for Duration of Study Follow-Up 
(14 Weeks) ............................................................................ 71
3.3.5.2
Rationale for Long-Term Follow-Up (50 Weeks) ................... 71
3.3.6
Rationale for Primary Outcome Measure:  
Clinical Dementia RatingSum of Boxes ............................... 72
3.3.7
Rationale for Pharmacokinetic Sampling............................... 72
3.3.8
Rationale for Biomarker Assessments................................... 73
3.3.8.1
Cerebral Spinal Fluid Biomarkers.......................................... 73
3.3.8.2
Positron Emission Tomography............................................. 74
3.3.8.3
Brain Volumetry, Connectivity, and Fiber Tract 
Integrity.................................................................................. 74
4.
MATERIALS AND METHODS .................................................................... 75
4.1
Participants with Alzheimer’s Disease ................................... 75
4.1.1
Inclusion Criteria.................................................................... 76
4.1.2
Exclusion Criteria................................................................... 77
4.1.2.1
Exclusions Related to Central Nervous System 
Disorders ............................................................................... 77
4.1.2.2
Imaging-Related Criteria........................................................ 78
4.1.2.3
Cardiovascular Disorders ...................................................... 79
4.1.2.4
Hepatic and Renal Disorders................................................. 79
4.1.2.5
Infections and Immune Disorders.......................................... 80
4.1.2.6
Metabolic and Endocrine Disorders....................................... 80
4.1.2.7
Exclusions Related to Medications........................................ 80
4.1.2.8
Other Exclusions ................................................................... 81
4.1.3
Eligibility for the Open-Label Extension ................................. 82


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4.2
Method of Treatment Assignment and Blinding..................... 83
4.3
Study Treatment.................................................................... 84
4.3.1
Formulation, Packaging, and Handling.................................. 84
4.3.1.1
Gantenerumab and Placebo.................................................. 84
4.3.2
Dosage, Administration, and Compliance.............................. 84
4.3.2.1
Gantenerumab and Placebo Administration 
during Double-Blind Treatment Period .................................. 84
4.3.2.2
Gantenerumab and Placebo Administration 
during the Open-Label Extension Period............................... 86
4.3.3
Investigational Medicinal Product Accountability ................... 88
4.3.4
Continued Access to Gantenerumab..................................... 89
4.4
Concomitant Therapy ............................................................ 90
4.4.1
Permitted Therapy................................................................. 90
4.4.2
Prohibited Therapy ................................................................ 91
4.5
Study Assessments ............................................................... 91
4.5.1
Informed Consent Forms and Screening Log........................ 91
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 92
4.5.3
Physical Examinations........................................................... 92
4.5.4
Vital Signs.............................................................................. 93
4.5.5
Cognitive, Functional, and Health Economics 
Assessments ......................................................................... 93
4.5.5.1
Clinical Dementia Rating Scale ............................................. 93
4.5.5.2
Alzheimer’s Disease Assessment 
ScaleCognitive Subscale..................................................... 94
4.5.5.3
Mini-Mental State Examination.............................................. 94
4.5.5.4
Free and Cued Selective Reminding 
TestImmediate Recall.......................................................... 94
4.5.5.5
Verbal Fluency Task.............................................................. 95
4.5.5.6
Coding ................................................................................... 95
4.5.5.7
Functional Activities Questionnaire........................................ 95
4.5.5.8
Alzheimer’s Disease Cooperative 
StudyActivities of Daily Living Inventory .............................. 95
4.5.5.9
Zarit Caregiver InterviewAlzheimer’s Disease ..................... 95
4.5.5.10
Quality of Life–Alzheimer’s Disease ...................................... 95


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4.5.5.11
EQ-5D.................................................................................... 96
4.5.5.12
Resource Utilization in Dementia Scale................................. 96
4.5.5.13
Neuropsychiatric Inventory Questionnaire............................. 96
4.5.5.14
Electronic Assessment of Rating Scales ............................... 97
4.5.6
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 97
4.5.6.1
Standard Laboratory Samples............................................... 97
4.5.6.2
Biomarker Sampling .............................................................. 98
4.5.6.3
Anti-Drug Antibody Sampling............................................... 100
4.5.6.4
Pharmacokinetic Sampling .................................................. 100
4.5.7
Electrocardiograms.............................................................. 101
4.5.8
ColumbiaSuicide Severity Rating Scale............................. 101
4.5.9
Brain Magnetic Resonance Imaging.................................... 101
4.5.10
Healthy Volunteer Magnetic Resonance Imaging 
Scans for Site Qualification.................................................. 103
4.5.11
Positron Emission Tomography Scan.................................. 103
4.5.12
Optional Samples for Research Biosample 
Repository ........................................................................... 104
4.5.12.1
Overview of the Research Biosample Repository................ 104
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee ................................................................ 104
4.5.12.3
Sample Collection................................................................ 104
4.5.12.4
Confidentiality...................................................................... 105
4.5.12.5
Consent to Participate in the Research 
Biosample Repository.......................................................... 105
4.5.12.6
Withdrawal from the Research Biosample 
Repository ........................................................................... 106
4.5.12.7
Monitoring and Oversight..................................................... 106
4.6
Timing of Study Assessments ............................................. 106
4.6.1
Screening and Pretreatment Assessments.......................... 106
4.6.2
Assessments at Baseline..................................................... 109
4.6.3
Assessments during the Double-Blind Treatment 
Period .................................................................................. 110
4.6.4
Assessments during Open-Label Extension 
Period .................................................................................. 111


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4.6.5
Procedures for New MRI Findings....................................... 112
4.6.6
Assessments at Study Completion or Early 
Termination Visit.................................................................. 113
4.6.7
Follow-Up Assessments ...................................................... 113
4.6.8
Unscheduled Assessments ................................................. 114
4.7
Treatment, Participant, Study, and Site 
Discontinuation.................................................................... 114
4.7.1
Study Treatment Discontinuation......................................... 114
4.7.2
Participant Discontinuation .................................................. 114
4.7.3
Study Discontinuation.......................................................... 115
4.7.4
Site Discontinuation............................................................. 115
5.
ASSESSMENT OF SAFETY..................................................................... 116
5.1
Safety Plan .......................................................................... 116
5.1.1
Risks Associated with Gantenerumab ................................. 116
5.1.1.1
Amyloid-Related Imaging Abnormalities.............................. 116
5.1.1.2
Injection-Site Reactions....................................................... 116
5.1.1.3
Immunogenicity ................................................................... 116
5.1.2
Management of Participants Who Experience 
Selected Adverse Events..................................................... 117
5.2
Safety Parameters and Definitions ...................................... 118
5.2.1
Adverse Events ................................................................... 118
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 119
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 120
5.2.4
Selected Adverse Events..................................................... 120
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 120
5.3.1
Adverse Event Reporting Period ......................................... 120
5.3.2
Eliciting Adverse Event Information..................................... 121
5.3.3
Assessment of Severity of Adverse Events ......................... 122
5.3.4
Assessment of Causality of Adverse Events ....................... 122
5.3.5
Procedures for Recording Adverse Events.......................... 122
5.3.5.1
ARIA Findings...................................................................... 122


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5.3.5.2
Injection Reactions .............................................................. 123
5.3.5.3
Diagnosis versus Signs and Symptoms............................... 123
5.3.5.4
Adverse Events That Are Secondary to Other 
Events.................................................................................. 123
5.3.5.5
Persistent or Recurrent Adverse Events.............................. 124
5.3.5.6
Abnormal Laboratory Values ............................................... 124
5.3.5.7
Abnormal Vital Sign Values ................................................. 125
5.3.5.8
Abnormal Liver Function Tests............................................ 125
5.3.5.9
Deaths ................................................................................. 126
5.3.5.10
Preexisting Medical Conditions............................................ 126
5.3.5.11
Lack of Efficacy or Worsening of 
Alzheimer’s Disease ............................................................ 126
5.3.5.12
Hospitalization or Prolonged Hospitalization........................ 127
5.3.5.13
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 127
5.3.5.14
Clinical Outcome Assessment Data .................................... 127
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 128
5.4.1
Emergency Medical Contacts.............................................. 128
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 129
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 129
5.4.2.2
Events That Occur after Study Drug Initiation...................... 129
5.4.3
Reporting Requirements for Pregnancies............................ 130
5.4.3.1
Pregnancies in Female Participants .................................... 130
5.4.3.2
Abortions ............................................................................. 130
5.4.3.3
Congenital Anomalies/Birth Defects .................................... 130
5.4.4
Reporting Requirements for Medical Device 
Complaints........................................................................... 130
5.5
Follow-Up of Participants after Adverse Events................... 131
5.5.1
Investigator Follow-Up......................................................... 131
5.5.2
Sponsor Follow-Up .............................................................. 131
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 131


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5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 131
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 132
6.1
Determination of Sample Size ............................................. 133
6.2
Summaries of Conduct of Study.......................................... 134
6.3
Summaries of Treatment Group Comparability ................... 134
6.4
Efficacy Analyses ................................................................ 134
6.4.1
Primary Efficacy Endpoint.................................................... 134
6.4.2
Secondary Efficacy Endpoints............................................. 135
6.4.3
Exploratory Efficacy Analyses ............................................. 136
6.4.4
Pharmacodynamic and Exploratory Biomarker 
Analyses.............................................................................. 136
6.5
Safety Analyses................................................................... 136
6.6
Pharmacokinetic Analyses................................................... 137
6.7
Interim Analysis ................................................................... 138
6.7.1
Planned Interim Analysis ..................................................... 138
6.7.2
Optional Interim Analyses.................................................... 138
6.8
China Extension Analysis .................................................... 139
7.
DATA COLLECTION AND MANAGEMENT ............................................. 139
7.1
Data Quality Assurance....................................................... 139
7.2
Electronic Case Report Forms............................................. 140
7.3
Electronic Clinical Outcome Data ........................................ 140
7.4
Source Data Documentation................................................ 141
7.5
Use of Computerized Systems ............................................ 141
7.6
Retention of Records........................................................... 141
8.
ETHICAL CONSIDERATIONS.................................................................. 142
8.1
Compliance with Laws and Regulations .............................. 142
8.2
Informed Consent................................................................ 142
8.3
Institutional Review Board or Ethics Committee.................. 143
8.4
Confidentiality...................................................................... 144
8.5
Financial Disclosure ............................................................ 144


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9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 144
9.1
Study Documentation .......................................................... 144
9.2
Protocol Deviations.............................................................. 144
9.3
Site Inspections ................................................................... 145
9.4
Administrative Structure....................................................... 145
9.5
Publication of Data and Protection of 
Trade Secrets...................................................................... 145
9.6
Protocol Amendments ......................................................... 146
10. REFERENCES ......................................................................................... 147
LIST OF TABLES
Table 1
Proposed Dose and Titration Regimen for Phase III Studies...... 55
Table 2
Objectives and Corresponding Endpoints for the Double-
Blind Treatment Period ............................................................... 58
Table 3
Objectives and Corresponding Endpoints for the Open-Label 
Extension Period......................................................................... 60
Table 4
Overall Gantenerumab Dosing Design in the Open-Label 
Extension .................................................................................... 87
Table 5
Adverse Event Severity Grading Scale ..................................... 122
LIST OF FIGURES
Figure 1
ADAS-Cog13 Treatment Response by Plasma 
Concentration:  Two-Year Completing Fast Progressors in 
Study WN25203.......................................................................... 47
Figure 2
Mean Percent Change from Baseline in Composite Amyloid 
PET SUVr by Cerebellum Gray Reference:  Study 
WN25203, PET Substudy ........................................................... 48
Figure 3
Median Changes over Time in Concentration-Dependent 
PET SUVr by Gantenerumab Serum Concentration and 
Cerebellum Gray Reference:  Study WN25203, PET 
Substudy..................................................................................... 49
Figure 4
Mean (SE) PET Amyloid Reductions in the OLE PET 
Substudies .................................................................................. 51
Figure 5
SUVR Reductions during the First Year of High-Dose 
Gantenerumab Treatment in the OLE PET Substudies .............. 52


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Figure 6
Patient-Level Amyloid Reductions Over 3 Years of 
Treatment in the OLE PET Substudies....................................... 53
Figure 7
Overall Study Design .................................................................. 64
Figure 8
Overall Gantenerumab Dosing Design in the Double-Blind 
Treatment Period ........................................................................ 85
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 156
Appendix 2
National Institute on Aging/Alzheimer’s Association Criteria 
for Mild Alzheimer’s Disease..................................................... 183
Appendix 3
National Institute on Aging/Alzheimer’s Association Criteria 
for Prodromal Alzheimer’s Disease (Mild Cognitive 
Impairment due to Alzheimer’s Disease) .................................. 185
Appendix 4
Population PK-PET Response Analysis of  Gantenerumab 
Phase III Study WN25203 Data and  Aducanumab Phase Ib 
Study PRIME Data.................................................................... 186
Appendix 5
Amyloid-Related Imaging Abnormality Hazard Model............... 197
Appendix 6
Management Rules for Amyloid-Related Imaging 
Abnormalities ............................................................................ 212


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED,
DOUBLE-BLIND, PLACEBO-CONTROLLED,
PARALLEL-GROUP EFFICACY AND SAFETY 
STUDY OF GANTENERUMAB IN PATIENTS WITH 
EARLY (PRODROMAL TO MILD) ALZHEIMER’S 
DISEASE
PROTOCOL NUMBER:
WN39658
VERSION NUMBER:
5
EUDRACT NUMBER:
2017-001365-24
IND NUMBER:
102,266
NCT NUMBER:
NCT03444870
TEST PRODUCT:
Gantenerumab (RO4909832)
MEDICAL MONITOR:
, MBBS, PhD
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 return the signed original of this form to the Sponsor or its designee.  Please retain a 
signed copy of the form for your study files.


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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED, PARALLEL-GROUP EFFICACY AND 
SAFETY STUDY OF GANTENERUMAB IN PATIENTS WITH 
EARLY (PRODROMAL TO MILD) ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
WN39658
VERSION NUMBER:
5
EUDRACT NUMBER:
2017-001365-24
IND NUMBER:
102,266
NCT NUMBER:
NCT03444870
TEST PRODUCT:
Gantenerumab (RO4909832)
PHASE:
Phase III
INDICATION:
Alzheimer’s disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy and safety of gantenerumab compared with placebo in 
participants with early (prodromal to mild) Alzheimer's disease (AD).  Specific objectives and 
corresponding endpoints for the study are outlined below for the double-blind treatment period 
and for the OLE period.


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Objectives and Corresponding Endpoints for the Double-Blind Treatment Period
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
gantenerumab administered by SC 
injection compared with placebo 
The change in global outcome from baseline (Day 1) 
to Week 116 a, as measured by the CDR-SOB 
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
gantenerumab versus placebo on 
cognition and function
The change from baseline to Week 116 a in cognition 
and/or function, as measured by:
MMSE total score
ADAS-Cog11 and ADAS-Cog13 
Verbal Fluency Task 
Coding
FAQ
ADCS-ADL total score and instrumental score
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
gantenerumab versus placebo
The change from baseline to Week 116 a in the 
following:
Clinically evident decline as measured using the CDR
Severity, as assessed by the CDR Global Score
Dependence level, as derived from the ADCS-ADL 
score
Health-related quality of life, as assessed by the 
QoL-AD scale
Behavioral and neuropsychiatric symptoms of AD, as 
measured by the NPI-Q
Study partner burden, as assessed by the ZCI-AD 
scale
Elements of resource utilization, as assessed by the 
RUD-Lite
Health outcomes in participant and study partner, as 
measured by EQ-5D questionnaire
Aamyloid-; 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; CSFcerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating 
Scale; DTIdiffusion tensor imaging; EQ-5DEuroQol-Five Dimensions; FAQ Functional 
Activities Questionnaire; MMSEMini-Mental State Examination; MRImagnetic resonance 
imaging; NPI-QNeuropsychiatric InventoryQuestionnaire; PET positron emission tomography; 
PKpharmacokinetic; QoL-ADQuality of LifeAlzheimer's Disease; RUD-LiteResource 
Utilization in DementiaLite; SCsubcutaneous; ZCI-ADZarit Caregiver InterviewAlzheimer's 
Disease.
a If the double-blind treatment period is extended by a total of 24 weeks, the endpoints will be 
based on change from baseline to Week 128.


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Objectives and Corresponding Endpoints for the Double-Blind Treatment Period (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
gantenerumab compared with placebo
Nature, frequency, severity, and timing of adverse 
events and serious adverse events
Physical examinations (including neurological 
systems), vital signs, blood tests, ECGs, and C-SSRS
Nature, frequency, severity, and timing of MRI 
findings:  ARIA-E and ARIA-H
Nature, frequency, severity, and timing of injection-site 
reactions
Presence of ADAs during the study relative to the 
presence of ADAs at baseline (in active treatment 
group only)
Pharmacodynamic 
Biomarker Objective
Corresponding Endpoints
To evaluate the effect of gantenerumab 
compared with placebo in participants 
with early (prodromal to mild) 
Alzheimer’s disease
Change from baseline to Week 116 in brain amyloid 
load, as measured by amyloid PET scan in a subset of 
participants
Change from baseline to Week 116 in brain tau load, 
as measured by tau PET scan in a subset of 
participants
Change from baseline to Week 116 in cerebral spinal 
fluid markers of disease in a subset of participants,
including, but not limited to, total tau, and 
phosphorylated tau
Exploratory Biomarker Objective
Corresponding Endpoints
To evaluate the effect of 
gantenerumab compared with placebo 
in participants with early (prodromal to 
mild) Alzheimer’s disease
Change over time in plasma and other CSF 
biomarkers
Change from baseline to Week 116 a in functional brain 
connectivity, as measured by resting-state functional 
MRI (where available)
Change from baseline to Week 116 a 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
Exploratory Pharmacokinetic 
Objective
Corresponding Endpoints
To characterize the PK profile of 
gantenerumab
Plasma concentration of gantenerumab (administered 
subcutaneously) at specified timepoints
Aamyloid-; 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; 
CSFcerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor 
imaging; EQ-5DEuroQol-Five Dimensions; FAQ Functional Activities Questionnaire; MMSEMini-
Mental State Examination; MRImagnetic resonance imaging; NPI-QNeuropsychiatric 
InventoryQuestionnaire; PET positron emission tomography; PKpharmacokinetic; 
QoL-ADQuality of LifeAlzheimer's Disease; RUD-LiteResource Utilization in DementiaLite; 
SCsubcutaneous; ZCI-ADZarit Caregiver InterviewAlzheimer's Disease.
a If the double-blind treatment period is extended by 24 weeks, the final endpoints will be based 
on change from baseline to Week 128.


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Objectives and Corresponding Endpoints for the Open-Label Extension Period
Safety Objective
Corresponding Endpoints
To evaluate the long-term safety and 
tolerability of SC gantenerumab in 
participants with early AD 
Nature, frequency, severity, and timing of adverse 
events and serious adverse events
Physical examinations (including neurological 
systems), vital signs, blood tests, ECGs, and C-SSRS
Nature, frequency, severity, and timing of MRI 
findings:  ARIA-E and ARIA-H
Nature, frequency, severity, and timing of injection-site 
reactions
Presence of ADAs during the study relative to the 
presence of ADAs at baseline
Exploratory Efficacy Objective
Corresponding Endpoints
To assess the long-term efficacy of 
SC gantenerumab in participants with 
early AD
The change in cognition, function and other outcomes 
over time, as measured by:
CDR
MMSE 
ADAS-Cog11 and ADAS-Cog13 
Verbal Fluency Task 
Coding
FAQ
ADCS-ADL 
Health-related quality of life, as assessed by the 
QoL-AD scale
Behavioral and neuropsychiatric symptoms of AD, as 
measured by the NPI-Q 
Study partner burden, as assessed by the ZCI-AD scale
Elements of resource utilization, as assessed by the 
RUD-Lite
Health outcomes in participant and study partner, as 
measured by EQ-5D questionnaire
Aamyloid-; 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; CSFcerebral spinal fluid; C-SSRSColumbiaSuicide 
Severity Rating Scale; DTIdiffusion tensor imaging; EQ-5DEuroQol-Five Dimensions; 
FAQFunctional Activities Questionnaire; MMSEMini-Mental State Examination; 
MRImagnetic resonance imaging; NPI-QNeuropsychiatric InventoryQuestionnaire;
PET positron emission tomography; PKpharmacokinetic; QoL-ADQuality of LifeAlzheimer's 
Disease; RUD-LiteResource Utilization in DementiaLite; SCsubcutaneous; ZCI-ADZarit 
Caregiver InterviewAlzheimer's Disease.


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19/Protocol WN39658, Version 5
Objectives and Corresponding Endpoints for the Open-Label Extension Period (cont.)
Exploratory Pharmacodynamic 
Biomarker Objective
Corresponding Endpoints
To evaluate the long-term effect of 
SC gantenerumab in participants 
with early AD
Brain amyloid load over time, as measured by amyloid 
PET scan in a subset of participants
Brain tau load over time, as measured by tau PET 
scan in a subset of participants
Cerebral spinal fluid markers of disease over time in a 
subset of participants, including, but not limited to, 
A1−42, total tau, and phosphorylated tau
MRI-derived measurements over time, such as 
volumetric changes in whole brain, ventricles, 
hippocampus, or other structures, functional brain 
connectivity, integrity of white matter in all participants
Plasma markers over time in all participants
Aamyloid-; 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; CSFcerebral spinal fluid; C-SSRSColumbiaSuicide 
Severity Rating Scale; DTIdiffusion tensor imaging; EQ-5DEuroQol-Five Dimensions; 
FAQFunctional Activities Questionnaire; MMSEMini-Mental State Examination; 
MRImagnetic resonance imaging; NPI-QNeuropsychiatric InventoryQuestionnaire;
PET positron emission tomography; PKpharmacokinetic; QoL-ADQuality of LifeAlzheimer's 
Disease; RUD-LiteResource Utilization in DementiaLite; SCsubcutaneous; ZCI-ADZarit 
Caregiver InterviewAlzheimer's Disease.
Study Design
Description of Study
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study designed to evaluate the efficacy and safety of gantenerumab in participants with early 
(prodromal to mild) AD. 
The planned number of participants for the global enrollment phase for the study is 
approximately 1016 participants: randomized in a 1:1 ratio to receive gantenerumab and 
placebo (508 participants randomized to gantenerumab and 508 randomized to placebo).  To 
maintain a balanced number of participants enrolled in each treatment arm and to ensure that 
the arms are comparable, randomization will be stratified by stage of disease (prodromal AD vs. 
mild AD), apolipoprotein E (APOE) allele status (presence vs. absence of the ε4 allele), use of 
AD medication (presence vs. absent), geographic region (Western Europe and Australia vs. 
Rest of the World vs. North America) and participation in longitudinal amyloid and tau positron 
emission tomography (PET) substudies.  Approximately 175 centers in approximately 
15 countries worldwide will participate in this study. 
Participants will be selected on the basis of clinical diagnosis of probable AD (according to the 
National Institute on Aging/Alzheimer’s Association [NIA/AA] diagnostic criteria and guidelines 
for AD) or prodromal AD (according to the NIA/AA diagnostic criteria and guidelines for mild 
cognitive impairment (MCI) due to AD).  The aim of the study is to recruit approximately 50% of 
the participants with prodromal AD. 
Eligible participants will be 5090 years old, inclusive, must show evidence of -amyloid 
pathology as indicated by the cerebral spinal fluid (CSF) tau to A42 ratio (CSF-enrolled 
participants) or positive amyloid PET scan by visual read (PET-enrolled participants), and meet 
eligibility criteria.


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The study will consist of a screening period of up to 12 weeks in length following the signing of 
informed consent.  Sites also have the option to prescreen participants on the Free and Cued 
Selective Reminding Test (FCSRT) and Mini-Mental State Examination (MMSE).  Participants 
must sign a separate Informed Consent Form before administration of these tests if used for 
prescreening.  If the results confirm a participant’s eligibility, then the FCSRT and MMSE will not 
have to be completed again during the screening period as long as the test has been done 
within 12 weeks prior the baseline.
Eligible participants will then undergo baseline visit assessments (Day 1) prior to receiving the 
first dose of blinded study drug (gantenerumab or placebo).  Participants will continue in the 
double-blind treatment period.
Due to the global impact of the COVID-19 pandemic and the resulting disruption in study drug 
administration, the duration of the double-blind treatment period will be extended by 12 weeks, 
with the possibility of an additional 12-week extension (for a total of 24 weeks).  This may result 
in the following scenarios: 

Scenario 1:  Participants who are enrolled and active in the double-blind treatment period 
after implementation of Protocol Version 4 will have the double-blind treatment period 
extended by 12 weeks, with the final efficacy and safety visit at Week 116.

Scenario 2:  If the COVID-19 pandemic results in greater than anticipated disruptions to 
study drug administration, then the Sponsor has the option to extend the double-blind 
treatment period by an additional 12 weeks, with the final efficacy and safety visit at Week 
128.  This extension will be mandatory for all patients who are active in the double-blind 
treatment period at the time that the extension decision is implemented.
Participants who have already had the last study drug administration at Week 102 and their final 
efficacy and safety visit at Week 104 and who have completed the double-blind treatment 
period prior to implementation of the study extension by 12 weeks, will continue into the OLE of 
either the WN39658 study or the WN42171 study.  Alternatively, they will continue into the 
safety follow-up period. 
For participants who enroll or who are active in the double-blind treatment period at the time of 
implementation of the study extension by 12 weeks, visits and study drug administration will 
occur Q4W until participants reach the target dose, which will be 510 mg Q2W.  After the last 
dose of study drug (Week 114 for scenario 1 and Week 126 for scenario 2, if applicable), final 
efficacy and safety assessments will be performed 2 weeks later (at Week 116 for scenario 1 
and at Week 128 for scenario 2, if applicable).  Participants may then enroll in an OLE study if 
they are eligible (either in the OLE part of this study or in the WN42171 study) or have safety 
follow-up visits 14 and 50 weeks after the last dose for safety and limited efficacy assessments.  
All participants who prematurely discontinue treatment will continue participating in the study 
and will be asked to return for collection of safety and limited efficacy data.
Participants will undergo brain magnetic resonance imaging (MRI) examinations for safety 
monitoring and longitudinal changes in brain structure.  MRI scans will be read by a central MRI 
reader.  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, function, and quality-of-life (QoL) status.  Blood samples for the assessment of PK
samples, pharmacodynamic (PD) biomarkers, and ADAs will be obtained from all participants. 
The incidence and nature of adverse events, serious adverse events, amyloid-related imaging 
abnormalitiesedema/effusion (ARIA-E) and ARIAhemosiderin deposition (ARIA-H), injection 
site reactions (ISRs), adverse events of special interest, ECGs, and laboratory abnormalities will 
be assessed on a regular basis by an unblinded independent Data Monitoring Committee 
(iDMC).
Once the double-blind treatment period is completed, participants who consent and are eligible 
may opt to participate in an OLE.  If the stand-alone open-label study (Study WN42171) is not 
open for enrollment at the time that a participant completes the double-blind treatment period of 
this study, then the participant will use the OLE procedures described in this study.  These 
participants will then transition to Study WN42171 after they have completed the entire 
schedule of activities in the OLE of this study and the protocol for Study WN42171 is available 
and approved as per local requirements.  If Study WN42171 is open for enrollment at the time 


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21/Protocol WN39658, Version 5
that a participant completes the double-blind treatment period of this study, then the participant 
will enroll directly in Study WN42171 and not in the OLE portion of this protocol. The OLE of 
Study WN39658 is not applicable in countries that cannot run Study WN42171.
The study consists of three distinct periods:

Screening (including an optional prescreening):  The screening period may last up to 
12 weeks for each eligible participant.

Double-blind treatment period:  After screening, participants who meet all eligibility criteria 
will be randomly assigned to one of two arms (gantenerumab or placebo) in a 1:1 ratio.  
Following baseline assessments, each participant will receive a minimum of nine SC Q4W 
administrations of study drug (uptitration period), followed by up to 40 administrations of 
study drug in the double-blind treatment period in scenario 1 or up to 46 administrations in 
scenario 2, if applicable.  The last dose of study drug will be administered at Week 114 in 
scenario 1 and at Week 126 in scenario 2, if applicable.  At the end of the double-blind 
treatment period, 2 weeks after the last dose, all participants will undergo the final safety 
and efficacy study visit.  Participants who have already completed the double-blind 
treatment period prior to implementation of the study extension by 12 weeks will have 
received 34 SC Q2W administrations of study drug during the double-blind treatment 
period.  The last dose will be administered at Week 102, and their final efficacy and safety 
visit will be at Week 104.

Postdouble-blind treatment period:  After the final efficacy and safety study visit, all 
participants will be asked to come back for the long-term follow-up visits or to continue in 
the OLE. 
Long-term follow-up:  Long-term follow-up will consist of a 50-week follow-up period with 
evaluations at Weeks 14 and 50 after completion of study drug administration.  
Participants who withdraw early during the double-blind treatment period or during the 
OLE period are also asked to complete the long-term follow-up visits.
OLE:  All eligible participants will have the opportunity to enter an OLE study.
–
Eligible participants who enrolled early in the WN39658 study may start the OLE 
and will then transition to the open-label study WN42171 (details will be provided in 
protocol WN42171).  Participants who terminated the WN39658 OLE early will be 
asked to come back for long-term follow-up visits.
–
If the WN42171 protocol is available and approved by local authorities, the 
remaining eligible participants will directly be enrolled in the open-label study 
WN42171. 
China Enrollment Plan
Based on historical data, participant recruitment is expected to take longer in China; therefore, a 
specific China enrollment plan has been established.  Thus, if at least 1 participant is enrolled at 
sites in mainland China, Hong Kong, and Taiwan that are recognized by the National Medical 
Products Administration (NMPA) during the global enrollment phase, additional participants may 
be enrolled in a China extension to ensure a total enrollment that is sufficient to support 
registration in China.  All participants enrolled at NMPA-recognized sites in the global 
enrollment phase will be included in the primary analysis.  All participants enrolled at 
NMPA-recognized sites in the global enrollment phase and the China extension phases will be 
included in a China-specific analysis.  Details will be provided in the Statistical Analysis Plan 
(SAP).
Substudies
The substudies associated with Study WN39658 will be described in separate protocols, and 
participants consenting to enroll in these substudies will be asked to sign the associated 
Informed Consent Forms.
To date, there are two substudies associated with Study WN39658:  a longitudinal Amyloid PET 
substudy and a longitudinal Tau PET substudy.  The amyloid- and tau-PET assessments will 
allow a longitudinal evaluation of the effect of gantenerumab on brain amyloid deposition as 
measured by florbetaben or flutemetamol PET radioligands and tau burden as measured by 
[18F] GTP1 (an investigational radioligand for in vivo imaging of tau protein aggregates) in 


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participants with early AD.  Details of any interim analyses relating to the substudies will also be 
described in the substudy protocols.
The PET data that are collected are expected to help in understanding the effects of 
gantenerumab on amyloid and tau pathology over time as well as the relationship between 
change in florbetaben/flutemetamol/[18F] GTP1-PET and changes in other endpoints in the 
study WN39658.
Data Monitoring Committee
The iDMC will evaluate participant safety and efficacy on a regular basis.  In addition to the data 
defined in the iDMC Charter (e.g., the incidence and nature of adverse events, serious adverse 
events, adverse events of special interest, ARIA-E, ARIA-H, and ISRs), the iDMC will review all 
necessary cumulative data at regular intervals during the study, including efficacy when needed.  
It is anticipated that these assessments will occur approximately every 3 months.  At the time of 
each review, the iDMC will make appropriate recommendations (e.g., the study should continue 
as planned, enrollment in a specific arm should be discontinued, the treatment regimen should 
be modified, the protocol should be amended, enrollment should be held pending further safety 
evaluations).  The iDMC will also evaluate planned or unplanned interim analyses for efficacy or 
futility.
Decisions will be made in consideration of the totality of the available data.  Ad-hoc meetings 
may be called in addition to scheduled meetings, as necessary, to provide recommendations on 
management of any new safety issues.  Specific operational details such as the committee's 
composition, frequency, and timing of meetings, and members' roles and responsibilities are 
detailed in the iDMC Charter. 
Final decisions will rest with the Sponsor.
Number of Patients
The planned enrollment specifies approximately 1016 participants.
Target Population
This study will enroll approximately 1016 participants with increased brain amyloid burden 
(defined according to CSF or 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.
An increase in sample size may be considered in the event of changes to the sample size 
assumptions on the basis of blinded data review or factors external to the study.
If at least 1 participant is enrolled at sites in mainland China, Hong Kong, and Taiwan that are 
recognized by the NMPA during the global enrollment phase, additional participants may be 
enrolled in a China extension to ensure a total enrollment that is sufficient to support registration 
in China.  All participants enrolled at NMPA-recognized sites in the global enrollment phase will 
be included in the primary analysis.  All participants enrolled at NMPA-recognized sites in the 
global enrollment phase and the China extension phases will be included in a China-specific 
analysis.  Details will be provided in the SAP.
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 or Institutional Review Board)

Age 5090 years old at screening, inclusive

Availability of a person (referred to as the “study partner” throughout this protocol) who:
–
Agrees to participate throughout the duration of study
–
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, including knowledge about domestic 
activities, hobbies, routines, social skills, and basic activities of daily life; work and 
educational history; cognitive performance including memory abilities, language abilities, 


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temporal and spatial orientation, judgment and problem solving; emotional and 
psychological state; and can report any changes in the general health status
–
Agrees to provide information and to complete all aspects of the study at clinic visits 
(which require partner input for scale completion)
–
Signs the necessary Informed Consent Form(s), and has sufficient cognitive capacity to 
accurately report on the participant’s behavior as well as cognitive and functional abilities
–
Is fluent in the language used at the site and has sufficiently good general health to have 
a high likelihood of maintaining the same level of interaction with the patient and 
participation in study procedures throughout the duration of the study
Every effort should be made to have same study partner 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, lumbar puncture 
[if applicable], clinical genotyping, and PET imaging [if applicable])
The participant should be capable of completing assessments either alone or with the 
help of the study partner.

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 CSF tau/Aβ42 or on amyloid PET 
scan by qualitative read by the core/central PET laboratory

Demonstrated abnormal memory function at screening (FCSRT cueing index 0.67 and
free recall 27)

Screening MMSE score 22 and CDR-GS of 0.5 or 1.0

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) 

If the participant is receiving symptomatic AD medications, a stable dosing regimen for at 
least 3 months prior to screening and until randomization

Participants receiving GV-971 or who are planning to take GV-971 during the study are 
not eligible

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 and its 
associated substudies

For enrollment in the China extension, participants must have residence in mainland China, 
Hong Kong, or Taiwan and be of Chinese ancestry

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 last dose of 
study drug
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
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.


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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 and approval by 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 MRI central 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 fluid-attenuated inversion recovery 
(FLAIR) sequence, which is 20 mm in any dimension


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
Combined number of microbleeds and areas of leptomeningeal hemosiderosis (i.e., 
cumulative ARIA-H) on MRI more than five (and should not include any disseminated 
leptomeningeal hemosiderosis) based on the review performed by the central reader prior 
to randomization

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
A participant may be rescreened if there is no improvement in cognition in the 
investigator's judgment after 3 months of adequate treatment for thyroid function.


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
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 rescreened 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 rescreened 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 or any other treatment with a monoclonal antibody 
within 5 half-lives or 4 months prior to screening, whichever is longer

Any previous administration of GV-971

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 randomization 
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 randomization 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 randomization
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 randomization 
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 randomization
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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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, the participant’s sufficient education or 
work experience.

Pregnancy or breastfeeding, or intention of becoming pregnant during the study

Deformity of the lumbosacral region of the spine that in the opinion of the investigator would 
contraindicate lumbar puncture in participants who will have lumbar puncture

Clinically significant abnormal screening blood, CSF (if applicable), or urine results that 
remain abnormal at retest

Impaired coagulation (screening prothrombin time [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 efficacy and safety, provided that they have a 
study partner who meets the minimum requirement
Eligibility for the Open-Label Extension
Participants who have been randomized and who have completed the double-blind treatment 
period will be eligible to participate in the OLE, provided they do not meet any of the following 
criteria: 

Discontinued from study treatment during the double-blind treatment period

Received any other investigational medication during the double-blind treatment period or 
after the end of double-blind treatment

Participation in the OLE deemed inappropriate by the investigator (e.g., any serious medical
condition or other concerns that preclude the participant’s safe participation in the OLE or 
ability to comply with the required procedures)

Presence of ARIA-E findings at the Week 116 (or Week 128, if applicable) MRI scan 
(participants who have ongoing ARIA-E findings at the Week 116 [or Week 128, if 
applicable]) MRI scan will stay in the double-blind treatment period until the finding is 
deemed resolved). For those participants who enroll into the GRADUATE OLE from 
Week 104, before the double-blind extension took place, eligibility for the OLE would be 
based on the Week 104 scan.


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End of Study
The end of the study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for safety analyses or safety follow-up is received for the last 
participant, whichever occurs later.
Length of Study
The study will consist of a screening period of up to 12 weeks (including the optional 
prescreening period) for each eligible participant who signs the Informed Consent Form and 
agrees to participate, followed by a double-blind treatment period of study drug treatment plus a 
visit 2 weeks after the last dose.  The duration of the double-blind treatment period is extended 
by 12 weeks (116 weeks in total in scenario 1). In case scenario 2 is implemented, the double-
blind treatment period will be extended by 24 weeks (128 weeks in total in scenario 2, if 
applicable).  For participants not entering the OLE period, this will be followed by the 
postdouble-blind treatment period of two follow-up visits at 14 and 50 weeks after the last 
dose.  Thus, for a participant not entering the OLE period, the maximum length of study is 
approximately 176 weeks in scenario 1 or 188 weeks in scenario 2 (if applicable).  
For participants entering the OLE period, the extension will consist of an open-label period of at 
least 35 weeks.  If a participant is ready to be uptitrated to the target dose and if the safety MRI 
allows, the participant will then be transitioned to the WN42171 open-label study.  If there is an 
ongoing ARIA-E, the participant will remain in Study WN39658 until the ARIA-E resolves and 
the participant is ready to be uptitrated to the target dose.  In case the dosing is temporarily 
interrupted for any other reason, the participant will be kept in the WN39658 study until they are 
ready to be uptitrated to the target dose.  Participants who are not willing to transition to the 
WN42171 open-label study after OLE Week 35 will be asked to come back for two follow-up 
visits at 14 and 50 weeks after the last dose (OLE Follow Up 1 and Follow Up 2, respectively). 
Investigational Medicinal Products
The investigational medicinal product (IMP) for this study is gantenerumab.
Test Product (Investigational Drug)
Gantenerumab or placebo will be administered by SC injection to all participants.
Double-Blind Treatment Period
Gantenerumab will be administered by SC injection to all patients randomized to the active 
treatment arm, regardless of APOE ε4 status, at a dose of 120 mg SC Q4W for 3 months, 
255 mg SC Q4W for 3 months, and 510 mg SC Q4W for 3 months, prior to reaching the target 
dose.  Once the target dose is reached, study drug will be administered every 2 weeks (Q2W 
administration of 510 mg SC gantenerumab).  The switch to a Q2W administration schedule 
allows decreasing the number of SC administrations in the abdomen per visit.
Note: A minimum of 3 doses during each dosing step must be administered prior to uptitration.
For Q4W injections, a time window of 7 days is allowed for dosing visits.  For Q4W injections, 
the recommended minimum time between doses is 3 weeks.  The maximum recommended 
time between doses should not exceed 6 weeks.  Once study drug is administered Q2W, the 
time window for dosing visits is 3 days.  For Q2W injections, the recommendation is not to 
administer more than 1020 mg (i.e., 2 times 510 mg Q2W) within 28 days.  Always return to the 
initial planned schedule per randomization for subsequent visits.
Regardless of dose, each participant will undergo up to a total of 49 dosing visits in scenario 1 
or 55 dosing visits in scenario 2 (if applicable) in the double-blind treatment period of the study.  
Participants who have completed the double-blind treatment period at the time of the 
implementation of the 12 week study extension, will have undergone up to 43 dosing visits.  
Injections will be administered as one 0.8-mL (120-mg dose), one 1.7-mL (255-mg dose), or two 
1.7-mL injections (510-mg dose) subcutaneously to the abdomen, respectively.
Placebo of identical composition (except protein) and identical volume to gantenerumab will be 
administered by SC injection to all participants randomized to placebo at the same frequency 
and using the same route of administration.
On study drug administration days that include efficacy assessments, study drug must be 
administered at the clinical site.  Study personnel preparing and administering study drug must 
not be involved with any efficacy assessments or safety evaluations.


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At applicable sites, study drug may be administered by a trained nursing professional at the 
participant's home or another suitable location, if the participant has given written informed 
consent to participate in home nursing visits.
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the 
Adverse Event eCRF.
Open Label Extension Period
During the OLE, participants previously randomized to the active treatment arm will continue to 
be administered the study drug every two weeks (Q2W administration of 510 mg SC 
gantenerumab).  Participants previously randomized to the placebo arm will be required to 
undergo 9 months of uptitration.
In order to maintain the previous study treatment blinding (Sponsor, site, and participant), all 
participants will be dosed every two weeks in the OLE.  As in the double-blind treatment period, 
a safety MRI has to be performed before each uptitration to ensure that the participant can be 
uptitrated safely to the next dose. 
To ensure blinding to previous treatment, administration will consist of one 0.8-mL and two 
1.7-mL injections for the 120-mg dose or will consist of two 1.7-mL injections for the 255 mg 
dose and 510-mg dose.  Injections will be administered subcutaneously to the abdomen.
Note:  As in the double-blind part, a minimum of 3 doses during each dosing step must be 
administered prior to uptitration.  During uptitration in the OLE, a minimum of 3 doses of each 
dosing step also have to be administered prior to be eligible for uptitration.  In the OLE, a dose 
is defined as two consecutive dosing visits (one with an even dose number and one with an odd 
dose number).
For the OLE, the time window for dosing visits is 3 days.  Always return to the initial planned 
schedule per randomization for subsequent visits.
Participants enrolled in the WN39658 OLE study will have to complete the full titration scheme 
(i.e., at least 12 weeks on each dosing step) prior to being able to enroll in the WN42171 open-
label study where they will receive 510 mg SC Q2W. 
On study drug administration days that include efficacy assessments (see the schedule of 
activities in Appendix 1), study drug must be administered at the clinical site.  Study personnel 
who prepare and administer the study drug must not be involved with any efficacy assessments 
or safety evaluations. 
At applicable sites, study drug may be administered by a trained nursing professional at the 
participant's home or another suitable location if the participant has given written informed 
consent to participate in home nursing visits.
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration electronic Case Report Form (eCRF).  Adverse events associated with an 
overdose or incorrect administration of study drug should be recorded on the Adverse Event 
eCRF.
PET Tracers
All participants who are enrolled in PET substudies will be assessed by PET imaging using an 
appropriate PET ligand.  For screening, the possible amyloid PET ligands will be florbetapir, 
florbetaben, and flutemetamol.  According to E.U. guidance, the PET tracers as used in the 
context of this study, are designated as non-IMP.  In some regions, according to local 
regulations, these PET tracers may be considered to be IMP.
In countries where the PET radioligands are approved for marketing, the approved local product 
information will be provided, and in countries where they are not approved for marketing, the 
Investigator’s Brochures will be provided.
Details about the PET substudies are described in separate protocols.
Statistical Methods
Primary Analysis
The primary efficacy outcome measure is the change in CDR-SOB from baseline (Day 1) to 
Week 116.  In the case where the double-blind treatment period is extended for an additional 12 


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weeks, the primary efficacy outcome measure will be the change in CDR-SOB from baseline 
(Day 1) to Week 128.
The clinical question of interest is to assess the study treatment effect on disease progression 
up to Week 116 (or Week 128, if applicable), irrespective of use or initiation of symptomatic 
treatments for AD, in the absence of the COVID-19 pandemic.
In accordance with the estimand framework outlined in the ICH-E9 addendum (EMA 2018), 
the attributes of the estimand for the primary endpoint are defined as follows:

Population: early (prodromal to mild) AD population including all randomized 
participants.

Variable: change from baseline at Week 116 (or Week 128) in the CDR-SOB.
Treatment: prescribed study drug including uptitration to the target dose, 
irrespective of use or initiation of symptomatic treatment for AD.

Intercurrent events (ICE): the list of ICE will be defined in the SAP, this includes:
Treatment discontinued for study drug or conditionrelated (SDCR) reasons (e.g., 
treatment-related adverse event or lack of efficacy):
Treatment discontinued for non-study drug or condition related reasons (NSDCR) 
reasons (e.g. purely administrative reason).

Population level summary: mean change from baseline to Week 116 (or Week 128, as 
appropriate) between gantenerumab-treated participants and placebo-treated participants.
The primary estimand is a combination of a treatment-policy strategy and a hypothetical 
strategy (FDA 2017) to account for the different assumptions for each type of ICE. Full 
details of the primary estimand, and of the corresponding estimator and estimation methods 
(e.g. statistical model, multiple imputation for missing or excluded data points) will be 
provided in the SAP. Supplementary estimands may also be considered and will be defined in 
the SAP.
Every effort will be made to minimize missing data.  Furthermore, the Sponsor has made every 
effort to expedite the implementation of the 12 week extension to the double-blind treatment 
period.  If the study is extended by an additional 12 weeks (for a total extension of 24 weeks), 
the number of patients in scenario 1 (who will have missing Week 128 efficacy data) will be 
minimized.
Participants who discontinue early from study treatment will be asked to return for collection of 
safety and limited efficacy data (i.e., the primary and secondary efficacy endpoints) until the end 
of the double-blind treatment period and follow-up visits.  To explore the robustness of MMRM 
results for the primary efficacy conclusions sensitivity analyses (e.g., using multiple imputation 
and pattern mixture models) will be performed.  Descriptive summaries of the number of 
participants with missing data, the number of participants in each scenario, the timing, and 
reasons for discontinuation from the study will also be provided by treatment group.
Determination of Sample Size
Determination of sample size is based on participants enrolled in the global enrollment phase.  
In this study, approximately 1016 participants will be enrolled and randomized in 1:1 ratio to 
each treatment arm (gantenerumab or placebo) during the global enrollment phase.  A sample 
size increase may be considered if factors external to the study or blinded study data review 
would warrant a change to the sample size assumptions.
Additional participants may be randomized during the China extension if at least 1 participant is 
enrolled at sites in mainland China, Hong Kong, and Taiwan that are recognized by the NMPA 
during the global enrollment phase.


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The estimated sample size required to demonstrate efficacy with regard to CDR-SOB is based 
on the following assumptions:

The mean change in the CDR-SOB from baseline to Week 104 is 2.5 points in the 
placebo arm

A common standard deviation across treatment arms for change of approximately 2.97 from 
baseline to Week 104 in the CDR-SOB 

Gantenerumab has a true effect of a 30% relative reduction in deterioration of CDR-SOB
Based on these assumptions, and using a student’s T-test with equal variance, a sample size 
was calculated for 90% power to detect a true treatment effect of 30% relative reduction in 
deterioration of CDR-SOB at a two-sided of 0.05.  
Uncertainties on parameters affecting the power (e.g., dropout rate, study drug discontinuation 
rate, standard deviation, and placebo decline) were assumed to be equivalent to a drop-in 
sample size of up to around 35% and were corrected for accordingly.  This calculation leads to 
a total of 1016 participants in the study.
At the date of writing Protocol Version 4, it is expected that participants would have missed an 
average of 8 weeks of study drug administration over the course of the original 2-year study due 
to the COVID-19 pandemic.  This has the potential to decrease the power of the study from 
~90% to ~80%.  To mitigate the impact of missed administrations, the double-blind treatment 
period was extended by 12 weeks.  Under current assumptions, this brings the study power 
back to the originally planned ~90%.
The sample size may be increased from 1016 up to 1322 participants (661 participants per 
arm).  The decision whether to increase sample size will be based on blinded study data review, 
e.g., by a review of the frequency of missed study drug administrations due to the COVID-19 
pandemic.  Further details will be described in the SAP.  The assessment will be performed by 
the Sponsor at a specified timepoint.  The sponsor will remain blinded.  The sample size will not 
be reduced on the basis of this assessment.  Other factors external to the study may also 
trigger a decision to increase sample size.
Interim Analyses 
Optional Futility Analysis
The Sponsor may perform an interim analysis for futility approximately 116 weeks after 50% of 
the targeted study enrollment has been reached.  If the study is extended by an additional 12 
weeks, the interim analysis will be performed approximately 128 weeks after 50% of the 
targeted study enrollment has been reached.  The exact timing of an interim analysis may be 
synchronized with study WN29922.
An independent data coordinating center will be responsible for the interim analyses. The study 
results will only be reviewed by the iDMC and the Sponsor will remain blinded. Other third 
party vendors may be involved in the data preparation and analyses, as appropriate.
The iDMC may recommend to stop for futility if the failure criterion is met.  The failure criterion 
will represent a low probability of a positive study outcome given the data observed at the time 
of interim analysis.  If the futility criteria are not met, the study continues beyond the interim 
analysis. The failure criterion will be prespecified in the iSAP.
Details of the futility analysis, including the final decision to conduct it, the rationale, 
timing, and statistical details for the analyses (such as the data that would be reviewed by the 
iDMC and futility thresholds) will be documented in the iSAP. This will be submitted to 
relevant health authorities at least 2 months prior to the conduct of the interim analysis.
Optional Interim Analyses
Based on availability of information pertaining to gantenerumab or other compounds with similar 
mode of action that may emerge during the course of this study, the Sponsor may choose to 
conduct an additional interim analysis, which may include efficacy, safety and biomarker 
outcomes including amyloid PET SUVr and/or other biomarkers to confirm PD effect. This 
analysis may be done on a whole study population or in a well predefined subgroup when 
approximately 50% of the overall population has reached Week 116. If the study is extended 
by an additional 12 weeks, the interim analysis will be performed once approximately 50% of 
the overall population has reached Week 128.


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An independent data coordinating center will be responsible for the interim analyses. The study 
results will only be reviewed by the iDMC and the Sponsor will remain blinded. Other third 
party vendors may be involved in data preparation and analyses, as appropriate.
The iDMC may indicate that a pre-specified success criterion has been met. If so, the Sponsor 
may decide to present the data to a health authority. Any interim, unblinded data will be 
strictly firewalled to ensure those involved in the conduct of the ongoing trial and the 
WN42171 OLE trial remain fully blinded. If needed, appropriate measures will be taken to 
control the overall Type I error rate and described in the SAP.
Details of the interim analyses, including the decision to conduct the optional interim analysis, 
the rationale, timing, and statistical details for the analyses (such as the data that would be 
reviewed by the iDMC and futility or efficacy thresholds) will be documented in the SAP, and the 
SAP will be submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
A
amyloid-beta
AD
Alzheimer’s disease
ADA
anti-drug antibody
ADAS-Cog11
Alzheimer's Disease Assessment ScaleCognition,
Subscale 11
ADAS-Cog13
Alzheimer's Disease Assessment ScaleCognition,
Subscale 13
ADCS-ADL
Alzheimer’s Disease Cooperative Study 
GroupActivities of Daily Living
ADL
activities of daily living
APOE 4
apolipoprotein E, 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
AUCinf
area under the concentration–time curve from Time 0 
to infinity
BOLD
blood oxygenation level-dependent 
BGTS
Barkhof grand total score 
CDR
Clinical Dementia Rating
CDR-GS
CDR global score
CDR-SOB
Clinical Dementia RatingSum of Boxes
Cmax
maximum concentration
CNS
central nervous system
COA
clinical outcome assessment
CRO
contract research organization
CSF
cerebral spinal fluid
C-SSRS
ColumbiaSuicide Severity Rating Scale
CT
CTAD
computed tomography
Clinical Trials in Alzheimer’s Disease
DTI
diffusion tensor imaging
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EMA
European Medicines Agency
EQ-5D
EuroQol-Five Dimensions questionnaire


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Abbreviation
Definition
FA
fractional anisotropy
FA
fractional anisotropy
FAQ
Functional Activities Questionnaire
FCSRT
Free and Cued Selective Reminding Test
FCSRT-IR
Free and Cued Selective Reminding TestImmediate 
Recall
FDA
(U.S.) 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 on Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ISR
injection-site reaction
ITT
intent to treat
IWG
International Working Group
IV
intravenous
IxRS
interactive voice or Web-based response system
LPLV
last patient, last visit
MAD
multiple-ascending dose
MCI
mild cognitive impairment
MMRM
mixed model repeated measure
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NIA/AA
National Institute on Aging/Alzheimer’s Association
NMPA
National Medical Products Administration 
NPI-Q
Neuropsychiatric InventoryQuestionnaire
NSDCR
non-study drug or condition-related
OLE
open-label extension
PD
pharmacodynamic
PET
positron emission tomography
PK
pharmacokinetic
PT
prothrombin time


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Abbreviation
Definition
p-tau
phosphorylated tau
QoL
quality of life
QoL-AD
Quality of LifeAlzheimer's Disease
Q2W
every 2 weeks
Q4W
every 4 weeks
RBR
Research Biosample Repository
rs-fMRI
resting-state functional magnetic resonance imaging
RUD-Lite
Resource Utilization in DementiaLite
SAD
single-ascending dose
SAP
Statistical Analysis Plan
SC
subcutaneous
SDCR
study drug or condition-related
SOB
Sum of Boxes
SUVr
standardized uptake value ratio
t-tau
total tau
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing
ZCI-AD
Zarit Caregiver InterviewAlzheimer’s Disease


Gantenerumab—F. Hoffmann-La Roche Ltd
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1.
BACKGROUND
1.1
BACKGROUND ON ALZHEIMER’S DISEASE
The World Health Organization estimates that around 50 million people worldwide are 
diagnosed with dementia and that there are 10 million new cases every year. The total 
number of people with dementia is estimated to reach 82 million in 2030 and will more 
than triple by 2050 to 152 million. Alzheimer’s disease (AD) is the most common form of 
dementia, accounting for 60%70% of cases (World Health Organization 2017). 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.
There is great inter-individual variability in AD progression with survival dependent on 
many factors, including age at onset.  In general, the clinical picture evolves from 
“predementia” or “prodromal AD” to mild, moderate, and then severe AD.  At the early 
stage of AD, a slight impairment of memory, language, and visuospatial function can be 
observed.  As AD advances, patients become progressively impaired and the burden on 
caregivers significantly increases.  The median survival time following a diagnosis of AD 
strongly depends on the patient’s age at diagnosis and ranges from 8.3 years for 
persons diagnosed with AD at 65 years old to 3.4 years for those 90 years old 
(Brookmeyer et al. 2002).  On average, individuals live 39 years after diagnosis 
(Helzner et al. 2008) and some 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 to treat the symptoms of AD, including
acetylcholinesterase inhibitors (AChEi) 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.
2016).  Recent efforts have mostly focused on therapies targeting amyloid (Bachurin 
et al. 2017) as these offer the most compelling therapeutic targets (Graham et al., 2017).  
These therapies are based on the amyloid hypothesis that posits amyloid-(A)
accumulation as the primary factor driving A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.
Preclinical evidence has suggested that monoclonal 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 


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transgenic models cognitive function (Janus et al. 2000).  Accumulating clinical evidence 
also supports that monoclonal Aantibodies can bind Aand promote its clearance 
(Salloway et al. 2009; Ostrowitzki et al. 2012), reduce deposition of Aaggregates, and 
reduce markers of neurodegeneration in the cerebral spinal fluid (CSF) (Roche 
Research Report No. 1066251).  In a Phase I study, 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 neurological 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-like Aoligomers, fibrils, and plaques, is expected to address this need 
(Bohrmann et al. 2012).
1.2
BACKGROUND ON GANTENERUMAB 
Gantenerumab (or RO4909832) is a fully human antiApeptide antibody developed by 
in vitro selection utilizing aggregated Aand in vitro maturation within a complete human 
Ig, subclass-1 framework (IgG1).  Gantenerumab recognizes a conformational epitope 
of Apresent in aggregated Aand that is demonstrated for both major species of 
Athat is, A1−40 and A1−42.  Gantenerumab has a molecular mass of 146.3 kDa.  
In vitro, gantenerumab recognizes synthetic aggregated Afibrils and Aoligomers with 
high nanomolar affinity (KD, ~0.61.2 nM).  Based on additional in vitro studies and 
studies in animal models, the pharmacologic profile suggests that in humans,
gantenerumab may prevent, inhibit, and reduce accumulation of A, which is believed to 
play an important role in the pathogenesis of AD.  
Gantenerumab is manufactured by cell culture of a recombinant Chinese hamster 
ovaryK1 mammalian cell line and subsequent purification of the antibody.  The 
gantenerumab drug substance manufacturing was optimized during development,
leading to several manufacturing processes (G1, G2, and G3).  Recently, the 
gantenerumab manufacturing process was further optimized from G3 to G4 to improve 
process robustness and increase overall process yield.  Drug material manufactured by 
G4 process is used in Phase III clinical trials (e.g., Study WN39658). Gantenerumab is 
in clinical development for patients with early (prodromal to mild) AD and is also being 
investigated in carriers of familial AD mutations (DIAN-TU) (Bateman et al. 2017).
Refer to the gantenerumab Investigator's Brochure for details on nonclinical and 
clinical studies.


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1.2.1
Nonclinical Studies
1.2.1.1
Nonclinical Pharmacology
The binding characteristics of gantenerumab were engineered to achieve specific and 
highly sensitive recognition of the assembly structure of aggregated human A1−42 and 
A1−40 peptides, which are major components in Aplaques.  Specificity was 
demonstrated ex vivo for genuine human Aplaques in AD brain slices.  The minimum 
effective concentration for staining of human Aplaques is 10 ng/mL (0.07 nM).
Gantenerumab showed a concentration-dependent increase in cellular phagocytosis of 
human Aplaques by human primary cells like microglia and differentiated 
macrophages in a brain-slice phagocytosis assay.  The measured minimal effective 
concentration of 10 ng/mL (0.07 nM) is consistent with the observed efficacy for human 
Aplaque binding.  
In single-dose and multiple-dose studies, effective brain penetration and binding to A
plaques in vivo were demonstrated in various models of AD-related amyloidosis, such as 
the PS2APP transgenic mouse model.  Gantenerumab showed significant and 
accumulative binding to Aplaques.  The data indicate that there is no requirement for 
continuous high peripheral levels to achieve a sustained binding of gantenerumab to 
amyloid plaques.
The plaque binding of gantenerumab from several manufacturing processes has been 
evaluated.  The degree of plaque binding for gantenerumab manufactured by the 
G1 and G2 processes was investigated by semi-quantitative fluorescence imaging and 
was comparable in a 2-week IV safety study in PS2APP transgenic mice at doses of 0,
2, 10, and 40 mg/kg every 3 days.
An additional study, which compared the plaque binding of gantenerumab from the 
G3 and G4 manufacturing processes following single IV administration to PS2APP 
transgenic mice at a dose level of 40 mg/kg and assessed by semi-quantitative 
fluorescence imaging after 7 days, indicated slightly increased target engagement of the 
G4 material consistent with observed differences in exposure (see Section 1.2.1.2).
Chronic treatment with gantenerumab showed significant efficacy by halting progression 
of amyloidosis in transgenic PS2APP, APPLondon, and tau PS2APP mouse models of AD.  
Amyloid reduction was evident by prevention of new plaque formation and removal of 
preexisting amyloid plaques by engaging microglia cells.


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1.2.1.2
Nonclinical Pharmacokinetics and Metabolism
The pharmacokinetics of gantenerumab were studied in mice, rats, and cynomolgus 
monkeys following IV administration.  Gantenerumab pharmacokinetics were 
characterized by a rapid initial decrease in plasma levels during the first 24 hours,
followed by a long half-life, ranging from 4 to 13 days in all species.  Overall, the studies 
demonstrate that gantenerumab has PK properties similar to other IgGs.
The pharmacokinetics of gantenerumab were also studied following SC administration in 
cynomolgus monkeys and mice.  In cynomolgus monkeys, maximum plasma levels were 
reached after 3 days.  The average bioavailability was estimated at 76%.
Gantenerumab was shown to penetrate the brain in both the monkey and mouse.  Brain 
penetration in the monkey was evident from analysis of CSF samples.  The CSF to 
plasma ratios ranged from 0.006% to 0.018%.  Penetration and binding to 
A1−42 plaques in the mouse brain were evident from immunostaining for gantenerumab 
of brain sections obtained from PS2APP mice dosed with gantenerumab.
Rat PK studies have been conducted to compare the pharmacokinetics of 
gantenerumab derived from different manufacturing processes (G1, G2, G3, and G4).
Following IV administration to rats, the pharmacokinetics of the G1 and G2 materials 
were similar.  The area under the concentrationtime curve (AUC) of the G2 material 
was slightly lower and accounted for about 80% of the of the G1 material.  Although 
standard bioequivalence criteria for AUC were not met, the observed difference in AUC 
was not considered to have an impact on the use of the G2 material in further clinical 
development as the difference in AUC is small.  The average terminal half-life of both 
materials was comparable (8.0 and 8.8 days for the G1 and G2 materials, respectively).
A study comparing the pharmacokinetics of gantenerumab derived from the G3 and 
G4 manufacturing processes showed that the AUC of G3 material (used in the ongoing
Phase III OLE studies WN25203 and WN28745) was lower compared with the G4 
material that will be used in Study WN39658 (meanSD:  932196 and 1270187 
(ghr/mL)/(mg/kg), respectively.  The average terminal half-life of both materials was 
similar (11.5 and 12.3 days for G3 and G4 materials, respectively).
1.2.1.3
Toxicology and Safety Pharmacology
Potential adverse effects in relation to the presence and destruction of A1−42 plaques 
were assessed in PS2APP transgenic mice that were treated with up to 375 mg/kg/wk of 
IV gantenerumab for up to 26 weeks.  No evidence of inflammatory reaction in general 
or other adverse effects were observed in these studies.  Decreases in neutrophils and 
protein (albumin) that were not considered adverse were seen in mice.  As a 
compensatory response, myeloid hyperplasia in the bone marrow was inconsistently 
detected in some animals.  The reason for the low neutrophil counts is unclear but may 
be a mouse-specific effect of gantenerumab on neutrophils.  Indeed, no such finding was 


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observed in long-term nonclinical (murine and monkey) and clinical studies, and there 
have been no symptoms indicating immunosuppression in either species.
In cynomolgus monkeys, gantenerumab was well tolerated in repeat-dose IV toxicity 
studies of 13 and 26 weeks in duration (3, 10, and 20 mg/kg) and in SC toxicity studies 
of 13 weeks in duration (20 mg/kg) and 39 weeks in duration (up to 375 mg/kg).  In the 
26-week toxicity study, in which gantenerumab was administered once weekly, one male 
monkey in Group 2 (3 mg/kg) was found dead 24 hours after receiving the 26th dose 
(Day 177).  The death was not considered to be related to gantenerumab treatment but 
rather to a bacterial infection detected on histopathology.  There was no 
treatment-related effect on hematologic parameters (i.e., neutrophil counts) in studies in 
cynomolgus monkeys.
In the absence of any adverse treatment-related effect in the 39-week toxicity study, a 
no-observed-adverse-effect level of 375 mg/kg/wk was established, which correlated 
with a mean maximum concentration (Cmax) of 2535 g/mL (male and female animals 
combined) and a mean area under the concentrationtime curve from Time 0 
to 168 hours (AUC0168hr) of 386,000 g hr/mL (male and female animals combined).
Reproductive toxicity studies in transgenic PS2APP mice did not reveal an effect of 
gantenerumab on fertility, embryofetal, or post-natal development.
1.2.2
Clinical Studies
Gantenerumab has been investigated in 10 completed Phase I clinical studies:  three 
single-ascending dose (SAD) studies (BN18726, JP22474, and BP30042) of healthy 
volunteers and patients with mild to moderate AD, two multiple-ascending dose (MAD)
studies (NN19866 and JP22431) of patients with mild to moderate AD, and three 
bioavailability studies of healthy subjects (one comparing the IV and SC formulations of 
gantenerumab [Study WP22461], two comparing lyophilized and high-concentration 
liquid formulations of gantenerumab [Studies WP27951 and BP29113]).  In addition, a 
tolerability study comparing the pain between faster and slower SC administrations of 
gantenerumab has been completed (Study WP39322).
In order to assess suitability of the G4 material for future Phase III studies, an extended 
analytical comparability program was conducted followed by the nonclinical studies.  
Since differences were observed in AUC, a human relative bioavailability study 
(WP40052) comparing G3 and G4 gantenerumab after SC administration has also been 
conducted.
A total of 543 subjects have participated in the Phase I studies; of these participants,
406 healthy volunteers and 101 patients with AD have received gantenerumab.  
Two Phase III studies designed to examine efficacy and safety of gantenerumab in 
patients with prodromal AD (Study WN25203) and mild AD (Study WN28745) have been 
converted to OLE studies.  The OLE studies examining the safety and tolerability of 


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higher doses of gantenerumab in prodromal AD (Study WN25203) and mild AD 
(Study WN28745) are ongoing.
Results of relevant studies are summarized below.  Refer to the Gantenerumab 
Investigator’s Brochure for further information.
In addition, gantenerumab is being investigated in the Dominantly Inherited Alzheimer 
Network Trial, a Phase II/III study sponsored by the Washington University School of 
Medicine, examining the safety, tolerability, biomarker status, and efficacy of 
gantenerumab (as measured by cognition) in patients who are known to have an 
AD-causing mutation and are therefore at risk for developing AD dementia.
1.2.2.1
Study NN19866
In the MAD study (NN19866), a total of 60 patients (34 males and 26 females)
diagnosed with mild to moderate probable AD received multiple IV doses of 
gantenerumab (doses ranging from 6 mg to 20 mg, 60 mg, and 200 mg) or placebo 
every 4 weeks (Q4W) for up to 7 months.  Owing to amyloid-related imaging 
abnormalities (ARIAs), or ARIAs of “vasogenic edema” (ARIA-E) and of “hemosiderosis 
or microbleeds” (ARIA-H), on brain magnetic resonance imaging (MRI) scans that 
occurred in some patients after two to four doses of 200 mg of gantenerumab in 
Cohort 4 (200 mg IV Q4W gantenerumab [equivalent to 330 mg SC Q4W] or placebo),
it was decided to terminate dosing for all patients on 9 June 2008.  The findings resolved 
spontaneously within 14 months after discontinuation of gantenerumab and no patient 
required treatment.
1.2.2.1.1
Study NN19866:  Pharmacodynamic Results in the 
NN19866-PET Substudy
In a PET substudy of Study NN19866 (NN19866-PET), the effects of gantenerumab on 
amyloid load in the brain (defined as standardized uptake value ratio [SUVr] of a cortical 
composite volume of interest over mean cerebellum gray and using 11C-PiB PET) were
evaluated in 18 patients (4 in the placebo group, 8 in the 60-mg IV gantenerumab dose 
group, and 6 in the 200-mg IV gantenerumab dose group) after 6 months.  A mean 
decrease of 14.9% from baseline was observed in the 200-mg gantenerumab dose 
group, while an increase was seen in the placebo group (mean, 20.9%), with relative 
stability compared with baseline in the 60-mg group (mean, 5.3%) (Ostrowitzki et al.
2012).
1.2.2.2
Study WN25203
Based on the results from Study NN19866 and from a relative bioavailability study 
WP27951, the doses of 105 mg SC Q4W (equivalent to 60 mg IV Q4W) and 225 mg SC 
Q4W (equivalent to 130 mg IV Q4W) were selected for Study WN25203.  
Study WN25203 was initially designed as a Phase III, randomized, double-blind,
placebo-controlled, parallel-group, multicenter study to evaluate the safety and efficacy 
of 105 mg and 225 mg of gantenerumab administered subcutaneously Q4W in 


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prodromal AD after 2 years of treatment.  Randomization was based on apolipoprotein 
E, allele 4 (APOE 4) status. Selection of gantenerumab doses was largely driven with 
the objective of reducing risk of MRI findings (in the context of the clinical understanding 
of ARIAs at the time of study design) and by pharmacodynamic (PD) results in the MAD 
study NN19866.  Study WN25203 enrolled 799 patients, and 797 patients were treated 
(the safety-evaluable population).  Following a planned interim futility analysis when 
approximately 50% of patients had completed 2 years of treatment, the study was 
declared futile and dosing with the originally selected doses (105 mg and 225 mg) was 
suspended in December 2014.  The mean duration of double-blind treatment was 
1.73 years.
Safety analyses confirmed ARIAs and injection-site reactions (ISRs) (associated with SC 
administration) as identified risks of gantenerumab (see Section 1.2.3 for more details).  
Approximately 90% of patients experienced at least one adverse event, with the 
incidence comparable between treatment arms.  The incidence of serious adverse 
events was 19.5%, 17.3%, and 16.9% in the placebo, 105-mg gantenerumab, and 
225-mg gantenerumab groups, respectively (Ostrowitzki et al. 2017).
Subsequently, the trial has been converted into an OLE study evaluating doses of up to 
1200 mg (see Section 1.3.1).
1.2.2.3
Study WN28745
Study WN28745 was initially designed as a Phase III, 2-year, double-blind,
placebo-controlled, efficacy, and safety study of gantenerumab in approximately 
1000 patients with mild AD.  Patients randomized to receive gantenerumab were to 
follow a slow titration scheme independent of APOE-4 genotype, starting at 105 mg of 
SC gantenerumab Q4W for the first 24 weeks, with progression to 225 mg, based on 
acceptable results of the control MRI scan.  Enrollment into the double-blind phase of 
the study was stopped in November 2015 because of the futility of Study WN25203.  
When Study WN28745 was stopped, 389 patients had been enrolled and 387 patients 
had been treated.  There were 108 patients who were also enrolled in a PET substudy of 
brain amyloid imaging (Study WN28745-PET).
In the double-blind phase of Study WN28745, gantenerumab was found to be safe and 
well tolerated by patients with mild AD. Adverse events were reported for 80.5% of 
patients in the placebo group and for 82.8% of patients in the gantenerumab groups,
respectively.  The most commonly reported adverse events across all treatment groups 
included fall (8.5%), nasopharyngitis (7.5%), headache (7.0%), dizziness (5.7%), ARIA-E 
(5.4%), and back pain (5.4%). ISRs, ARIA-E, and ARIA-H were reported more 
commonly in patients in the gantenerumab group than in the placebo group
(ISR: 8.3% vs. 1.0%; ARIA-E: 9.4% vs. 1.5%; ARIA-H: 6.3% vs. 4.1%).


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Following the WN25203 futility analysis, the study was converted to an OLE study,
evaluating the safety and tolerability of gantenerumab at higher doses (up to 1200 mg).
1.2.2.4
OLE Studies WN25203 and WN28745 
Additional analyses of Study WN25203 results indicated that higher doses of 
gantenerumab may achieve clinically relevant effects on cognition and function (see 
Section 1.3.1). Thus, both Studies WN25203 and WN28745 were converted to OLE 
studies to provide participants, including those in the placebo group, the opportunity for 
treatment with higher doses of gantenerumab expected to have a clinically meaningful 
effect.  Doses up to 1200 mg SC Q4W of G3 gantenerumab are being tested, using 
dosing regimens designed to minimize the risk of ARIAs and taking into account the 
APOE genotype and the previous double-blind treatment and dose.  
As of 1 May 2019, 383 patients had been enrolled in the OLE studies WN25203 and 
WN28745, with 363 patients exposed to G3 gantenerumab doses higher than 225 mg 
(i.e., more than the highest repeat dose previously tested in AD patients) and 
309 patients having reached the OLE target 1200-mg dose.  ISRs and ARIAs remain the 
identified risks for gantenerumab.  Continuous monitoring of safety data and MRI 
findings by the Sponsor has not identified any new safety signal in these ongoing 
studies. These OLE studies will be ending in 2020, and patients will be provided with an 
option to enroll in an open-label, rollover study to evaluate the safety and tolerability of 
long-term administration of gantenerumab (WN41874).
1.2.2.5
Study WP40052
A total of 114 healthy male and female subjects received a single dose of 600 mg of 
gantenerumab high concentration, liquid formulation (containing gantenerumab 
manufactured by either G3 or G4 process, N57 in each treatment group). The results 
showed that the plasma exposure in terms of area under the concentration–time curve 
from Time 0 to infinity (AUCinf) was approximately 1.18 fold higher after SC 
administration of material manufactured by G4 process compared with material
manufactured by G3 process, whereas Cmax was similar (1.05 fold higher after 
administration of G4 material). Single-dose SC administration of 600 mg of 
gantenerumab as G3 or G4 material was safe and well tolerated.
Refer to the Gantenerumab Investigator's Brochure for details on clinical studies.
1.2.3
Safety Overview 
Nonclinical characterization of gantenerumab did not show any relevant safety findings.  
To date, ARIAs and ISRs are the identified risks for gantenerumab. No differences 
between active and placebo groups have been observed in laboratory parameters,
physical and neurological examinations, vital signs, or electrocardiogram (ECG)
parameters.


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Amyloid-Related Imaging Abnormalities 
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 patients (1.8%) from the 
105-mg gantenerumab arm and 6 patients (2.3%) from the 225-mg gantenerumab arm 
experienced symptoms related to ARIA findings; the most commonly reported symptom 
was headache (5 patients). 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 patients transitioned into OLE.
In the double-blind phase of Study WN28745, the frequency of ARIA-E was 1.5% and 
11.5% in the placebo and gantenerumab groups, respectively.  The frequency of ARIA-H 
was 11.8% and 15.1% in the placebo and gantenerumab groups, respectively. The 
median BGTS of ARIA-E was 3. Most ARIAs were asymptomatic and did not lead to 
clinically significant consequences.  Two patients reported CNS adverse events as 
symptoms of ARIAs: one patient (0.5%) in the placebo group reported irritability that 
was mild in intensity and non-serious, and one patient (0.5%) in the gantenerumab 
group reported headache that was moderate in intensity and non-serious.
The WN25203 and WN28745 OLE studies are ongoing and consequently, data are still 
accruing.  As of 1 May 2019, all 154 patients dosed with gantenerumab in the WN25203 
OLE study had a post-baseline MRI scan. Of 154 patients, 47 (30.5%) had new ARIA-E 
(median maximum BGTS of 7.0), and 14 of 154 patients (9.1%) had new ARIA-H without 
ARIA-E. The majority of ARIA-E findings were asymptomatic, with 11 out of 47 patients 
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. Most symptomatic ARIA-E cases 
resolved with protocol-defined ARIA management rules. In 3 of the 11 patients with 


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ARIA-E MRI findings who reported associated CNS adverse events, the events were 
reported as serious (confusional state, seizure, and epilepsy).
As of 1 May 2019, 219 of 225 patients dosed with gantenerumab in the WN28745 OLE 
study had a post-baseline MRI scan.  Seventy-one of 219 patients (32.4%) had new 
ARIA-E (median maximum BGTS of 9.0), and 24 of 219 patients (11.0%) had ARIA-H 
without ARIA-E. The majority of ARIA-E events were asymptomatic, with 18 of 
71 patients 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 18 patients with symptomatic ARIA-E, the events 
were reported as serious (ischemic stroke, generalized tonic-clonic seizure, epilepsy,
and hemiplegia).
Overall, gantenerumab uptitration is associated with a lower rate of ARIA than the 
predicted rate for fixed dose, and the ARIA-E incidence observed in the OLEs has been 
in the expected range and in alignment with the ARIA-E PK/PD model. ARIAs are 
clinically manageable by protocol-defined MRI monitoring and dose intervention 
algorithms.
Injection-Site Reactions
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 patients (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 patients discontinued study treatment due to ISR.
As of 1 May 2019, ISRs have been reported in 56 of 154 (36.4%) patients dosed with
gantenerumab in the WN25203 OLE study, and 45 of 154 (29.2%) patients have had 
recurrent ISRs.  All ISRs were non-serious and mild, and the majority resolved without 
treatment.  Overall, 3 of 56 (5.4%) patients who had an ISR received treatment, which 
included topical steroids and antihistamines.
As of 1 May 2019, ISRs have been reported in 86 of 225 (38.2%) patients treated with 
gantenerumab in the WN28745 OLE study and 58 of 225 (25.8%) patients have had 
recurrent ISRs. All ISRs were non-serious, with the majority being mild and resolving 
without treatment. Overall, 9 of 86 (10.5%) patients who had an ISR received treatment,


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which included topical steroids and antihistamines. One patient (0.3%) 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.
The Sponsor performs regular reviews of OLE Studies WN25203 and WN28745 data 
and, to date, has not identified any new or unexpected safety findings.  
For safety data from all studies, refer to the Gantenerumab Investigator’s Brochure.  
1.3
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
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 one 
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.
Despite compelling results in AD animal models (Wisniewski and Goñi 2014), clinical 
success with passive immunization targeting brain amyloid in global Phase III trials 
remains an unachieved goal.  It has been suggested that lack of sufficient target 
engagement of anti-amyloid antibodies has been a factor in the failure of these Phase III 
studies (Cummings et al. 2016).  An important advancement for therapies targeting 
aggregated amyloid was provided based on data from the Phase Ib PRIME study of 
aducanumab (Biogen) (Sevigny et al. 2016).
Aducanumab is a fully human IgG1 monoclonal antibody with similar PK and PD 
properties as gantenerumab that binds to aggregated target fibrillary and oligomeric 
forms of Athrough microglia-mediated clearance of amyloid plaques (Sevigny et al.
2016).  The results from the PRIME study showed that monthly IV injections of 
aducanumab for 1 year led to a dose- and time-dependent reduction of amyloid plaques 
in the brain.  In addition, in patients with early (prodromal to mild) AD, a slowing of 
clinical decline, as measured on the Clinical Dementia RatingSum of Boxes 
(CDR-SOB) and MMSE scores, has also been observed providing support to the 
hypothesis that Aplaque reduction confers clinical benefit.
1.3.1
Study Rationale
The results of the preplanned futility analysis of data from approximately 300 patients in 
Study WN25203 revealed the low likelihood for trial success with the original doses 
studied.  Indeed, no significant differences were observed on any cognitive or functional 
measures (i.e., CDR-SOB, MMSE, Alzheimer Disease Assessment ScaleCognition,
Subscale 13 [ADAS-Cog13], and Functional Activities Questionnaire [FAQ]) or in a 
subgroup analysis of baseline characteristics (demographics, cognitive, CSF 
biomarkers, disease severity, or APOE ε4 allele status).  Additional post-hoc analyses 


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indicated that the overall rate of clinical decline was lower than expected for this study 
population (and with higher-than-expected proportion of “slow progressors”) and strongly 
suggested that the doses studied in Study WN25203 (105 and 225 mg) were 
subtherapeutic and that a higher gantenerumab dose may have a clinically relevant 
effect (Ostrowitzki et al. 2017).
Results of the post-hoc analyses of patients who were predicted to be progressors using 
a model derived from the Alzheimer’s Disease Neuroimaging Initiative data 
(Delor et al. 2013) showed a drug concentration-dependent effect on clinical decline 
present for the ADAS-Cog13, MMSE, and Cambridge Neuropsychological Test 
Automated Battery results.  Figure 1 displays the effects on increasing plasma 
gantenerumab concentrations (three concentration groups) on ADAS-Cog13 decline 
over the 2-year study.  Greater concentrations of gantenerumab were associated with 
less clinical decline.
Figure 1
ADAS-Cog13 Treatment Response by Plasma Concentration:  
Two-Year Completing Fast Progressors in Study WN25203
ADAS-Cog13Alzheimer Disease Assessment ScaleCognition, Subscale 13.
Notes:  low exposure1.485 g/mL; medium exposure510 g/mL; 
high exposure1026.68 g/mL.  Linemedian; shaded50% observations.
Furthermore, a PET substudy of Study WN25203 using [18F] florbetapir confirmed a 
reduction in brain amyloid in gantenerumab-treated patients in a larger, less-impaired 
patient sample compared with Study NN19866, which had also demonstrated reduced 


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accumulation of brain amyloid.  Time-dependent reductions in SUVr were observed in 
patients treated with 225 mg of gantenerumab compared with placebo using the 
composite cortical SUVr and reference region of mean cerebellar gray.  Week 100 
results showed the mean percent change from baseline in SUVr was 1.09%, 0.72%,
and 4.82% in the placebo, 105-mg gantenerumab, and 225-mg gantenerumab groups,
respectively (see Figure 2).  A small number of patients (n8) continued to receive 
225 mg of gantenerumab for approximately 3 years (Week 156).  Analysis suggested 
that the effect on SUVr reduction was continuous over time because SUVr reductions 
observed with the 225-mg dose of gantenerumab relative to placebo increased with the 
duration of long-term exposure, suggesting a sustained effect with continued exposure.
Figure 2
Mean Percent Change from Baseline in Composite Amyloid PET 
SUVr by Cerebellum Gray Reference:  Study WN25203, PET 
Substudy
PET positron emission tomography; SUVr standardized uptake value ratio.
In Study WN25203, a concentration-based analysis of the PET results showed a clear 
response relationship between gantenerumab concentration in plasma and SUVr 
reduction, with greater mean concentrations resulting in greater amyloid clearance.  As 
depicted in Figure 3, small changes in SUVr were present in the placebo and 
1.95-g/mL gantenerumab groups, whereas the higher concentration groups 
(510 g/mL gantenerumab and 1020.72 g/mL gantenerumab) displayed SUVr 
reductions of up to 5% and 10%, respectively.  These analyses indicate that higher 
doses may produce greater Aclearance that may translate into greater clinical effect.


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Figure 3
Median Changes over Time in Concentration-Dependent PET 
SUVr by Gantenerumab Serum Concentration and Cerebellum 
Gray Reference:  Study WN25203, PET Substudy
PET positron emission tomography; SUVr standardized uptake value ratio.
Note:  low1.95 g/mL; medium 510 g/mL; high1020.7 g/mL.
In addition, CSF analyses performed in Study WN25203 showed dose-dependent 
reductions in both CSF tau species (total tau [t-tau] and phosphorylated tau [p-tau]) in 
patients receiving gantenerumab compared with placebo.  No change in CSF A42 was 
present over the 2-year period, as expected, given the mechanism of action of 
gantenerumab that targets fibrillar over monomeric A.
Overall, these findings indicate the presence of clinical and biological effects of 
gantenerumab in subjects who had the highest exposure.  In overall study population,
results from the futility analysis of Study WN25203 indicated that the likelihood of the 
225-mg dose of gantenerumab achieving a clinical effect was very low.  These findings 
indicate that higher doses are required to achieve a clinical effect associated with the 
biological activity indicated by the amyloid and tau biomarker findings in 
Study WN25203.  As a result, the decision was made to convert Studies WN25203 and 
WN28745 into OLE studies to give all patients the opportunity to receive higher doses of 
gantenerumab and to assess the safety of higher doses.
Additional support for using higher doses of gantenerumab comes from PK-PD models.  
Based on the established similarities between gantenerumab and aducanumab (see
Section 1.3), 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 data to 
determine the target dose of gantenerumab for the OLE studies (for further details see 


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Appendix 4).  In the OLE studies, the 1200-mg dose of SC gantenerumab Q4W is 
predicted to achieve plasma levels comparable to 10 mg/kg of IV aducanumab Q4W and 
to be associated with a comparable (~20%) amyloid brain reduction, which, in the case 
of aducanumab, was associated with a statistically significant clinical effect after 1 year 
of treatment.  In order to minimize the occurrence of ARIA-E while achieving the target 
dose within a reasonable time frame, several titration schedules have been explored in 
the WN25205 OLE and WN28745 OLE studies.
Gantenerumab PK-PET models of amyloid reduction have been confirmed by PET data 
from the OLE studies (Klein et al. 2019). There were 89 patients from the OLE studies 
included in an amyloid PET substudy using [18F] florbetapir (Amyvid).  Of these 
89 patients, 67 received follow-up scans at Week 52 of the OLE, 42 received scans at 
Week 104 of the OLE, and 30 received scans at Week 156 OLE, before the cutoff date 
of 31 Aug 2019.
Patients were divided into three analysis cohorts because of heterogeneous baseline 
characteristics, time off-dose before OLE dosing, and OLE titration schedules: 
1) MR-DBP (Marguerite RoAD [Study WN28745] double-blind placebo subgroup), which 
included patients in the placebo arm of Marguerite RoAD (Study WN28745); 2) MR-DBA
(Marguerite RoAD double-blind active subgroup), which included patients in the active 
treatment arms of WN28745; and 3) SR (Scarlet RoAD [Study WN25203] subgroup),
which included a combined cohort of all patients from the Scarlet RoAD. SR patients 
were combined into a single cohort because all patients were off-dose for 1619 months 
prior to OLE dosing. Out of 67 patients, 27 were in the MR-DBP, 21 were in the MR-
DBA, and 19 were in the SR analysis cohorts. In the OLE PET substudies, a marked 
and consistent reduction of amyloid load in patients receiving high-dose gantenerumab 
was observed (see Figure 4).  Mean PET centiloid reductions from baseline were 42,
48 , and 21 at Week 52; 71 , 62 , and 36 at Week 104; and 90, 75 , and 57 at 
Week 156 in the MR-DBP, MR-DBA, and SR analysis cohorts, respectively (see 
Figure 4). Amyloid reductions are consistently seen in nearly all patients of the three 
analysed subgroups (see Figure 5 and Figure 6).


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Figure 4
Mean (SE) PET Amyloid Reductions in the OLE PET Substudies
Data presented at Clinical Trials in Alzheimer’s Disease (CTAD) Asia in 2019
MR-DBAMarguerite RoAD (WN28745) pretreated subgroup; MR-DBPMarguerite RoAD 
(WN28745) non-pretreated subgroup; OLEopen-label extension; PET positron emission
tomography; SEstandard error; SRScarlet RoAD (WN25203) subgroup; SUVRstandardized 
uptake value ratio.
a Analysed using a mixed-model for repeated measures.
The data from the OLE PET substudies showed higher reductions of amyloid plaque 
over a shorter time period with the 1200-mg dosing regimen of gantenerumab compared 
with the 105- or 225-mg dosing regimen. Mean amyloid levels were reduced by 
39 centiloids by Week 52 and by 59 centiloids by Week 104, a 3.5-times greater 
reduction than was seen after 2 years at 225 mg.


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Figure 5
SUVR Reductions during the First Year of High-Dose 
Gantenerumab Treatment in the OLE PET Substudies
Data presented at CTAD in 2017.
OLE, open-label extension; SUVR, standardized uptake value ratio; wk, week
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 of 24 
is generally recognized as the amyloid positivity threshold for florbetapir (Klein et al.
2019). Results in this ongoing study confirm the amyloid plaque removal component of 
the gantenerumab mechanism of action and show that following two years of treatment,
51% of subjects achieved below-threshold PET SUVr signals based on quantitative 
measures and that 74% of subjects were below threshold after three years of treatment 
(see Figure 6).


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Figure 6
Patient-Level Amyloid Reductions Over 3 Years of Treatment in 
the OLE PET Substudies
Data presented at CTAD Asia in 2019
SUVR, standardized uptake value ratio
1.3.2
Rationale for Dosing Strategy 
As indicated in Section 1.3.1, the target dose of 1200 mg G3 material administered in 
the WN25203 and WN28745 OLE studies has been identified based on PK-PD modeling 
and simulations (details about the model are presented in Appendix 4) and is predicted 
to lead to an amyloid PET reduction similar to 10 mg/kg IV aducanumab Q4W. The OLE 
PET data have been consistent with these predictions.  
In the OLE studies WN25203 and WN28745, patients were allocated to different titration 
schedules (two schedules in Study WN25203 and four schedules in Study WN28745)
according to their APOE allele status and treatment arm during the double-blind period 
of the parent studies.  These titration schedules were implemented in order to mitigate 
the risk of ARIA events.  An ARIA-E hazard model was first developed on bapineuzemab
data (Hutmacher et al. 2013).  This model, which includes drug concentrations, time 
since first dose, and APOE ε4 allele status, was applied to the double-blind results in 
Study WN25203; the model was then tested on publicly available aducanumab data 
from the PRIME study and were used to predict the incidence of ARIA-E events with a 
high degree of accuracy, including the observed ARIA-E rate differences across 
APOE ε4 allele groups.
Recently, the ARIA-E hazard model has been updated with observations from the 
WN25203 and WN28745 OLE trials using higher doses of gantenerumab (see 
Appendix 5).


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Using the validated PK-PET and ARIA-E hazard model, multiple titration options have 
been simulated, including separate simulations for APOE 4 allele carriers and non-
carriers.  Two different types of titration schedules, reflecting the different risk for ARIA 
events between APOE 4 allele carriers and non-carriers were considered.  Although an 
APOE 4 genotypebased titration regimen could permit APOE 4 non-carriers to 
achieve the target dose more quickly, an option with a single, slower titration schedule 
for all patients is favored as it provides an overall lower risk for ARIA.  Given the chronic 
and gradually progressive nature of AD, the favored option is a single, slow titration 
schedule for all patients because it is simpler for clinicians, less prone to error, and does 
not require APOE genotyping before the initiation of treatment.
Thus, based on the information from the WN25203 and WN28745 OLE studies, in which 
gantenerumab (manufactured with G3 process) up to 1200 mg Q4W was assessed and 
shown to be safe for APOE 4 allele carriers and non-carriers, and based on the 
internally developed PK-PD models, the following dosing regimen for Study WN39658
was selected: 150 mg Q4W for 3 months, then 300 mg Q4W for 3 months, and then 
600 mg Q4W for 3 months, followed by 600 mg Q2W until the end of the study. The 
switch to a Q2W administration schedule allows patients to decrease the number of SC 
administrations in the abdomen per visit.
The PK-PD models referenced above were developed based on information from the G3 
material and were used to establish the initial dosing regimen for this study.  As 
indicated previously, gantenerumab drug substance manufacturing process was 
optimized from G3 to G4, and a relative bioavailability study (WP40052) assessed the 
pharmacokinetic difference between the G3 and G4 material in humans.
The results of this relative bioavailability study (WP40052) show that the AUCinf is 
approximately 1.18 fold and the Cmax is approximately 1.05 fold higher after 
administration of G4 compared with G3. As AUC is considered the driver of the 
treatment effect, the conversion factor of 1.18 from the G3 to G4 material has been 
based on the AUCinf. The association between microglial-driven removal of aggregated 
brain amyloid and AUC has been shown in preclinical experiments and clinical studies.
In addition, as gantenerumab exhibits linear pharmacokinetics, the AUCinf after single 
dose reflects the steady state exposure (AUCtau) after multiple doses.
Based on the above rationale and the fact that gantenerumab manufactured with G4 
process was safe and well tolerated, the G3 dosing regimen has been converted into the 
following G4 dosing regimen for the WN39658 study: 120 mg Q4W for 3 months, then 
255 mg Q4W for 3 months, and then 510 mg Q4W for 3 months, followed by 510 mg 
Q2W until the end of the study. This schedule enables titration to target dose within 
9 months (see Table 1), with 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 


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APOE carriers and non-carriers.  An MRI scan, confirming the absence of ARIA-E 
findings, will be required prior to each dose increase.
Table 1
Proposed Dose and Titration Regimen for Phase III Studies
Month
1
2
3
4
5
6
7
8
9
10
Dosing frequency
Q4W
Q4W
Q4W
Q4W
Q4W
Q4W
Q4W
Q4W
Q4W
Q2W
Dose (mg)
120
120
120
255
255
255
510
510
510
510
1.3.3
Risk-Mitigation Measures for ARIA Findings
ARIA is the most significant adverse event reported in therapies against aggregated 
forms of A.  These findings appear to be dose, time, and APOE 4 allele dependent 
(Piazza and Winblad 2016).
The mechanism underlying the development of ARIA-E and ARIA-H during anti-amyloid 
treatment is unknown.  Because antibodies target removal of 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).
Thus, an anti-Atherapy that effectively maintains vascular -amyloid clearance would 
allow vascular remodeling and may, with time, decrease the risk of such extravasation 
events (Sperling et al. 2012).  This is consistent with experience in previous and ongoing 
studies and with reported data from the long-term extension study of aducanumab 
treatment (Viglietta et al. 2016).
Previous and ongoing studies with gantenerumab showed that ARIAs are manageable 
with MRI monitoring and dose intervention algorithms (i.e., temporary study drug 
interruption or temporary suspension of uptitration) and that these events are mostly 
asymptomatic.  Data from the long-term extension of the PRIME study (aducanumab)
suggested also that a titration up to 10 mg/kg (predicted to be comparable to 1200 mg of 
SC Q4W G3 gantenerumab (or 510 mg of SC Q2W G4 gantenerumab) per the PK-PD 
model (see Appendix 4) may reduce the incidence of ARIA-E compared with higher fixed 
dosing (Viglietta et al. 2016).
In Study WN39658, imaging-related criteria are used to exclude patients with clinically 
important cerebral vascular disease at baseline, as well as ARIA-related lesions.  A slow 
titration schedule will be implemented to reach the target dose, and MRI monitoring will 
be conducted during the study at regular intervals (see Appendix 1 for the schedule of 
activities for the uptitration and MRI schedules).  An MRI scan documenting the absence 
of ARIA-E findings will be required prior to each dose increase.  If ARIA findings occur,
more intense MRI monitoring, dose adjustments, temporary dose holding, or permanent 


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discontinuation will be implemented according to an ARIA-related dose-adjustment plan,
described in Section 5.1.2.  Safety findings (including unblinded individual patient and 
aggregate data) will be reviewed on a regular basis by the iDMC.  
1.3.4
Risk to Participants without Alzheimer’s Disease Pathology
Owing to the rigorous screening procedures in this study, including measurement of the 
CSF tau to A42 ratio and/or amyloid PET scan, it is anticipated that only participants 
with AD pathology will be enrolled.  In the event that a participant without amyloid 
pathology is enrolled, no additional risk is expected.  However, such participants may 
still experience side effects related to administration of gantenerumab (e.g., ISRs and 
development of anti-drug antibodies [ADAs]).
1.3.5
Overall BenefitRisk Summary
Overall, the benefitrisk assessment of gantenerumab is based on the following:

Gantenerumab has shown evidence of reducing amyloid plaques (i.e., observed 
evidence of brain amyloid reduction) and, thus, shows potential benefit in slowing
the progression of AD.

Findings from the WN25203 and aducanumab PRIME studies provide additional 
support for the hypothesis that anti-amyloid treatment may be associated with a 
beneficial clinical 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 5.1.2.

No new safety signal has been identified in the data from the ongoing OLE studies 
with doses of up to 1200 mg Q4W G3 material.  These data support the 
administration of the target dose of 510 mg Q2W G4 material to both ApoE 4 
carriers and non-carriers in the WN39658 study.

The benefit risk ratio of conducting the WN39658 study during the pandemic 
remains unchanged. This is supported by the preclinical and clinical data collected 
through the development program of gantenerumab where there has been no 
indication that gantenerumab administration compromised the immune system or 
made individuals more susceptible to infections. 
Thus, there are no data or biological rationale suggesting that Gantenerumab 
administration could increase the risk of infection by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) or more severe coronavirus disease 2019 
(COVID-19) outcomes. 
Participating in study visits at the investigational sites may however increase the 
risk of exposure to SARS-COV-2, therefore, whenever appropriate, the Sponsor 
allows the possibility to perform home visits by adequately trained health care 
professionals. All necessary precautions will be taken to protect the health of the 
study participants and minimize the risk of exposure. As such the PI, in addition to 


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all appropriate study staff that come into contact with the study participants, will 
wear personal protective equipment during the visit as per local requirements.
Thus, the anticipated benefitrisk profile of gantenerumab supports clinical trials with 
higher doses in the population with early (prodromal to mild) AD.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy and safety of gantenerumab compared with placebo
in participants with early (prodromal to mild) AD.  Specific objectives and corresponding 
endpoints for the study are outlined in Table 2 for the double-blind treatment period and 
in Table 3 for the OLE period.


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Table 2
Objectives and Corresponding Endpoints for the Double-Blind 
Treatment Period
Primary Efficacy Objective
Corresponding Endpoint
To evaluate the efficacy of 
gantenerumab administered by SC 
injection compared with placebo 
The change from baseline (Day 1) to Week 116 a in global 
outcome, as measured by the CDR-SOB
Secondary Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
gantenerumab versus placebo on 
cognition and function
The change from baseline to Week 116 a in cognition 
and/or function as measured by:
MMSE total score
ADAS-Cog11 and ADAS-Cog13 
Verbal Fluency Task 
Coding
FAQ
ADCS-ADL total score and instrumental score
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the efficacy of 
gantenerumab versus placebo
The change from baseline to Week 116 a, in the following:
Clinically evident decline as measured using the CDR
Severity, as assessed by the CDR Global Score
Dependence level, as derived from the ADCS-ADL 
score
Health-related quality of life, as assessed by the 
QoL-AD scale
Behavioral and neuropsychiatric symptoms of AD, as 
measured by the NPI-Q 
Study partner burden, as assessed by the ZCI-AD scale
Elements of resource utilization, as assessed by the 
RUD-Lite
Health outcomes in participant and study partner, as 
measured by EQ-5D questionnaire
Aamyloid-; 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; CSFcerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating 
Scale; DTIdiffusion tensor imaging; EQ-5DEuroQol-Five Dimensions; FAQ Functional 
Activities Questionnaire; MMSEMini-Mental State Examination; MRImagnetic resonance 
imaging; NPI-QNeuropsychiatric InventoryQuestionnaire; PET positron emission tomography; 
PKpharmacokinetic; QoL-ADQuality of LifeAlzheimer's Disease; RUD-LiteResource 
Utilization in DementiaLite; SCsubcutaneous; ZCI-ADZarit Caregiver InterviewAlzheimer's 
Disease.
a If the double-blind treatment period is extended by a total of 24 weeks, the endpoints will be 
based on change from baseline to Week 128.


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Table 2
Objectives and Corresponding Endpoints for the Double-Blind 
Treatment Period (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of 
gantenerumab 
compared with placebo
Nature, frequency, severity, and timing of adverse events and 
serious adverse events
Physical examinations (including neurological systems), vital 
signs, blood tests, ECGs, and C-SSRS
Nature, frequency, severity, and timing of MRI findings:  
ARIA-E and ARIA-H
Nature, frequency, severity, and timing of injection-site 
reactions
Presence of ADAs during the study relative to the presence of 
ADAs at baseline (in active treatment group only)
Pharmacodynamic 
Biomarker Objective
Corresponding Endpoints
To evaluate the effect of 
gantenerumab 
compared with placebo 
in participants with early 
(prodromal to mild)
Alzheimer’s disease
Change from baseline to Week 116 in brain amyloid load, as 
measured by amyloid PET scan in a subset of participants
Change from baseline to Week 116 in brain tau load, as 
measured by tau PET scan in a subset of participants
Change from baseline to Week 116 in cerebral spinal fluid 
markers of disease in a subset of participants, including, but not 
limited to, total tau, and phosphorylated tau
Exploratory Biomarker 
Objective
Corresponding Endpoints
To evaluate the effect of 
gantenerumab 
compared with placebo 
in participants with early 
(prodromal to mild)
Alzheimer’s disease
Change over time in plasma and other CSF biomarkers (see 
Section 4.5.6.2)
Change from baseline to Week 116 a in functional brain 
connectivity, as measured by resting-state functional MRI 
(where available)
Change from baseline to Week 116 a 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
Exploratory 
Pharmacokinetic 
Objective
Corresponding Endpoint
To characterize the PK 
profile of gantenerumab
Plasma concentration of gantenerumab (administered 
subcutaneously) at specified timepoints
Aamyloid-; 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; CSFcerebral spinal fluid; 
C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor imaging; 
EQ-5DEuroQol-Five Dimensions; FAQ Functional Activities Questionnaire; 
MMSEMini-Mental State Examination; MRImagnetic resonance imaging; 
NPI-QNeuropsychiatric InventoryQuestionnaire; PETpositron emission tomography; 
PKpharmacokinetic; QoL-ADQuality of LifeAlzheimer's Disease; RUD-LiteResource 
Utilization in DementiaLite; SCsubcutaneous; ZCI-ADZarit Caregiver 
InterviewAlzheimer's Disease.
a If the double-blind treatment period is extended by 24 weeks, the final endpoints will be based 
on change from baseline to Week 128.


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Table 3
Objectives and Corresponding Endpoints for the Open-Label 
Extension Period
Safety Objective
Corresponding Endpoints
To evaluate the long-term safety and 
tolerability of SC gantenerumab in 
participants with early AD
Nature, frequency, severity, and timing of adverse 
events and serious adverse events
Physical examinations (including neurological 
systems), vital signs, blood tests, ECGs, and C-SSRS
Nature, frequency, severity, and timing of MRI 
findings:  ARIA-E and ARIA-H
Nature, frequency, severity, and timing of injection-site 
reactions
Presence of ADAs during the study relative to the 
presence of ADAs at baseline
Exploratory Efficacy Objective
Corresponding Endpoints
To assess the long-term efficacy of 
SC gantenerumab in participants with
early AD
The change in cognition, function and other outcomes 
over time, as measured by:
CDR
MMSE
ADAS-Cog11 and ADAS-Cog13 
Verbal Fluency Task 
Coding
FAQ
ADCS-ADL 
Health-related quality of life, as assessed by the 
QoL-AD scale
Behavioral and neuropsychiatric symptoms of AD, as 
measured by the NPI-Q 
Study partner burden, as assessed by the ZCI-AD scale
Elements of resource utilization, as assessed by the 
RUD-Lite
Health outcomes in participant and study partner, as 
measured by EQ-5D questionnaire
Aamyloid-; 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; CSFcerebral spinal fluid; C-SSRSColumbiaSuicide 
Severity Rating Scale; DTIdiffusion tensor imaging; EQ-5DEuroQol-Five Dimensions; 
FAQFunctional Activities Questionnaire; MMSEMini-Mental State Examination; 
MRImagnetic resonance imaging; NPI-QNeuropsychiatric InventoryQuestionnaire;
PET positron emission tomography; PKpharmacokinetic; QoL-ADQuality of LifeAlzheimer's 
Disease; RUD-LiteResource Utilization in DementiaLite; SCsubcutaneous; ZCI-ADZarit 
Caregiver InterviewAlzheimer's Disease.


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Table 3
Objectives and Corresponding Endpoints for the Open-Label 
Extension Period (cont.)
Exploratory Pharmacodynamic 
Biomarker Objective
Corresponding Endpoints
To evaluate the long-term effect of 
SC gantenerumab in participants 
with early AD
Brain amyloid load over time, as measured by amyloid 
PET scan in a subset of participants
Brain tau load over time, as measured by tau PET 
scan in a subset of participants
Cerebral spinal fluid markers of disease over time in a 
subset of participants, including, but not limited to,
A1−42, total tau, and phosphorylated tau
MRI-derived measurements over time, such as 
volumetric changes in whole brain, ventricles,
hippocampus, or other structures, functional brain 
connectivity, integrity of white matter in all participants
Plasma markers over time in all participants
Aamyloid-; 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; CSFcerebral spinal fluid; C-SSRSColumbiaSuicide 
Severity Rating Scale; DTIdiffusion tensor imaging; EQ-5DEuroQol-Five Dimensions; 
FAQFunctional Activities Questionnaire; MMSEMini-Mental State Examination; 
MRImagnetic resonance imaging; NPI-QNeuropsychiatric InventoryQuestionnaire;
PET positron emission tomography; PKpharmacokinetic; QoL-ADQuality of LifeAlzheimer's 
Disease; RUD-LiteResource Utilization in DementiaLite; SCsubcutaneous; ZCI-ADZarit 
Caregiver InterviewAlzheimer's Disease.
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled,
parallel-group study designed to evaluate the efficacy and safety of gantenerumab in 
participants with early (prodromal to mild) AD.
The planned number of participants for the global enrollment phase for the study is 
approximately 1016 participants randomized in a 1:1 ratio to receive gantenerumab and 
placebo (508 participants randomized to gantenerumab and 508 randomized to placebo)
(see Section 6.1).  To maintain a balanced number of participants enrolled in each 
treatment arm and to ensure that the arms are comparable, randomization will be 
stratified by stage of disease (prodromal AD vs. mild AD), APOE allele status (presence 
vs. absence of the ε4 allele), use of AD medication (presence vs. absent), geographic 
region (Western Europe and Australia vs. Rest of the World vs. North America) and 
participation in longitudinal amyloid and tau PET substudies.  Approximately 175 centers 
in approximately 15 countries worldwide will participate in this study.


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Participants will be selected on the basis of clinical diagnosis of probable AD (according 
to the National Institute on Aging/Alzheimer’s Association [NIA/AA] diagnostic criteria 
and guidelines for AD; see Appendix 2) (McKhann et al. 2011) or prodromal AD 
(according to the NIA/AA diagnostic criteria and guidelines for MCI due to AD; see 
Appendix 3) (Albert et al. 2011). The aim of the study is to recruit approximately 50% of 
the participants with prodromal AD.
Eligible participants will be 5090 years old, inclusive, must show evidence of -amyloid 
pathology as indicated by the CSF tau to A42 ratio (CSF-enrolled participants) or 
positive amyloid PET scan by visual read (PET-enrolled participants), and meet eligibility 
criteria as detailed in Section 4.1.  
The study will consist of a screening period of up to 12 weeks in length following the 
signing of informed consent.  Sites also have the option to prescreen participants on the 
FCSRT and MMSE.  Participants must sign a separate Informed Consent Form before 
administration of these tests if used for prescreening.  If the results confirm a 
participant’s eligibility, then the FCSRT and MMSE will not have to be completed again 
during the screening period as long as the test has been done within 12 weeks prior the 
baseline.
Eligible participants will then undergo baseline visit assessments (Day 1) prior to 
receiving the first dose of blinded study drug (gantenerumab or placebo).  Participants 
will continue in the double-blind treatment period. 
Due to the global impact of the COVID-19 pandemic and the resulting disruption in study 
drug administration, the duration of the double-blind treatment period will be extended by 
12 weeks, with the possibility of an additional 12-week extension (for a total of 24 
weeks). This may result in the following scenarios:

Scenario 1: Participants who are enrolled and active in the double-blind treatment 
period after implementation of Protocol Version 4 will have the double-blind 
treatment period extended by 12 weeks, with the final efficacy and safety visit at
Week 116 (Appendix 1).

Scenario 2: If the COVID-19 pandemic results in greater than anticipated 
disruptions to study drug administration, then the Sponsor has the option to extend  
the double-blind treatment period by an additional 12 weeks, with the final efficacy 
and safety visit at Week 128 (Appendix 1). This extension will be mandatory for all 
patients who are active in the double-blind treatment period at the time that the
extension decision is implemented.
Participants who have already had the last study drug administration at Week 102 and
their final efficacy and safety visit at Week 104 and who have completed the 
double-blind treatment period prior to implementation of the study extension by 
12 weeks, will continue into the OLE of either the WN39658 study or the WN42171 study.  
Alternatively, they will continue into the safety follow-up period.


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For participants who enroll or who are active in the double-blind treatment period at the 
time of implementation of the study extension by 12 weeks, visits and study drug 
administration will occur Q4W until participants reach the target dose, which will be 510
mg Q2W.  After the last dose of study drug (Week 114 for scenario 1 and Week 126 for 
scenario 2, if applicable), final efficacy and safety assessments will be performed 
2 weeks later (at Week 116 for scenario 1 and at Week 128 for scenario 2, if applicable).  
Participants may then enroll in an OLE study if they are eligible (either in the OLE part of 
this study or in the WN42171 study) or have safety follow-up visits 14 and 50 weeks 
after the last dose for safety and limited efficacy assessments.
All participants who prematurely discontinue treatment will continue participating in the 
study and will be asked to return for collection of safety and limited efficacy data (see
Section 4.7.1).
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, ECG), as well as the 
ColumbiaSuicide Severity Rating Scale (C-SSRS) to monitor for suicidality, tests for 
cognition, function, and QoL status.  Blood samples for the assessment of PK samples,
PD biomarkers, and ADA will be obtained from all participants.
The incidence and nature of adverse events, serious adverse events, ARIA-E, ARIA-H,
ISRs, adverse events of special interest, ECGs, and laboratory abnormalities will be 
assessed on a regular basis by an unblinded iDMC.
An overview of the study design is provided in Figure 7.  The schedule of activities is 
provided in Appendix 1.
Once the double-blind treatment period is completed, participants who consent and are 
eligible may opt to participate in an OLE. If the stand-alone open-label study 
(Study WN42171) is not open for enrollment at the time that a participant completes the 
double-blind treatment period of this study, then the participant will follow the OLE 
procedures described in this study (Section 4.3.2.2 and Appendix 1). These participants 
will then transition to Study WN42171 after they have completed the entire schedule of 
activities in the OLE of this study and the protocol for Study WN42171 is available and 
approved as per local requirements.  If Study WN42171 is open for enrollment at the 
time that a participant completes the double-blind treatment period of this study, then the 
participant will enroll directly in Study WN42171 and not in the OLE portion of this 
protocol. The OLE of Study WN39658 is not applicable in countries that cannot run 
Study WN42171.


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Figure 7
Overall Study Design
  
Wweek


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The study consists of three distinct periods:

Screening (including an optional pre-screening):  The screening period may last up 
to 12 weeks for each eligible participant.

Double-blind treatment period:  After screening, participants who meet all eligibility 
criteria will be randomly assigned to one of two arms (gantenerumab or placebo) in 
a 1:1 ratio.  Following baseline assessments, each participant will receive a 
minimum of nine SC Q4W administrations of study drug (uptitration period), followed 
by up to 40 administrations of study drug in the double-blind treatment period in 
scenario 1 or up to 46 administrations in scenario 2, if applicable.  The last dose of 
study drug will be administered at Week 114 in scenario 1 and at Week 126 in 
scenario 2, if applicable.  At the end of the double-blind treatment period, 2 weeks 
after the last dose, all participants will undergo the final safety and efficacy study
visit. Participants who have already completed the double-blind treatment period 
prior to implementation of the study extension by 12 weeks will have received 34 SC 
Q2W administrations of study drug during the double-blind treatment period. The 
last dose will be administered at Week 102, and their final efficacy and safety visit 
will be at Week 104.

Postdouble-blind treatment period:  After the final efficacy and safety study visit, all 
participants will be asked to come back for the long-term follow-up visits or to 
continue in the OLE.
Long-term follow-up:  Long-term follow-up will consist of a 50-week follow-up 
period with evaluations at Weeks 14 and 50 after completion of study drug 
administration. Participants who withdraw early during the double-blind treatment 
period or during the OLE period are also asked to complete the long-term 
follow-up visits.
OLE:  All eligible participants will have the opportunity to enter an OLE study.
–
Eligible participants who enrolled early in the WN39658 study may start the 
OLE as detailed in Appendix 1, Table 5, and Table 6, and will then transition 
to the open-label study WN42171 (details will be provided in protocol 
WN42171).  Participants who terminated the WN39658 OLE early will be 
asked to come back for long-term follow-up visits.
–
If the WN42171 protocol is available and approved by local authorities, the 
eligible participants will directly be enrolled in the open-label study 
WN42171.
For the schedule of activities at each visit, see Appendix 1.
China Enrollment Plan
Based on historical data, participant recruitment is expected to take longer in China; 
therefore, a specific China enrollment plan has been established.  Thus, if at least 
1 participant is enrolled at sites in mainland China, Hong Kong, and Taiwan that are 
recognized by the NMPA during the global enrollment phase, additional participants may 
be enrolled in a China extension to ensure a total enrollment that is sufficient to support 


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registration in China.  All participants enrolled at NMPA-recognized sites in the global 
enrollment phase will be included in the primary analysis. All participants enrolled at 
NMPA-recognized sites in the global enrollment phase and the China extension phases 
will be included in a China-specific analysis. Details will be provided in the SAP.
3.1.2
Substudies
The substudies associated with Study WN39658 will be described in separate protocols,
and participants consenting to enroll in these substudies will be asked to sign the 
associated Informed Consent Forms.
To date, there are two substudies associated with Study WN39658:  a longitudinal 
Amyloid PET substudy and a longitudinal Tau PET substudy.  The amyloid- and tau-PET 
assessments will allow a longitudinal evaluation of the effect of gantenerumab on brain 
amyloid deposition as measured by florbetaben or flutemetamol PET radioligands and 
tau burden as measured by [18F] GTP1 (an investigational radioligand for in vivo imaging 
of tau protein aggregates) in participants with early AD. Details of any interim analyses 
relating to the substudies will also be described in the substudy protocols.
The PET data that are collected are expected to help in understanding the effects of 
gantenerumab on amyloid and tau pathology over time as well as the relationship 
between change in florbetaben/flutemetamol/[18F] GTP1-PET and changes in other 
endpoints in the study WN39658.
3.1.3
Data Monitoring Committee
The iDMC will evaluate participant safety and efficacy on a regular basis.  In addition to 
the data defined in the iDMC Charter (e.g., the incidence and nature of adverse events,
serious adverse events, adverse events of special interest, ARIA-E, ARIA-H, and ISRs),
the iDMC will review all necessary cumulative data at regular intervals during the study,
including efficacy when needed.  It is anticipated that these assessments will occur 
approximately every 3 months.  At the time of each review, the iDMC will make 
appropriate recommendations (e.g., the study should continue as planned, enrollment in 
a specific arm should be discontinued, the treatment regimen should be modified, the 
protocol should be amended, enrollment should be held pending further safety 
evaluations).  The iDMC will also evaluate planned or unplanned interim analyses for 
efficacy or futility (see Section 6.7.1).
Decisions will be made in consideration of the totality of the available data.  Ad-hoc 
meetings may be called in addition to scheduled meetings, as necessary, to provide 
recommendations on management of any new safety issues.  Specific operational 
details such as the committee's composition, frequency and timing of meetings, and 
members' roles and responsibilities are detailed in the iDMC Charter.
Final decisions will rest with the Sponsor.


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3.2
END OF STUDY AND LENGTH OF STUDY
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for safety analyses or safety follow-up is 
received for the last participant, whichever occurs later.  
The study will consist of a screening period of up to 12 weeks (including the optional 
prescreening period) for each eligible participant who signs the Informed Consent Form 
and agrees to participate, followed by a double-blind treatment period of study drug 
treatment plus a visit 2 weeks after the last dose. The duration of the double-blind 
treatment period is extended by 12 weeks (116 weeks in total in scenario 1). In case
scenario 2 is implemented, the double-blind treatment period will be extended by 
24 weeks (128 weeks in total in scenario 2, if applicable). For participants not entering 
the OLE period, this will be followed by the postdouble-blind treatment period of 
two follow-up visits at 14 and 50 weeks after the last dose. Thus, for a participant not 
entering the OLE period, the maximum length of study is approximately 176 weeks in 
scenario 1 or 188 weeks in scenario 2 (if applicable).
For participants entering the OLE period, the extension will consist of an open-label 
period of at least 35 weeks. If a participant is ready to be uptitrated to the target dose 
and if the safety MRI allows, the participant will then be transitioned to the WN42171
open-label study.  If there is an ongoing ARIA-E, the participant will remain in Study
WN39658 until the ARIA-E resolves and the participant is ready to be uptitrated to the 
target dose. In case the dosing is temporarily interrupted for any other reason, the 
participant will be kept in the WN39658 study until they are ready to be uptitrated to the 
target dose. Participants who are not willing to transition to the WN42171 open-label 
study after OLE Week 35 will be asked to come back for two follow-up visits at 14 and 
50 weeks after the last dose (OLE Follow Up 1 and Follow Up 2, respectively).
3.3
RATIONALE FOR STUDY DESIGN
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled,
parallel-group study of the efficacy and safety of gantenerumab in participants with early 
(prodromal to mild) AD, increased amyloid burden (defined according to CSF or PET 
criteria), and clinical symptoms.
3.3.1
Rationale for Participant Population
As the accumulation of Abrain amyloid begins before the onset of AD dementia, it is 
reasonable to postulate that the benefit of anti-amyloid therapy may be greater if initiated 
at an early stage of the disease.  For this reason, Roche has focused clinical 
development of gantenerumab on early (prodromal to mild) AD.
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 2) or 
prodromal AD (according to the NIA/AA research criteria and guidelines for MCI due to 


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AD; see Appendix 3).  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 an MMSE between 22 and 30 (inclusive) points and a CDR global score (CDR-GS)
of 0.5 or 1.0.  The MMSE score provides evidence of no more than mild disease severity 
and the CDR-GS score indicates that the participants have prodromal AD or cognitive 
and functional deficits consistent with mild AD. The aim of the study is to recruit 
approximately 50% of the participants with prodromal 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 (EMA’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’s) 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% 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 -amyloid deposition will be 
assessed either by a centralized visual assessment of PET amyloid imaging, using 
one of the three following amyloid PET imaging tracers (VizamylTM, NeuraceqTM, and 
AmyvidTM according to country and site availability) or by the CSF tau to A42 ratio (using 
a prespecified cutoff and the Roche Diagnostics Elecsys immunoassay).
Both methods (CSF and PET) are established approaches to identify Aaccumulation in 
the brain in vivo (Pannee et al. 2016; Vos et al. 2016) and both have been used in 
research and in clinical practice.  There is also emerging evidence that indicates 
consistency between PET amyloid imaging and CSF biomarkers.  Indeed, in biomarker 
research studies, concordance between amyloid PET and the combination of CSF A1−42
with t-tau has been shown to be very high with properly controlled CSF methodologies 
(EMA 2012).
To enrich for participants who are more likely to decline over the 2-year trial, all 
participants have to demonstrate amnestic deficits as measured by the FCSRT’s total 


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free recall score and cueing index (Sarazin et al. 2007).  The use of the FCSRT to 
support a hippocampal-related memory deficit (Buschke 1984; Grober and Buschke 
1987) has been recommended by the International Working Group (IWG-1; Dubois et al.
2007, 2010).  Indeed, the core clinical symptom of AD is significant and progressive 
episodic memory impairment.  Memory impairments because of AD are known to be 
hippocampal dependent and are thought to be characterized by a deficit in recall, which 
is often not recovered with cueing.
The FCSRT is a cued recall test that uses controlled encoding to ensure that impaired 
recall and cueing results are due to memory impairment and are not a failure at 
encoding (e.g., by means of attentional impairment).  The FCSRT has demonstrated 
high sensitivity and specificity in differentiating participants with AD from both healthy 
controls and participants with other forms of dementia (Grober et al. 2008, 2010).  More 
recently, the choice of the FCSRT as a valid clinical marker for typical prodromal AD 
(amnestic MCI) has been endorsed by the IWG-2 (Dubois et al. 2014) and is supported 
by studies showing that this test is a good tool to use for predicting progression to AD for 
participants with prodromal AD (Mura et al. 2014; Lemos et al. 2015).  In addition, data 
generated from Roche datasets showed that a cueing index of 0.67 is a good predictor 
of cognitive decline.  Therefore, the FCSRT cueing index of 0.67 and a free recall 
score of 27 have been selected as inclusion criteria for this study.  The cueing index 
measures the ability of a participant to benefit from being reminded using specific cue 
words to recall the target word.  To prevent participants who have a high free recall and 
who do not appear to benefit from being reminded from being included simply because 
of apparent low cueing index, a free recall score of 27 will also be required.  
The FCSRT index is consistent with that published by Sarazin et al. (2007) and 
Auriacombe et al. (2010).
3.3.2
Rationale for Use of a Placebo Control Group 
Study WN39658 is a placebo-controlled trial in which participants will be eligible for 
study participation whether or not participants are receiving standard-of-care 
medications for AD (i.e., acetylcholinesterase inhibitors, memantine, and/or medical food 
supplements).  Given that there are currently no approved disease-modifying 
compounds that could serve as an active control, participants will be randomized to 
receive gantenerumab or placebo on top of background therapies.
3.3.3
Rationale for Gantenerumab Dosage and Titration Schedule
In the OLE studies (WN28745 and WN25203), different titration schedules (based on 
prior double-blind treatment exposure and APOE 4 status) have been utilized to enable 
all participants to reach a target dose of 1200 mg SC Q4W while managing the risk for 
ARIA with MRI monitoring and dose intervention algorithms.  In addition, data from the 
OLE studies support treatment at a low starting dose with a gradual increase in dosing 
(i.e., slow titration schedule) to reach target dose and to reduce the risk of ARIA findings.  


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As presented in Section 1.3.2, a target dose of 510 mg Q2W along with a titration 
schedule with a low starting dose and gradual increase in dosing (i.e., slow titration 
schedule) that is expected to reduce the risk of ARIA-E for both APOE carriers and non-
carriers have been identified for the current study.
Therefore, all participants in Study WN39658 (regardless of APOE 4 status) will receive 
120 mg of SC gantenerumab Q4W for 3 months, 255 mg SC Q4W for 3 months, and 
510 mg SC Q4W for 3 months prior to reaching target dose of 510 mg Q2W after 
9 months of titration (see Section 1.3.2 for additional details about the conversion of G3 
dosing regimen to G4 dosing regimen).  Based on the model predictions (see 
Appendix 5), the overall ARIA-E rate is expected to be approximately 26%.  An MRI 
scan, confirming the absence of ARIA-E findings, will be required prior to each dose 
increase.
3.3.4
Rationale for Treatment Duration
3.3.4.1
Rationale for Double-Blind Treatment Duration 
According to the EMA’s guidance on medicinal products for the treatment of AD and 
other dementias (EMA 2018) controlled clinical trials aimed at demonstrating short-term 
improvement in mild to moderate AD should last at least 6 months.  In order to establish 
an effect on disease progression, a distinction between symptomatic and 
disease-modifying effects of a medicinal product has to be made.  In addition to 
demonstrating a relationship between clinical outcomes and an effect on biomarkers of 
disease pathology, clinical improvement must be shown over a time period that is 
relevant to the proposed mechanism of action and the expected natural progression rate 
of the disease.  In AD research, long-term placebo-controlled trials are needed in order 
to allow time for an efficacious therapy to reverse a longstanding disease process as 
well as to allow time for a sufficient number of placebo-treated participants to progress.  
Eighteen months was assumed to be of sufficient length in some recently completed 
Phase III studies of anti-Aantibodies (EMA 2018).  In prodromal disease stages, even 
longer studies may be necessary. In addition, placebo decline is expected to be greater 
in longer studies; this greater decline allows an increased potential to demonstrate a 
treatment effect.
A 2-year treatment duration was selected as the most appropriate duration for 
assessment of the primary endpoint.  The duration was based on the mechanism of 
action of gantenerumab, which is expected to delay and reduce AD progression over 
time compared with control.  As 9-month titration period to reach the target dose is 
needed, a 2-year treatment period may also be appropriate for the assessment of the 
primary endpoint. To capture an earlier signal of efficacy, should it be present,
assessments relevant to the study objectives will also be obtained at 6, 12, and 
18 months.
Measures taken globally during the COVID-19 pandemic are expected to affect the 
protocol-specified administration of study drug. At the date of writing Protocol Version 4, 


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it is expected that participants will miss an average of 8 weeks of study drug 
administration over the course of the original 2-year study. This has the potential to 
decrease the power of the study (see Section 6.1 for details).  To mitigate the impact of 
missed administrations, the double-blind treatment period is being extended by 
12 weeks. The continuing impact of the COVID-19 pandemic on study procedures will 
be closely monitored. If the COVID-19 pandemic results in greater than anticipated 
disruptions to study drug administration, the Sponsor may further extend the 
double-blind treatment period by an additional 12 weeks (24 weeks in total). 
3.3.4.2
Rationale for OLE Treatment Duration 
An open-label treatment duration of at least 9 months has been selected to offer the first 
participants randomized in Study WN39658 open-label gantenerumab until the protocol 
WN42171 open-label study is available and approved. A duration of 9 months
corresponds to the uptitration period; thus, when these first participants reach the target 
dose, they will be able to start the WN42171 open-label study at the target dose
(i.e. 510 mg Q2W).
3.3.5
Rationale for Long-Term Follow-Up
The primary objective of the long-term follow-up is to estimate the long-term safety of 
gantenerumab over an extended period of time.  Study assessments performed 14 and 
50 weeks after the last dose of study drug will be used to evaluate the effects of 
treatment on both efficacy and safety parameters over an extended period after study 
drug discontinuation.  Assessments will be conducted for all participants who discontinue 
treatment during the double-blind treatment period, during the OLE period, or who 
complete the double-blind period but do not enter the OLE period or who complete the 
OLE period but do not enter in the WN42171 open-label study.  Assessments will also 
allow for the exploration of the long-term effects with declining drug exposure.
3.3.5.1
Rationale for Duration of Study Follow-Up (14 Weeks)
The primary purpose of the 14-week follow-up visit (i.e., 14 weeks after the last dose) is 
to evaluate the long-term safety of gantenerumab.  The apparent terminal half-life of 
gantenerumab is in the order of 24 days, and gantenerumab is cleared from plasma after 
approximately 16 weeks (approximately 5 half-lives).  Therefore, safety assessments 
performed 14 weeks after the last dose are considered sufficient to evaluate residual 
effects on peripheral safety outcomes.  In addition, efficacy assessments at the follow-up 
visit may support an enduring effect of gantenerumab after treatment is stopped.
3.3.5.2
Rationale for Long-Term Follow-Up (50 Weeks)
Assessments performed 50 weeks after the last dose will be used to evaluate the 
long-term effects of study drug on both efficacy and safety parameters.  The 
assessments will allow for the exploration of the long-term effects of study drug given the 
expected level of decline over this period.  Participants will not be restricted from starting 
new treatment and therefore, the analysis will be considered exploratory.


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3.3.6
Rationale for Primary Outcome Measure:  Clinical Dementia 
RatingSum of Boxes
AD is considered a continuous disease that passes through consecutive stages without 
discrete transition points.  Thus, the use of a single endpoint across both subpopulations 
of early (prodromal to mild) AD is consistent with the current understanding of AD.
Showing the benefit of new therapies for participants in the early stages of AD is 
challenging, owing to the lack of sensitive assessment tools.  Use of the CDR-SOB as 
the primary outcome measure for studies of early (prodromal to mild) AD enables 
simultaneous demonstration of benefit on primary symptoms and clinical relevance 
(Aisen 2009, 2011), while also ensuring use of a clinical outcome assessment with 
adequate measurement properties (FDA 2013).
The Washington University CDR is a global assessment instrument that yields global 
scores (GS) and SOB scores.  The CDR is derived from a semi-structured interview with 
the participant and an appropriate informant, and it rates impairment in six categories 
(memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care) on a 5-point scale for which 0no impairment,
0.5questionable impairment, and 1, 2, and 3mild, moderate, and severe impairment,
respectively.  From the six individual category ratings, or box scores, the CDR-GS is 
established by clinical scoring rules, for which CDR 0no dementia and CDR 0.5, 1, 2,
or 3questionable, mild, moderate, or severe dementia, respectively (Morris 1993).  The 
CDR-SOB score is a detailed quantitative general index that provides more information 
than the CDR-GS in participants with early (prodromal to mild) dementia (Coley et al.
2011; Cedarbaum et al. 2013).  In particular, the CDR-SOB has been proposed for use 
in longitudinal assessment of dementia and is widely used in AD studies as a global 
measure of disease progression (Williams et al. 2013).  The FDA’s draft guidance for 
developing drugs for the early stages of disease suggests that a composite scale,
validated in participants with early-stage disease that includes both cognition and 
function as a single primary efficacy outcome measure, is appropriate.  The CDR-SOB is 
an example of a measure that fulfills these criteria (FDA 2013) and is now being utilized 
as the sole primary endpoint in several studies utilizing participant populations with early 
(prodromal to mild) AD, including the CREAD (crenezumab), PRIME (aducanumab),
ENGAGE/EMERGE (aducanumab), and Clarity AD (BAN2401) studies.
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.  The 
PK data may be combined with available data from other gantenerumab studies and 
may be used to assess exposureresponse relationships for relevant imaging, CSF,
plasma PD biomarkers, ECGs, and efficacy and safety outcomes in participants with 
early (prodromal to mild) AD, as appropriate.


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3.3.8
Rationale for Biomarker Assessments 
The following biomarker assessments described in Sections 3.3.8.1 (CSF), 3.3.8.2 (PET 
imaging), and 3.3.8.3 (brain volumetry, connectivity, and fiber tract integrity) will be used 
to investigate the effect of gantenerumab on the underlying pathology of AD in the 
participant population.
3.3.8.1
Cerebral Spinal Fluid Biomarkers
Amyloid plaque deposition, neurofibrillary tangle formation, and neuronal degeneration 
are known pathologic features of AD.  Decreased CSF A1−42 and elevated CSF t-tau 
and p-tau are considered a biochemical signature of AD.  Accumulating evidence 
suggests that low CSF A1−42 reflects underlying amyloid plaque pathology, whereas 
increased t-tau and p-tau levels may be reflective of neurodegeneration and/or tau 
pathology.  Amyloid deposition may be the initiating event in the cascade of pathologic 
processes underlying AD, whereas tau pathology appears to be a subsequent event,
and more associated with neurodegeneration.  Therefore, t-tau and p-tau may be 
studied as downstream biomarkers of the primary target of anti-amyloid therapies such 
as gantenerumab.
Although biomarkers indicative of certain neuropathologies are not surrogate markers for 
efficacy, there is some evidence that anti-Atreatments may cause changes in these 
biomarkers.  A neuropathologic study of participants with AD from Study AN1792 
suggests that active amyloid immunotherapy ameliorates neurite abnormalities and tau 
pathology through decreased tau phosphorylation (Serrano-Pozo et al. 2010).  In a 
pooled analysis of CSF data from two Phase II trials with bapineuzumab in participants 
with mild to moderate AD, a decrease in both p-tau and t-tau levels relative to baseline 
was observed in the bapineuzumab group after 12 months of therapy (Blennow et al.
2010).  These findings were confirmed in two Phase III studies with bapineuzumab 
(Sperling et al. 2012) as well as in Study WN25203 with gantenerumab.  In Study 
WN23203, CSF biomarkers were analysed for changes in multiple proteins, including 
Aβ1-42, t-tau, p-tau, and neurogranin, over the 2-year period.  Markers of 
neurodegeneration were significantly reduced in the 225-mg gantenerumab group 
compared with placebo over 2 years, with greater relative reduction in p-tau relative to 
t-tau.  The greatest effect was reduction in p-tau in the 225-mg gantenerumab arm at 
2 years relative to the change in the placebo arm.  There was no treatment effect on 
CSF A1−42 (Nikolcheva et al. 2015).  Because no evidence of efficacy was 
demonstrated with these therapies in clinical trials yet, changes in these biomarkers 
provide meaningful information about the pharmacodynamic effects of gantenerumab 
and the effect on pathologic processes underlying AD.
Based on these data and on the proposed mechanism of action of gantenerumab, levels 
of CSF t-tau and p-tau and additional exploratory biomarkers reflecting 
neurodegeneration will be assessed at baseline and following treatment.  Because 


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gantenerumab is expected to clear amyloid from the brain, levels of CSF A1−42 will also 
be measured.
3.3.8.2
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 -amyloid aggregates and neurofibrillary tangles formed from 
hyperphosphorylated tau protein).  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).
3.3.8.3
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 (Grecius 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 
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 
(PiBPET scans).  Alteration of the decreased brain functional connectivity has been 
shown using therapeutic interventions such as memantine (Lorenzi et al. 2011) or 


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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 
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 diffuse tensor imaging (DTI)-MRI techniques.  DTI-MRI is based on 
the measurement of diffusion properties of water molecules in the axonal fiber tracts in 
white matter.  Whereas water molecules can diffuse isotropically in CSF, they are 
restricted axially in white matter bundles.  Widespread group differences in the degree of 
anisotropic diffusion, or fractional anisotropy (FA), has been seen between participants 
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 
participants 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.
4.
MATERIALS AND METHODS
4.1
PARTICIPANTS WITH ALZHEIMER’S DISEASE
This study will enroll approximately 1016 participants with increased brain amyloid 
burden (defined according to CSF or 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 blinded data review or factors external to the study.
If at least 1 participant is enrolled at sites in mainland China, Hong Kong, and Taiwan 
that are recognized by the NMPA during the global enrollment phase, additional 
participants may be enrolled in a China extension to ensure a total enrollment that is 
sufficient to support registration in China.  All participants enrolled at NMPA-recognized 
sites in the global enrollment phase will be included in the primary analysis. All 
participants enrolled at NMPA-recognized sites in the global enrollment phase and the 
China extension phases will be included in a China-specific analysis. Details will be 
provided in the SAP.


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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

Availability of a person (referred to as the “study partner” throughout this 
protocol) who:
– Agrees to participate throughout the duration of study
– 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, including knowledge about 
domestic activities, hobbies, routines, social skills, and basic activities of daily 
life; work and educational history; cognitive performance including memory 
abilities, language abilities, temporal and spatial orientation, judgment and 
problem solving; emotional and psychological state; and can report any changes 
in the general health status
– Agrees to provide information and to complete all aspects of the study at clinic 
visits (which require partner input for scale completion)
– Signs the necessary Informed Consent Form(s), and has sufficient cognitive 
capacity to accurately report on the participant’s behavior as well as cognitive 
and functional abilities
– Is fluent in the language used at the site and has sufficiently good general health 
to have a high likelihood of maintaining the same level of interaction with the 
participant and participation in study procedures throughout the duration of the 
study
Every effort should be made to have same study partner 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, lumbar 
puncture [if applicable], clinical genotyping, and PET imaging [if applicable])  
The participant should be capable of completing assessments either alone or 
with the help of the study partner.

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 CSF tau/Aβ42 or on amyloid 
PET scan by qualitative read by the core/central PET laboratory


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
Demonstrated abnormal memory function at screening (FCSRT cueing 
index 0.67 and free recall 27)

Screening MMSE score 22 and CDR-GS of 0.5 or 1.0

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 
diagnostic criteria and guidelines for mild cognitive decline due to AD) (Albert et al.
2011)

If the participant is receiving symptomatic AD medications, a stable dosing regimen 
for at least 3 months prior to screening and until randomization
Participants receiving GV-971 or who are planning to take GV-971 during the 
study are not eligible 

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 
and its associated substudies

For enrollment in the China extension, participants must have residence in mainland 
China, Hong Kong, or Taiwan and be of Chinese ancestry.

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 last 
dose of study drug
A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (12 continuous months of amenorrhea 
with no identified cause other than menopause), and has not undergone surgical 
sterilization (removal of ovaries and/or uterus).
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.
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,


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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 and approval by 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.
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 MRI central reader, MRI evidence of any of the following: 


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– 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

Combined number of microbleeds and areas of leptomeningeal hemosiderosis 
(i.e., cumulative ARIA-H) on MRI more than five (and should not include any 
disseminated leptomeningeal hemosiderosis) based on the review performed by the 
central reader prior to randomization

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 ULN or total bilirubin 2ULN 


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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 
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
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 rescreened 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 rescreened 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 rescreened 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 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


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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 randomization 
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 randomization 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 randomization
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 randomization 
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 randomization
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.
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, the participant’s sufficient education or 
work experience.

Pregnancy or breastfeeding, or intention of becoming pregnant during the study


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
Deformity of the lumbosacral region of the spine that in the opinion of the 
investigator would contraindicate lumbar puncture in participants who will have 
lumbar puncture

Clinically significant abnormal screening blood, CSF (if applicable), or urine results 
that remain abnormal at retest

Impaired coagulation (screening prothrombin time [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 efficacy and safety,
provided that they have a study partner who meets the minimum requirement
4.1.3
Eligibility for the Open-Label Extension
Participants who have been randomized and who have completed the double-blind 
treatment period will be eligible to participate in the OLE, provided they do not meet any 
of the following criteria: 

Discontinued from study treatment during the double-blind treatment period

Received any other investigational medication during the double-blind treatment 
period or after the end of double-blind treatment

Participation in the OLE deemed inappropriate by the investigator (e.g., any serious 
medical condition or other concerns that preclude the participant’s safe participation 
in the OLE or ability to comply with the required procedures)

Presence of ARIA-E findings at the Week 116 (or Week 128, if applicable) MRI scan 
(participants who have ongoing ARIA-E findings at the Week 116 [or Week 128, if 
applicable] will stay in the double-blind treatment period until the finding is deemed 


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resolved). For those participants who enroll into the GRADUATE OLE from Week 
104, before the double-blind extension took place, eligibility for the OLE would be 
based on the Week 104 scan.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Randomization will be performed centrally using an interactive voice or Web-based 
response system (IxRS).  After screening, participants who meet all eligibility criteria will 
be randomly assigned to one of two treatment groups (gantenerumab or placebo).  The 
ratio will be 1:1, one active to one placebo.  The randomization method will be stratified 
block-randomization.  Randomization to treatment allocation will be stratified by 
geographic region (Western Europe and Australia vs. Rest of the World vs. North 
America), participant APOE ε4 status (carrier vs. non-carrier), participant stage of 
disease (prodromal vs. mild AD), use of AD medication (present vs. absent), and 
participation in the longitudinal amyloid and tau PET substudies.  Except in 
circumstances in which a health authority, EC, or IRB requires it, a participant will not be 
told of his or her APOE ε4 status.  Individual participant APOE ε4 genotype results will 
be blinded to participants, investigators, and the Sponsor.  APOE ε4 status information 
will be supplied directly to the IxRS vendor by the central testing laboratory so that the 
information can be incorporated at the time of randomization.  For participants for whom 
APOE ε4 status is already known, the results will be blinded to the Sponsor and as much 
as possible to the site and central MRI reader.  
The study is to be conducted in a double-blind manner to minimize potential bias from 
investigators and participants.  The Sponsor will be blinded to study treatment.  Sponsor,
participants, and site staff will remain blinded to previous treatment allocation in the OLE
period. The Master Randomization or Master Medication List will not be available at the 
study center, to Roche monitors, Roche project statisticians, or to the project team at 
Roche.  Unblinding should not occur except in the case of emergency situations where 
knowledge of the study drug assigned would affect participant care.  The investigator 
should make every effort to contact Roche before unblinding a participant.  In the event 
that the investigator unblinds a participant without prior notification, the investigator must 
contact Roche within 1 working day of the event.  Any request from the investigator for 
information about the treatment administered to study participants for another purpose 
must be discussed with the Medical Monitor.
If unblinding is necessary for participant management (e.g., in the case of a serious 
adverse event for which participant management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  Treatment codes should not be broken except in emergency 
situations.  If the investigator wants to know the identity of the study drug for any other 
reason, he or she should contact the Medical Monitor directly.  The investigator should 
document and provide an explanation for any premature unblinding (e.g., accidental 
unblinding, unblinding due to a serious adverse event).


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For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions (see Section 5.2.2) that are considered by the investigator or Sponsor to be 
related to study drug.
4.3
STUDY TREATMENT
The IMP for this study is gantenerumab.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Gantenerumab and Placebo
Gantenerumab and placebo will be supplied by the Sponsor as liquid formulation ready 
for SC administration.  Packaging of the study drug will be overseen by the Roche 
Clinical Trial Supplies Department and will bear a label with the identification required by 
local law, the protocol number, study drug identification, and dose.  The packaging and 
labeling will be in accordance with Roche standard and local regulations.  Upon receipt 
of the investigational products at the site, site personnel should check the product for 
damage and verify the proper identity, quantity, and integrity of the study drug.  Site 
personnel should report any deviations or product complaints to the monitor upon 
discovery.  For further details, please refer to the Gantenerumab Investigator’s Brochure.
For information on the formulation and handling of gantenerumab, see the pharmacy 
manual and Gantenerumab Investigator’s Brochure.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Gantenerumab and Placebo Administration during 
Double-Blind Treatment Period
Gantenerumab or placebo will be administered by SC injection to all participants.
Gantenerumab will be administered by SC injection to all participants randomized to the 
active treatment arm, regardless of APOE ε4 status, at a dose of 120 mg SC Q4W for 
3 months, 255 mg SC Q4W for 3 months, and 510 mg SC Q4W for 3 months, prior to 
reaching the target dose (see Figure 8).  Once the target dose is reached, study drug will 
be administered every 2 weeks (Q2W administration of 510 mg SC gantenerumab).  The 
switch to a Q2W administration schedule allows decreasing the number of SC 
administrations in the abdomen per visit.
Note: A minimum of 3 doses during each dosing step must be administered prior to 
uptitration.


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Figure 8
Overall Gantenerumab Dosing Design in the Double-Blind 
Treatment Period
Q2W every 2 weeks; Q4W every 4 weeks; SCsubcutaneous.
For Q4W injections, a time window of 7 days is allowed for dosing visits.  For Q4W 
injections, the recommended minimum time between doses is 3 weeks.  The maximum 
recommended time between doses should not exceed 6 weeks. Once study drug is 
administered Q2W, the time window for dosing visits is 3 days. For Q2W injections,
the recommendation is not to administer more than 1020 mg (i.e., 2 times 510 mg Q2W)
within 28 days.  Always return to the initial planned schedule per randomization for 
subsequent visits.
Regardless of dose, each participant will undergo up to a total of 49 dosing visits in 
scenario 1 or 55 dosing visits in scenario 2 (if applicable, see Section 3.3.1) in the
double-blind treatment period of the study. Participants who have completed the 
double-blind treatment period at the time of the implementation of the 12 week study 
extension, will have undergone up to 43 dosing visits. Injections will be administered as 
one 0.8-mL (120-mg dose), one 1.7-mL (255-mg dose), or two 1.7-mL injections 
(510-mg dose) subcutaneously to the abdomen, respectively.
Placebo of identical composition (except protein) and identical volume to gantenerumab 
will be administered by SC injection to all participants randomized to placebo at the 
same frequency and using the same route of administration.  
On study drug administration days that include efficacy assessments (see the schedule 
of activities in Appendix 1), study drug must be administered at the clinical site.  Study 


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personnel preparing and administering study drug must not be involved with any efficacy 
assessments or safety evaluations.
At applicable sites, study drug may be administered by a trained nursing professional at 
the participant's home or another suitable location, if the participant has given written 
informed consent to participate in home nursing visits.
Rules for dosage modification and treatment interruption or discontinuation are provided 
in Section 5.1.2.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.
4.3.2.2
Gantenerumab and Placebo Administration during the 
Open-Label Extension Period
During the OLE, participants previously randomized to the active treatment arm will 
continue to be administered the study drug every two weeks (Q2W administration of 
510 mg SC gantenerumab). Participants previously randomized to the placebo arm will 
be required to undergo 9 months of uptitration.
In order to maintain the previous study treatment blinding (Sponsor, site, and 
participant), all participants will be dosed every two weeks in the OLE as illustrated in 
Table 4. As in the double-blind treatment period, a safety MRI has to be performed 
before each uptitration to ensure that the participant can be uptitrated safely to the next 
dose.
To ensure blinding to previous treatment, gantenerumab and/or placebo will be 
administered every 2 weeks as one 0.8-mL and two 1.7-mL injections or two 1.7-mL 
injections subcutaneously to the abdomen. Injections may contain active gantenerumab 
or placebo to ensure the correct total dose of active gantenerumab at each visit (see 
Table 4).
Note: As in the double-blind part, a minimum of 3 doses during each dosing step must 
be administered prior to uptitration. During uptitration in the OLE, a minimum of 3 doses 
of each dosing step also have to be administered prior to be eligible for uptitration. In 
the OLE, a dose is defined as two consecutive dosing visits (one with an even 
dose number and one with an odd dose number, see Table 4).


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Table 4
Overall Gantenerumab Dosing Design in the Open-Label Extension
Open-Label Extension
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
18
Wk
20
Wk
22
Wk
24
Wk
26
Wk
28
Wk
30
Wk
32
Wk
34
Dose 
Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Participants 
previously 
on placebo
Dose 
120 mg Q4W
255 mg Q4W
510 mg Q4W
Injections
(mL)
1
0.8A +
2
1.7P
1
0.8P +
2
1.7P
1
0.8A +
2
1.7P
1
0.8P +
2
1.7P
1
0.8A +
2
1.7P
1
0.8P +
2
1.7P
1
1.7A +
1
1.7P
2 
1.7P
1
1.7A +
1
1.7P
2
1.7P
1
1.7A +
1
1.7P
2
1.7P
2
1.7A
2
1.7P
2
1.7A
2
1.7P
2
1.7A
2
1.7P
Participants
previously 
on active
Dose 
510 mg Q2W
Injections 
(mL)
21.7A
+ 1
0.8P
2x 1.7A
+ 1
0.8P
21.7A
+ 1
0.8P
21.7A
+ 1
0.8P
21.7A
+ 1
0.8P
21.7A
+ 1
0.8P
21.7A21.7A21.7A21.7A21.7A21.7A21.7A21.7A21.7A21.7A21.7A
2
1.7A
A Active treatment; Num number; P placebo; Wk week


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For the OLE, the time window for dosing visits is 3 days.  Always return to the initial
planned schedule per randomization for subsequent visits.
Rules for dosage modification and treatment interruption or discontinuation are provided 
in Section 5.1.2.
Participants enrolled in the WN39658 OLE study will have to complete the full titration 
scheme (i.e., at least 12 weeks on each dosing step) prior to being able to enroll in the 
WN42171 open-label study where they will receive 510 mg SC Q2W.
On study drug administration days that include efficacy assessments (see the schedule 
of activities in Appendix 1), study drug must be administered at the clinical site.  Study 
personnel who prepare and administer the study drug must not be involved with any 
efficacy assessments or safety evaluations.
At applicable sites, study drug may be administered by a trained nursing professional at 
the participant's home or another suitable location if the participant has given written 
informed consent to participate in home nursing visits.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.
PET Tracers
All participants who are enrolled in PET substudies will be assessed by PET imaging 
using an appropriate PET ligand.  For screening, the possible amyloid PET ligands will 
be florbetapir, florbetaben, and flutemetamol.  According to E.U. guidance, the PET 
tracers, as used in the context of this study, are designated as non-IMP.  In some 
regions, according to local regulations, these PET tracers may be considered to be IMP.
In countries where the PET radioligands are approved for marketing, the approved local 
product information will be provided, and in countries where they are not approved for 
marketing, the Investigator’s Brochures will be provided.
For the safety reporting requirements dealing with the PET tracers used in this study,
please refer to Section 5.7).
Details about the PET substudies are described in separate protocols.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (gantenerumab or placebo) will be 
provided by the Sponsor where required by local health authority regulations.  The study 
site will acknowledge receipt of IMPs, using the IxRS to confirm the shipment condition 
and content.  Any damaged shipments will be replaced.


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IMPs either will be disposed of at the study site according to the study site’s institutional 
standard operating procedure or will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed,
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Gantenerumab
The Sponsor will offer continued access to Sponsor study drug (gantenerumab) free of 
charge to eligible patients 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
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
All eligible participants will be offered to receive gantenerumab as part of an extension 
study, as described in Section 3.1.


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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.  Randomization will be stratified for participants taking and not taking approved 
anti-dementia medications.
Adding a new medication or changing the dose of a medication after randomization 
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 randomization: 

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)

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


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
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
Refer to Appendix 1 for the schedule of activities to be performed during the study.
At applicable sites, certain study assessments may be performed by a home nursing 
(HN) professional at the participant's home or nursing center 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.  HN visits are scheduled on 
specified visit days to allow relevant assessments to be performed by the HN 
professional.  The schedule of activities (see Appendix 1) specifies which assessments 
may be performed by an HN professional.
4.5.1
Informed Consent Forms and Screening Log
All participants and study partners must review, sign, and date the most current 
IRB/EC-approved written informed consent for participation in the study before 
any study-specific prescreening assessments, screening tests or evaluation are 
performed.  Informed Consent Forms for enrolled participants and their study partners 
and for those who are not subsequently enrolled will be maintained at the study site.


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All prescreening and screening evaluations must be completed and reviewed to confirm 
that participants meet all eligibility criteria before randomization.  The investigator will 
maintain a screening log to record details of all participants prescreened and screened 
and to confirm eligibility or record reasons for screening failure, as applicable.
Prescreening is optional and is covered by a dedicated Informed Consent Form.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), smoking history, 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, dermatological, musculoskeletal, respiratory,
gastrointestinal, genitourinary (optional), and neurological systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF.
The schedule of activities indicates when complete physical examinations (including 
neurological 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 
should be recorded as adverse events on the Adverse Event eCRF.
In addition, weight will be obtained at screening, and at every visit at which creatinine
clearance is tested as well as at any other visit as deemed necessary by the 
investigator.  Height will be obtained at screening only.


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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.
Vital sign measurements may be performed by an HN professional.
The schedule of activities indicates when vital signs (blood pressure and pulse rate) are 
to be recorded (see Appendix 1).
4.5.5
Cognitive, Functional, and Health Economics Assessments
The assessments described in this section will be performed as outlined in the schedule 
of activities (see Appendix 1) and in the order specified in Section 4.6.
Whenever possible, there should be consistency in the rater and study partner 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-randomization visits, if the caregiver, the primary 
rater, or even the participant cannot perform these assessments as per the schedule of 
activities, they may be performed up to 4 weeks out of window.
Given that the primary outcome measure in this trial involves subjective judgment, the 
adequacy of participant and study partner 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 the primary endpoint 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).
4.5.5.1
Clinical Dementia Rating Scale 
The CDR global score (CDR-GS) characterizes a participant’s level of impairment 
according to the following categories: 0 (normal), 0.5 (very mild dementia), 1 (mild 
dementia), 2 (moderate dementia), and 3 (severe dementia). The SOB score is a 
detailed quantitative general index that provides more information than the CDR-GS in 


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participants with mild dementia (Berg 1988; Morris et al. 2001, O'Bryant et al. 2010) and 
is scored from 018 with higher scores indicating greater impairment.  The CDR 
characterizes six domains:  memory, orientation, judgment and problem solving,
community affairs, home and hobbies, and personal care.  The necessary information to 
make each rating is obtained through a semi-structured interview with the participant and 
a reliable informant or collateral source (e.g., a study partner).
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, FAQ, 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 interview 
but before ADAS-Cog, MMSE, Verbal Fluency Task, Coding, and other scales are 
completed. Nevertheless, at screening, baseline, Week 104, Week 116 or Week 128 (if 
applicable), 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.
4.5.5.2
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 participant-based assessment that 
measures learning and memory, language production, language comprehension,
constructional praxis, ideational praxis, and orientation.  The modified version will be 
used; it has 13 items and includes the addition of delayed word recall and a number of 
cancellation subtests, as well as use of only one trial for word recognition (Mohs et al.
1997).  Equivalent alternate forms of the word recall, word recognition, and number 
cancellation subtests will be used in successive test administrations.
4.5.5.3
Mini-Mental State Examination
The MMSE is a set of standardized questions used to evaluate possible cognitive 
impairment and help stage the severity level of this impairment (Folstein et al. 1975).  
The questions target six areas:  orientation, registration, attention, short-term recall,
language, and constructional praxis/visuospatial abilities.  The MMSE is a 
participant-based assessment.
4.5.5.4
Free and Cued Selective Reminding TestImmediate Recall 
The FCSRT-Immediate Recall (FCSRT-IR) is a participant-based assessment that 
measures memory under conditions that control attention and cognitive processing.  
Impairments in FCSRT-IR performance have been associated with preclinical and early 
dementia in several longitudinal epidemiological studies (Grober and Buschke 1987; 
Sarazin et al. 2007).  The 16-word version of the test will be used in this study.


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4.5.5.5
Verbal Fluency Task 
The category verbal fluency (e.g., animals) is a participant-based assessment that 
measures speed and flexibility of verbal thought.  Verbal fluency tests are sensitive tools 
for detecting dementia (Pasquier et al. 1995; Lezak et al. 2004) and for monitoring 
decline over time (Clark et al. 2009).
4.5.5.6
Coding
The Coding, also called Digit Symbol Substitution Test (or DSST), is a subtest from the 
Wechsler Adult Intelligence ScaleFourth Edition (WAISIV; Wechsler 2008). The 
Coding is a participant-based assessment that measures speed of processing and 
associative memory. The test is known to be sensitive to disease progression (Lezak et 
al. 2004). The 120-second version of the test will be used in this study.
4.5.5.7
Functional Activities Questionnaire
The FAQ (Pfeffer et al. 1982) is an informant-based measure of functional abilities.  
Informants provide performance ratings of the target person on ten complex higher-order 
activities.
4.5.5.8
Alzheimer’s Disease Cooperative StudyActivities of Daily 
Living Inventory 
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in participants with AD (Vellas et al. 2008).  The ADCS-ADL is a 23-item 
informant-based questionnaire that covers both basic ADL (e.g., eating and toileting) and 
more complex ADL or instrumental ADL (e.g., using the telephone, managing finances,
preparing a meal). It has a 4-week recall period. Total scores range from 078, with 
higher scores indicating better functioning.
4.5.5.9
Zarit Caregiver InterviewAlzheimer’s Disease 
The Zarit Caregiver InterviewAlzheimer’s Disease (ZCI-AD) is a modified version of the 
Zarit Burden Interview, which was originally designed to reflect the stresses experienced 
by caregivers for people with dementia (Zarit and Zarit 1990).  The modified version 
includes slight modifications in item and title wording (e.g., removal of “your relative” to 
refer directly to the participant, removal of “burden” from title) and the use of 11-point 
numerical rating scales.  The ZCI-AD scale consists of 30 items and is completed by the 
study partner without involvement from the site staff. It has a 4-week recall period.
4.5.5.10
Quality of Life–Alzheimer’s Disease
The Quality of LifeAlzheimer’s Disease (QoL-AD) was developed to assess QoL in 
participants who have dementia (Logsdon et al. 1999, 2002).  The QoL-AD consists of 
13 items covering aspects of participants’ relationships with friends and family, physical 
condition, mood, concerns about finances, and overall assessment of QoL.  The total 
score is the sum of the 13 items and ranges from 1352, with higher scores indicating 
better HRQOL.


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In this study, the QoL-AD will be administered in a standardized, structured interview 
format to participants by investigative staff in order to gather participant responses about 
QoL.  The study partner will also complete the study partner version of the questionnaire 
to enable proxy responses from the study partner.
4.5.5.11
EQ-5D
The EuroQoLFive Dimensions (EQ-5D) is a standardized measure of health status 
designed to provide a simple generic measure of health for clinical and economic 
appraisal.  It is broadly applicable across a wide range of health conditions and 
treatment.
The EQ-5D assesses five domains to provide a health state index.  These are 
anxiety/depression, pain/discomfort, usual activities, mobility, and self-care.
The following two versions will be used in this study:

EQ-5D-5L Proxy, Version 1:  The study partner (the proxy) is asked to rate the 
participant’s health-related QoL in his or her (the proxy’s) opinion.

EQ-5D-5L, Self-Complete Version:  The study partner is asked to rate his or her 
own health-related QoL.
4.5.5.12
Resource Utilization in Dementia Scale 
The Resource Utilization in Dementia (RUD) scale (Wimo et al. 2003) aims to document 
formal and informal resource use in a clinical trial setting.  The RUD-Lite captures the 
most important elements in dementia care:  accommodation, informal care,
hospitalizations, and community care services.  Information on study partner 
sociodemographics in addition to working status and effect on productivity will be 
collected.  The amount of informal care will be collected according to three types of care:  
personal ADL, instrumental ADL, and supervision.  Data on accommodation and 
temporary changes in accommodation during the last month and the duration of these 
will be collected according to four levels of accommodation:  own home, intermediate 
forms of accommodation, dementia-specific residential accommodation, and nursing 
home.  Resource utilization will be recorded as the number of nights spent in different 
types of hospital wards, the number of visits to the most common types of outpatient 
care, and the number of visits in community care services.  
4.5.5.13
Neuropsychiatric Inventory Questionnaire
The Neuropsychiatric InventoryQuestionnaire (NPI-Q) (Kaufer et al. 2000) was 
developed to assess a wide range of behaviors encountered in dementia participants, to 
provide a means of distinguishing severity of behavioral changes, and to facilitate rapid 
behavioral assessment through the use of screening questions.  It is an informant-based 
instrument in which 12 behavioral domains are evaluated. The recall period is the past 
month, and severity scores range from 036, with higher scores indicating greater 
severity. The study partner's distress portion of the scale will not be used in this study.


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4.5.5.14
Electronic Assessment of Rating Scales
The following rating scales will be captured electronically and transferred to the 
database directly from the core laboratory:  ADAS-Cog, Verbal Fluency Task,
ADCS-ADL, CDR, MMSE, FCSRT, FAQ, AD QoL, EQ-5D, RUD-Lite, NPI-Q,
and CSSR-S.
4.5.6
Laboratory, Biomarker, and Other Biological Samples 
4.5.6.1
Standard Laboratory Samples
Samples for the following laboratory tests will be sent to a central laboratory for analysis.  
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  

Serum chemistry:  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)
HbA1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive 
protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone 
levels will also be assessed according to the schedule of activities.

Hematology:  hemoglobin, hematocrit, RBC count (with morphology), WBC count,
platelets, basophils, eosinophils, lymphocytes, monocytes, neutrophils, and 
WBC–other total counts

Screening serology:  HIV, hepatitis B, and hepatitis C

Coagulation:  PT

Urine for drugs of abuse:  At screening only, urine samples will be analysed 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 each dosing 
visit (prior to dose administration) 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.


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4.5.6.2
Biomarker Sampling
Samples will be obtained from all participants and will be used for research purposes to 
identify dynamic biomarkers that may be predictive of response to treatment with 
gantenerumab (in terms of dose, safety, and tolerability) and will help to better 
understand the pathogenesis, course, and outcome of AD and related diseases.
For participants who consent to the optional Roche Research Biosample Repository 
(RBR) residual biomarker samples will be kept for future biomarker research (see 
Section 4.5.12).
The procedures for the collection, handling, and shipping of biomarker samples are 
specified in the Sample Handling and Logistic Manual.
Unless the participant gives specific consent for his or her leftover samples to be stored 
for optional exploratory research (see Section 4.5.12), biomarker samples will be 
destroyed no later than 5 years after the final Clinical Study Report has been completed.  
However, the storage period will be in accordance with the IRB/EC-approved Informed 
Consent Form and applicable laws (e.g., health authority requirements).
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.
Cerebrospinal Fluid and Serum Sampling (for CSF-Enrolled Participants 
Only)
CSF samples and matching serum samples will be obtained from participants who 
choose to provide CSF samples during screening (CSF-enrolled participants) for 
confirmation of Aand tau levels for eligibility purposes (mandatory) and for monitoring 
Aand tau levels, as well as other CSF biomarkers at different timepoints during the 
study. The matching serum samples may be used to determine parameters that allow 
the assessment of the blood-brain barrier status and/or inflammatory processes in the 
brain, such as CSF/serum albumin ratio, CSF/serum IgG and IgM indices, and 
oligoclonal bands.  CSF and serum samples will be collected according to the schedule 
of activities (see Appendix 1).  Lumbar puncture will be performed by an individual who 
meets all local requirements and is proficient in the procedure.  Lumbar puncture 
procedures and postlumbar puncture care will be performed in accordance with local 
practice.  CSF sampling should be performed in the morning (between 8:00 a.m. and 
noon) to minimize potential diurnal variation of CSF parameters.  Procedures for the 
processing of the CSF samples can be found in the Sample Handling and Logistics 
Manual.


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Approximately 12 mL of CSF will be collected at each timepoint.  The sample will be 
divided into aliquots onsite and used for the following:

Central measurement of gantenerumab levels in the CSF and biomarker analysis,
including A142, t-tau, p-tau, as well as some exploratory markers.  Samples may 
also be used to support the development of biomarker assays for diagnostic use.
Unused CSF samples will be kept for future biomarker research if the participant gives 
consent to participate in the RBR (see Section 4.5.12.5).  
Clinical Genotyping
During screening, three mandatory 3-mL whole blood samples will be obtained for DNA 
extraction from every participant who has consented to participate in the study.  All 
participants will be evaluated for APOE ε4 status, clusterin (apolipoprotein J) genotypes,
and Fc-receptor genotype.  The Fc-receptor genotype may play a role in PK and PD 
variability of antibody-based therapeutic agents and may be predictive of response 
and non-response.
APOE ε4 status will be determined and will be blinded to the Sponsor, investigator, and 
participant and will not be shared with the investigator or the participant until the study is 
unblinded (unless required for participant safety or by the relevant health authority or 
IRB/EC).  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 and 
should be kept blinded from the Sponsor.  In addition, as much as possible, participant
APOE ε4 status should remain blinded to the site and central MRI readers.
Samples and data may be used for future research or diagnostic test development.
RNA Sampling
During screening and at a subsequent visit as detailed in the schedule of activities (see 
Appendix 1), two 2.5-mL whole blood samples will be obtained for RNA extraction from 
every participant who has consented to participate in the study.  The sample may be 
used to evaluate clusterin messenger RNA and other exploratory genetic markers in 
peripheral blood (see Section 4.5.12).
Plasma Sampling
At screening and at subsequent visits as detailed in the schedule of activities (see 
Appendix 1), two 6-mL whole blood sample will be obtained for plasma extraction from 
every participant who has consented to participate in the study.  
This sample will be used to evaluate exploratory plasma biomarkers in peripheral blood,
which may include, but will not be limited to A, tau, p-Tau, and neurofilament.
An additional plasma sample for the assessment of exploratory plasma biomarkers will 
be obtained as soon as is practical (e.g., at an unscheduled visit) once the site becomes 


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aware of the occurrence or worsening of ARIA-E or of the occurrence of ARIA-H meeting 
discontinuation criteria.
4.5.6.3
Anti-Drug Antibody Sampling
Blood samples will be collected to assess the possible development of ADAs in all 
participants as noted in the schedule of activities (see Appendix 1).  Plasma samples will 
be analysed for antibodies to gantenerumab using a bridging ELISA.
Samples collected from participants receiving placebo will not be assessed in the first 
instance but retained for subsequent analysis if appropriate.
Unused sample material may also be used for the purposes of current ADA assay 
improvement.
The procedures for the collection, handling, and shipping of ADA samples are specified 
in the Sample Handling and Logistics Manual supplied to the site.  
4.5.6.4
Pharmacokinetic Sampling
Plasma Gantenerumab Samples
Blood samples will be collected to evaluate the pharmacokinetics of gantenerumab in 
plasma as noted in the schedule of activities (see Appendix 1).
An additional PK sample for the assessment of plasma concentrations of gantenerumab 
will be obtained as soon as 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.
Samples from participants receiving placebo may not be assessed at once but will be 
retained for subsequent analysis if appropriate.  Samples will not be analysed in real 
time but will be batched for analysis throughout the study.
Unused sample material may be used for the purpose of current gantenerumab assay 
improvement, for the quantification of specific gantenerumab glycan species, and for the 
assessment of exploratory plasma biomarkers.
The procedures for the collection, handling, and shipping of PK samples are specified in 
the Sample Handling and Logistics Manual supplied to the site.
Cerebral Spinal Fluid for Assessment of Gantenerumab Concentration 
(for Participants Enrolled on the Basis of CSF Criteria Only)
For participants enrolled on the basis of CSF criteria and willing to perform lumbar 
puncture in the schedule of activities, an aliquot of CSF obtained by lumbar puncture,
described in Section 4.5.6.2, will be allocated for the measurement of gantenerumab 
concentration.  Samples from participants receiving placebo may not be assessed at 
once but will be retained for subsequent analysis if appropriate.


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Unused sample material may also be used for the purposes of current assay 
improvement.
4.5.7
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.  ECG recordings must be 
performed after the participant has been resting in a supine position for at least 
5 minutes.  All ECGs are to be obtained prior to other procedures scheduled at that 
same time (e.g., vital sign measurements, blood draws, brain MRI scans, and lumbar 
puncture).  Circumstances that may induce changes in heart rate, including 
environmental distractions (e.g., television, radio, conversation), should be avoided 
during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the participant's 
permanent study file at the site.
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.
4.5.8
ColumbiaSuicide Severity Rating Scale 
The C-SSRS (http://www.cssrs.columbia.edu) is an assessment tool used to assess the 
lifetime suicidality of a participant (C-SSRS at baseline) as well as any new instances of 
suicidality (C-SSRS since last visit).  The structured interview prompts recollection of 
suicidal ideation, including the intensity of the ideation, behavior, and attempts with 
actual or potential lethality.  The C-SSRS baseline 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 during the study visit.
4.5.9
Brain Magnetic Resonance Imaging
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.  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 
substudies (for the schedule of activities, see Appendix 1).


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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).
MRI will be used during the study to help assess safety such as the occurrence of 
microbleeds or signs potentially indicative of inflammation or ARIA-E.  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 gradient recalled echo (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)
For details on the specific imaging sequences and acquisition times required, refer to the 
MRI Manual.
MRI should not be performed unless at least 3 days have passed since a lumbar 
puncture.  If an MRI and lumbar puncture are both scheduled for the same day, the MRI 
should be performed first.  
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.  MRI results must be made 
available to investigators prior to next dosing (refer to Section 5.1.2 for additional details 
on MRI safety management).


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MRI facility qualification and scan quality control will be performed by the central MRI 
core laboratory.
Additional instructions regarding the procedures for MRI scan acquisition and transmittal 
to the central reading facility can be found in the MRI Manual.
4.5.10
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, then 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 
found in the MRI Manual.
4.5.11
Positron Emission Tomography Scan 
A PET scan will be performed for confirmation of Alevels for eligibility purposes in 
participants (PET-enrolled participants).  Three radioligands are be used for screening 
purposes: [18F] florbetapir (Amyvid), [18F] flutemetamol (Vizamyl), and [18F] 
florbetaben (Neuraceq).
Screening PET scans must not be acquired prior, potentially exclusionary screening 
results are available in order to minimize radiation burden to participants.  In order 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 [18F] florbetapir, [18F] flutemetamol, or [18F] florbetaben 
acquired outside this study protocol may be permissible to confirm participant inclusion 
with Medical Monitor approval.  Previously acquired PET scans must meet quality 
standards detailed in the PET Technical Operations Manual and must be centrally 
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Detailed instructions regarding the procedures for PET scan methodology, including 
scanning procedures can be found in the PET Technical Operations Manual.
4.5.12
Optional Samples for Research Biosample Repository 
4.5.12.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
participants in the future.
Specimens for the RBR will be retained from participants who give specific consent to 
participate in this optional research.  
RBR specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or 
disease progression

To increase knowledge and understanding of disease biology

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
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee
Collection and submission of biological samples to the RBR 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 4.5.12) will not be applicable at that site.
4.5.12.3
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 Clinical Genotyping sample and clinical RNA sample and any 
derivatives thereof (e.g., DNA, RNA, proteins, peptides), plasma biomarker sample,
CSF samples, and serum samples
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via whole genome sequencing (WGS), whole exome sequencing 
(WES), next-generation sequencing, or other genomic analysis methods.


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Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome,
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches.  Data will be analysed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways,
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR specimens 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).
4.5.12.4
Confidentiality
Specimens and associated data will be labeled with a unique participant identification 
number.
Participant medical information associated with RBR specimens 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 specimens, data 
derived from these analyses will generally not be provided to study investigators or 
participants unless required by law.  The aggregate results of any conducted research 
will be available in accordance with the effective Sponsor policy on study data 
publication.
Data generated from RBR specimens 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.
4.5.12.5
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 specimens at 
any time and for any reason during the storage period.  A separate, specific signature 


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will be required to document a participant's agreement to provide optional RBR 
specimens.  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 
specimens and data will continue to be used as part of the RBR research.
4.5.12.6
Withdrawal from the Research Biosample Repository
Participants who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  If a participant wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the participant's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Research Sample Withdrawal of Informed Consent eCRF.  The participant will be 
provided with instructions on how to withdraw consent after the trial is closed.  A 
participant's withdrawal from Study WN39658 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a participant's withdrawal from the RBR does not 
constitute withdrawal from Study WN39658.
4.5.12.7
Monitoring and Oversight
RBR specimens 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 specimens 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 
12 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.


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The FCSRT and MMSE assessments may also be completed at prescreening.  
However, in this case, a separate prescreening consent would need to be signed and 
FCSRT and MMSE would not need to be repeated during the screening process.  In 
case the participant would not qualify based on the FCSRT inclusion criteria,
investigators have the option to repeat the FCSRT once after at least 6 months have 
elapsed if recruitment for the study is still ongoing. Rescreening of participants who 
failed MMSE 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 
12-week screening window) once to confirm the test results before randomizing a 
participant at baseline.
In rare cases in which an 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 12 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 as follows:
ECG electrocardiogram; FCSRT Free and Cued Selective Reminding Test; MRImagnetic 
resonance imaging; PET positron emission tomography.
The recommended order of clinical assessments and rating scales at screening is 
shown below.


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Participant Assessments
Study Partner Assessments
1. FCSRT (performed at 
prescreening or at screening)
10-min break (optional)
2. MMSE (performed at 
prescreening or at screening)
3. CDR (participant interview)
CDR (study partner input)
CDRClinical Dementia Rating; FCSRT Free and Cued Selective Reminding 
Test; MMSEMini-Mental State Examination.
CSF sampling, 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, the participant may be 
rescreened again after at least 3 months (6 months for FCSRT) have elapsed if 
recruitment for the study is still ongoing.
As noted in the exclusion criteria (see Section 4.1.2), participants may be rescreened 
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.
Participants may be rescreened 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 lumbar puncture (if 
performed within the previous 12 months for this study and within eligible ranges) and 
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 rescreening.
Participants may be rescreened 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 the lumbar puncture, 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, CSF collection and/or PET scan and MRI 
scan should be performed, if required.  
It will take several days to receive the results of the MRI or CSF.  On occasion, the 
originally scheduled MRI or CSF collection 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.


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For participants enrolling on the basis of PET criteria, and for participants willing to 
participate in any of the PET substudies, scans can be obtained after all other screening 
results are available.  For these participants, it is recommended that the MRI 
appointment should be scheduled to allow sufficient time for the PET scan to be 
performed and evaluated before the end of the screening period.
A positive PET scan using Amyvid, Vizamyl, or Neuraceqacquired outside this 
study may be permissible to confirm participant inclusion with Sponsor approval.  
Previously acquired PET scans must meet quality standards detailed in the PET 
Technical Operations Manual and must be centrally evaluated.
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
In order to be randomized and to receive double-blind treatment, participants must have 
no significant change in medical, psychiatric, or neurological 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 input, should be completed before any invasive safety 
assessments.

Vital sign measurements, ECGs, blood draws for clinical laboratory assessments,
PK, ADA, and plasma biomarker sampling, and urine samples are recommended to 
be conducted following scale assessments and all 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 Assessments
1.
ADAS-Cog13
2.
CDR (participant interview)
10-min break (optional)
3.
MMSE
4.
Coding
5.
Verbal Fluency Task
10-min break (optional)
6.
QoL-AD
7.
C-SSRS
1.
CDR (study partner input)
2.
FAQ
3.
ADCS-ADL
4.
ZCI-AD
5.
QoL-AD
6.
EQ-5D
7.
RUD-Lite 
8.
NPI-Q
ADAS-Cog13 Alzheimer’s Disease Assessment ScaleCognition, Subscale 
13; ADCS-ADL Alzheimer’s Disease Cooperative Study-Activities of Daily 
Living; CDR Clinical Dementia Rating; C-SSRSColumbiaSuicide Severity 
Rating Scale; EuroQol-Five Dimensions; FAQ Functional Activities 
Questionnaire; MMSEMini-Mental State Examination; 
NPI-QNeuropsychiatric InventoryQuestionnaire; QoL-ADQuality of 
LifeAlzheimer’s Disease; RUD-LiteResource Utilization in DementiaLite; 
ZCI-ADZarit Caregiver InterviewAlzheimer’s Disease.
If assessments are split over 2 days, all safety assessments must be performed on the 
same day as the study drug administration.
4.6.3
Assessments during the Double-Blind Treatment Period
In the double-blind treatment period, participants will receive up to 49 (in scenario 1) or
55 (in scenario 2, if applicable) SC administrations of study drug over the course of
114 or 126 (if applicable) weeks, respectively.  The final on-treatment efficacy and safety 
assessments are scheduled 2 weeks after the last dose. Participants who have 
completed the double-blind treatment period at the time of the implementation of the 
study extension by 12 weeks received up to 43 doses and underwent the final efficacy 
and safety assessments at Week 104, 2 weeks after the last 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). However, in exceptional circumstances, for 
post-randomization visits, if the caregiver, the primary rater or even the participant 
cannot perform these assessments as per schedule of activities, they may be performed 
up to 4 weeks out of window.
Vital sign measurements, ECGs, blood draws for clinical laboratory assessments, PK,
ADA, plasma biomarkers, and urine must be performed prior to study drug 
administration. They are also recommended to be conducted following scale assessments.


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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 or matching placebo will be 
administered subcutaneously at room temperature.  For the first four 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, study drug administration 
may be performed only by qualified health care providers, as defined by local 
regulations, who must remain with the participants for a minimum of 1 hour after each 
injection and be equipped with rescue medications.
Rescue medications to treat anaphylactic and anaphylactoid reactions must be available 
at the site or at the dosing location for HN visits.  Participants and their study partners 
will be alerted to watch for signs of anaphylactic and anaphylactoid reactions and to 
contact the study center as soon as possible if any such signs are noted.
Visits at which the participant receives study drug may take place within 7 days of the 
protocol-specified date for Q4W administration and 3 days of the protocol-specified 
date for Q2W administration per the schedule of activities in Appendix 1. For Q4W 
injections, the recommended minimum time between doses is 3 weeks.  The maximum 
recommended time between doses should not exceed 6 weeks. For Q2W injections, the 
recommendation is not to administer more than 1020 mg (i.e., 2 times 510 mg Q2W)
within 28 days. Always return to initial planned schedule per randomization for 
subsequent visits.
All visits should be scheduled as close as possible to the exact day.  It is preferred that 
all assessments for a visit be performed on the same day, but if necessary, assessments 
may be performed over more than 1 day.  Preferably, all clinical scales and assessments 
should be performed on the same day.  Study drug administration should be performed 
only after all assessments and rating scales for the participant have been completed.
For sites and participants for whom this is practical, visits that require only dosing, vital 
sign measurements, urine pregnancy test, C-SSRS assessment, and adverse event 
assessment may be performed at an alternate location conducted by appropriate health 
care professionals.
Refer to Appendix 1 for the schedule of activities during the treatment period.
4.6.4
Assessments during Open-Label Extension Period
The same recommended order of clinical assessments and rating scales as in the 
double-blind treatment period (see Appendix 1), as well as vital sign measurements,


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ECGs, blood draws for clinical laboratory assessments, PK, ADA, plasma biomarkers,
and urine samples must be performed prior to study drug administration. They are also 
recommended to be conducted following scale assessments. If assessments are split over 
2 days, all safety assessments must be performed on the same day as the treatment 
administration.
On each dosing day, after all assessments prior to dosing have been completed (see
Appendix 1), gantenerumab and/or matching placebo will be administered 
subcutaneously at room temperature.  For the first eight 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 9 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, study drug administration may be 
performed only by qualified health care providers, as defined by local regulations, who 
must remain with the participants for a minimum of 1 hour after each injection and be 
equipped with rescue medications.
Rescue medications to treat anaphylactic and anaphylactoid reactions must be available 
at the site or at the dosing location for HN visits.  Participants and their study partners 
will be alerted to watch for signs of anaphylactic and anaphylactoid reactions and to 
contact the study center as soon as possible if any such signs are noted.
In the OLE, visits at which the participant receives study drug may take place 3 days of 
the protocol-specified date for Q2W administration per the schedule of activities in 
Appendix 1. Always return to the initial planned schedule per randomization for 
subsequent visits.
For sites and participants for whom this is practical, visits that require only dosing, vital 
sign measurements, urine pregnancy test, C-SSRS assessment, and adverse event 
assessment may be performed at an alternate location conducted by appropriate health 
care professionals.
Refer to Appendix 1, Table 3 for the schedule of activities during the OLE.
4.6.5
Procedures for New MRI 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 4.5.9).


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Refer to Section 5.1.2 for instructions in the event of new MRI findings (ARIA-E and 
ARIA-H).
4.6.6
Assessments at Study Completion or Early Termination Visit
Participants who complete the double-blind treatment period at Week 114 in scenario 1 
or at Week 126 in scenario 2 (if applicable) will have to complete the final efficacy and 
safety assessment period 2 weeks following the last dose. Some participants may have 
already received the last study drug administration at Week 102 and performed the final 
efficacy and safety visit at Week 104 at the time of implementation of the study 
extension by 12 weeks.
All participants will be asked to come back for the follow-up assessments 14 weeks 
and 50 weeks after the last dose, unless they are transitioning to an OLE.
All participants who withdraw from treatment or discontinue from the study early (during 
the double-blind treatment period or during the OLE) will be asked to return 2 weeks 
after the last dose of study drug in order to complete the early termination visit.
In addition, participants who withdraw from treatment will be asked to return for 
collection of safety (except MRI) and limited efficacy data (i.e., the primary and 
secondary endpoints) at visits that have efficacy assessments per the schedule of 
activities until the end of the double-blind treatment period or until the last OLE follow-up 
visit (OLE Follow up 2) for those who enrolled in the OLE period.
Autopsy reports, including cause of death, for all participants who die during the study 
(i.e., prior to the Week 50 follow-up visit) should be requested.
Refer to the schedule of activities to be performed at the study completion in Appendix 1.
4.6.7
Follow-Up Assessments
Participants who complete the double-blind treatment period and who are not willing to 
enroll in an OLE or these who complete the OLE period (defined as administration of at 
least three 510-mg doses Q4W) and are not willing to enroll in the WN42171 open-label 
study will be asked to return to the clinic 14 weeks and 50 weeks after the last dose of 
study drug for the follow-up visits (Follow Up 1 and Follow Up 2 or OLE Follow Up 1 and 
OLE Follow Up 2, respectively)..
When participants complete the treatment period or discontinue early, every effort 
should be made to ensure that the safety follow-up period and all related assessments 
are completed.
After the study completion or early termination visit, adverse events should be followed 
as outlined in Sections 5.5 and 5.7.  Refer to the schedule of activities (see Appendix 1)
for the list of assessments to be performed at the follow-up visits.


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4.6.8
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 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 determines it 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 2 weeks after last 
dose in order to complete the early termination visit assessments.
In addition, participants who withdraw from treatment will be asked to return for 
collection of safety (except MRI) and limited efficacy data (i.e., the primary and 
secondary endpoints) at visits that have efficacy assessments according to the schedule 
of activities until the end of the double-blind treatment period, and then the follow-up 
visits, or until the last OLE follow-up visit (OLE Follow Up 2) for those who enrolled in 
the OLE.
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
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 withdrawal from the study may include, but are not 
limited to, the following:

Participant withdrawal of consent at any time

Study termination or site closure

Any medical condition that the investigator and 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


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
Participant non-compliance with the study and/or study procedures, defined as 
missing more than three consecutive dose administrations (with Q4W dosing 
regimen) or more than six consecutive dose administrations (with Q2W 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 2 weeks after 
last dose in order to complete the early termination visit.
Participant should be informed of circumstances under which their participation may be 
terminated by the investigator without the participant’s consent.  Any administrative or 
other reasons for withdrawal must be explained to the participant.
Every effort should be made to obtain information on participants who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, participants will not be followed for any reason after 
consent has been withdrawn.  
Participants who withdraw from the study will not be replaced.
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

Futility analyses suggesting that treatment with gantenerumab is likely not effective.

Sponsor determines it is the best interest of the participants.
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.7.4
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)


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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 enrolled 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
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 6.
5.1.1.2
Injection-Site Reactions
Gantenerumab may cause a reaction when given as an SC injection.  In studies with 
gantenerumab, the most common events occurring more frequently with gantenerumab 
than with placebo were local ISRs, such as injection-site erythema.  The majority of 
events were of mild intensity and resolved without treatment (see Section 1.2.3 for 
details).
Detailed information on the characteristic signs and symptoms of ISRs (e.g., erythema,
pruritus) will be recorded on the dedicated eCRF page (see Section 5.3.5.2 for details on 
recording of ISRs).
5.1.1.3
Immunogenicity
As with administration of any exogenous protein, there is the potential for the 
development of ADAs, which can be neutralizing and/or sensitizing and which can 
potentially lead to febrile or allergic reactions, including anaphylaxis. The immunogenic 
risk of gantenerumab is considered low since it is a fully human antibody.


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There are no clinical findings indicative of an immunogenic response to gantenerumab.
Participants should be told how to recognize the signs and symptoms of hypersensitivity
reactions and be monitored.
5.1.2
Management of Participants Who Experience Selected 
Adverse Events
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. In the double-blind treatment period, a minimum of 3 doses of each 
dosing step have to be administered before the participant is eligible for the next 
uptitration dose.  In the OLE, a minimum of 3 doses of each dosing step must be 
administered prior to be eligible for uptitration. In the OLE, a dose is defined as 
two consecutive dosing visits (one with an even dose number and one with an odd dose 
number, see Table 4, Section 4.3.2.2).
Participants will be eligible for uptitration if there are no new ARIA-E, if the ARIA-E is 
resolved (BGTS0), and if the criteria for discontinuation because of ARIA-H have not 
been met.  
In addition, the following dose adjustment and discontinuation rules for MRI findings 
will apply:

In case of asymptomatic ARIA-E 1 and 4 BGTS:  Continue study drug at the 
same dose level (i.e., do not uptitrate) and repeat MRI 4 weeks later.
As long as BGTS is 4 and 1, continue study drug at the same dose level and 
continue MRI monitoring at 4-week intervals until the event resolves.  When 
ARIA-E resolves, resume uptitration and MRI monitoring according to the 
schedule of activities.
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 4 BGTS:  Temporarily interrupt study drug (but 
continue all assessments per schedule of activities) and implement MRI monitoring 
performed 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 and perform an MRI scan after the first dose for participants on Q4W 
regimen and after the second dose for participants on the Q2W regimen.
If no new ARIA-E is detected, resume uptitration and obtain an MRI scan per the 
titration schedule.  For participants on the Q2W regimen, perform another MRI 
scan 3 months after study drug reintroduction.

In exceptional cases of 1) an ARIA-E that is asymptomatic with BGTS 4 and that is 
considered stable over consecutive MRI images by the Sponsor and investigator; or 
2) symptomatic ARIA-E for which the imaging evidence of ARIA-E has resolved but 


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the CNS symptoms continue, the study drug can either be reintroduced or 
uptitrated, as applicable, and 4-weekly MRI monitoring may no longer be necessary,
as determined by the Sponsor and investigator.

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 15 ARIA-H cumulatively will be discontinued from study
drug (the cumulative number should not include any disseminated leptomeningeal 
hemosiderosis, i.e., up to 3 focal leptomeningeal hemosiderosis either on the same 
scan or cumulatively; a focal leptomeningeal hemosiderosis is counted as an ARIA-
H).

In cases where both ARIA-E and ARIA-H occur, the most conservative approach 
should be followed.

A PK sample and a plasma biomarker sample 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 ARIA-H that meet the discontinuation criteria.

The investigators may choose to perform additional MRI monitoring for ARIA at 
any time.

MRI monitoring of ARIA findings should be conducted at approximately 4-week 
intervals.

Any other new significant findings will be reviewed by the medical monitor and 
appropriate dose action will be taken.
The iDMC reviews the incidence of ARIA in an unblinded manner and may recommend 
adjustment of dosing regimen and/or ARIA management for the overall study population 
or for a specific APOE ε4 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 
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 


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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), except as described in 
Section 5.3.5.10

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to 
the Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
participant at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.12)

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; 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.


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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 
include the following:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy’s Law (see Section 5.3.5.8)

Suspected transmission of an infectious agent by the study drug, as defined below
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a participant exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected.
5.2.4
Selected Adverse Events 
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 Sections 5.45.6.
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). The investigator is also responsible for 
reporting medical device complaints (see Section 5.4.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each participant contact.  All 
adverse events, whether reported by the participant, the study partner, or noted by study 


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personnel, will be recorded in the participant’s medical record and on the Adverse Event 
eCRF.
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 
visit (including long-term follow-up visits).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all participant evaluation timepoints.  Examples of 
non-directive questions include the following:
“How have you felt since your last clinic visit?”
“Have you had any new or changed health problems since you were last here?” 


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5.3.3
Assessment of Severity of Adverse Events
Table 5 provides guidance for assessing adverse event severity.
Table 5
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether an adverse event is considered to be related to the study drug,
indicating “yes” or “no” accordingly.  The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction,
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the participant or use of concomitant medications known 
to increase the occurrence of the event

Presence of nontreatment-related factors that are known to be associated with the 
occurrence of the event
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
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., accompanied by CNS symptoms), and/or

ARIA findings that result in a change in study treatment (e.g., dosage modification,
treatment interruption, or treatment discontinuation), and/or


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
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).
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.


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
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.
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.


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


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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 5.3.5.2)
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.9
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  
This includes death attributed to progression of AD.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death.  The term “sudden death” should not 
be used unless combined with the presumed cause of death (e.g., “sudden cardiac 
death”).
If the death is attributed 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 because of disease progression, it should be reported as an adverse event.


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5.3.5.12
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

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
Adverse Events Associated with an Overdose or Error in 
Drug Administration
An overdose is the accidental or intentional use of a study drug in an amount higher than 
the dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, 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).
5.3.5.14
Clinical Outcome Assessment Data 
Adverse event reports will not be derived from clinical outcome assessment (COA) data 
by the Sponsor, and safety analyses will not be performed using COA data.  Sites are 
not expected to review the COA data for adverse events.


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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 
than 24 hours after becoming aware of the information).  New significant information 
includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor:
, MBBS, PhD (Primary)
Mobile Telephone No.:
Medical Monitor:
., MSc (Secondary)
Mobile Telephone No.:
To ensure the safety of study participants, an Emergency Medical Call Center Help Desk 
will access the Roche Medical Emergency List, escalate emergency medical calls,
provide medical translation service (if necessary), connect the investigator with a Roche 
Medical Responsible (listed above and/or on the Roche Medical Emergency List), and 
track all calls.  The Emergency Medical Call Center Help Desk will be available 24 hours 


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per day, 7 days per week.  Toll-free numbers for the Help Desk, as well as Medical 
Monitor and Medical Responsible contact information, will be distributed to all 
investigators.
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
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 Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
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 
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 Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur after the adverse event 
reporting period are provided in Section 5.6.


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5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Participants
Female participants of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 16 weeks after the last 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the participant, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the participant should continue until 
conclusion of the pregnancy.  Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF.  In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.  
5.4.3.2
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF,
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).  
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event,
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  A therapeutic 
or elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
5.4.3.3
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
study drug should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF, and reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
5.4.4
Reporting Requirements for Medical Device Complaints
The investigator must report all medical device complaints (e.g., devices for study drug 
administration) to the Sponsor.  The investigator should document as much information 
as possible on the IMP Deviation Form, including the product batch number, and forward 


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the form to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event) (refer to the pharmacy manual for further details).  If the medical device results in 
an adverse event to the study participant, the event must be reported on the Adverse 
Event eCRF and submitted through the EDC system.  If the event is serious, the 
Adverse Event eCRF must be completed immediately (i.e., no more than 24 hours after 
learning of the event), as outlined in Section 5.4.2.
5.5
FOLLOW-UP OF PARTICIPANTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the participant is lost to 
follow-up, or the participant withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the participant’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
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 
the participant’s last study visit), 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 Serious Adverse Event/Adverse Event of Special Interest Reporting 
Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES,
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 


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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 using the reference safety information in the 
documents listed below:
Drug
Document
Gantenerumab
Gantenerumab Investigator’s Brochure
[18F] Florbetaben (Neuraceq™)
[18F] Florbetaben Investigator’s Brochure
[18F] Flutemetamol (Vizamyl™)
[18F] Flutemetamol Investigator’s Brochure
[18F] Florbetapir (Amyvid™)
[18F] Florbetapir Investigator’s Brochure
[18F] GTP1 
[18F] GTP1 Investigator’s Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The purpose of this study is to investigate the treatment effect of gantenerumab relative 
to placebo.  The primary efficacy analysis will be based on an intent-to-treat (ITT)
population, which will include all randomized participants during the global enrollment 
phase, with participants grouped according to their randomly assigned treatment.
Approximately 1016 participants will be randomized in the global enrollment phase of 
this study.  An increase in sample size may be considered in case of changes to sample 
size assumptions based on blinded data review or factors external to the study.
If at least 1 participant is enrolled at sites in mainland China, Hong Kong, and Taiwan 
that are recognized by the NMPA during the global enrollment phase, additional 
participants may be enrolled in a China extension to ensure a total enrollment that is 
sufficient to support registration in the China.
The primary analyses of this study will include participants enrolled during the global 
enrollment phase; data from participants enrolled during the China extension will not be 
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Details of the planned statistical analyses mentioned below will be fully specified in a 
separate SAP, which will be finalized prior to the locking and unblinding of the study 
database.
6.1
DETERMINATION OF SAMPLE SIZE
Determination of sample size is based on participants enrolled in the global enrollment 
phase.  In this study, approximately 1016 participants will be enrolled and randomized in 
1:1 ratio to each treatment arm (gantenerumab or placebo) during the global enrollment 
phase.  A sample size increase may be considered if factors external to the study or 
blinded study data review would warrant a change to the sample size assumptions.
Additional participants may be randomized during the China extension if at least 
1 participant is enrolled at sites in mainland China, Hong Kong, and Taiwan that are 
recognized by the NMPA during the global enrollment phase.
The estimated sample size required to demonstrate efficacy with regard to CDR-SOB is 
based on the following assumptions:

The mean change in the CDR-SOB from baseline to Week 104 is 2.5 points in the 
placebo arm

A common standard deviation across treatment arms for change of approximately 
2.97 from baseline to Week 104 in the CDR-SOB 

Gantenerumab has a true effect of a 30% relative reduction in deterioration of 
CDR-SOB
Based on these assumptions, and using a student’s T-test with equal variance, a sample 
size was calculated for 90% power to detect a true treatment effect of 30% relative 
reduction in deterioration of CDR-SOB at a two-sided of 0.05.
Uncertainties on parameters affecting the power (e.g., dropout rate, study drug 
discontinuation rate, standard deviation, and placebo decline) were assumed to be 
equivalent to a drop-in sample size of up to around 35% and were corrected for 
accordingly. This calculation leads to a total of 1016 participants in the study.
At the date of writing Protocol Version 4, it is expected that participants would have 
missed an average of 8 weeks of study drug administration over the course of the 
original 2-year study due to the COVID-19 pandemic. This has the potential to decrease 
the power of the study from ~90% to ~80%. To mitigate the impact of missed 
administrations, the double-blind treatment period was extended by 12 weeks.  Under 
current assumptions, this brings the study power back to the originally planned ~90%.
The sample size may be increased from 1016 up to 1322 participants (661 participants 
per arm). The decision whether to increase sample size will be based on blinded study 
data review, e.g., by a review of the frequency of missed study drug administrations due 
to the COVID-19 pandemic. Further details will be described in the SAP.  The 


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assessment will be performed by the Sponsor at a specified timepoint.  The sponsor will 
remain blinded. The sample size will not be reduced on the basis of this assessment.  
Other factors external to the study may also trigger a decision to increase sample size.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, participant disposition, and incidence of protocol deviations will be 
summarized for the ITT population according to the randomly assigned treatment arms.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (such as age, sex, race, disease stage,
APOE 4 status, use, and non-use of background therapy for AD) will be summarized 
descriptively for the ITT population, grouped according to the assigned treatment arm.
Descriptive summaries of continuous data will present the mean, standard deviation,
median, and minimum and maximum.  Descriptive summaries of discrete data will 
include frequencies expressed in terms of number and percentage of participants.
6.4
EFFICACY ANALYSES
The primary and secondary efficacy analyses will use the ITT population, with 
participants grouped according to the treatment assigned at randomization.
6.4.1
Primary Efficacy Endpoint
The primary efficacy outcome measure is the change in CDR-SOB from baseline 
(Day 1) to Week 116. In the case where the double-blind treatment period is extended 
for an additional 12 weeks, the primary efficacy outcome measure will be the change in 
CDR-SOB from baseline (Day 1) to Week 128. 
The clinical question of interest is to assess the study treatment effect on disease 
progression up to Week 116 (or Week 128, if applicable), irrespective of use or initiation 
of symptomatic treatments for AD, in the absence of the COVID-19 pandemic.
In accordance with the estimand framework outlined in the ICH-E9 addendum (EMA 
2018), the attributes of the estimand for the primary endpoint are defined as follows:

Population: early (prodromal to mild) AD population including all randomized 
participants.

Variable: change from baseline at Week 116 (or Week 128) in the CDR-SOB
o
Treatment: prescribed study drug including uptitration to the target 
dose, irrespective of use or initiation of symptomatic treatment for AD.

Intercurrent events (ICE): the list of ICE will be defined in the SAP, this includes:
o
Treatment discontinued for study drug or conditionrelated (SDCR) 
reasons (e.g., treatment-related adverse event or lack of efficacy):


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o
Treatment discontinued for non-SDCR (NSDCR) reasons (e.g. purely 
administrative reason)

Population level summary: mean change from baseline to Week 116 (or Week 128, 
as appropriate) between gantenerumab-treated participants and placebo-treated 
participants.
The primary estimand is a combination of a treatment-policy strategy and a 
hypothetical strategy (FDA 2017) to account for the different assumptions for each type 
of ICE, SDCR or NSDCR.
Full details of the primary estimand, and of the corresponding estimator and estimation 
methods (e.g. statistical model, multiple imputation for missing or excluded data 
points) will be provided in the SAP. Supplementary estimands may also be considered 
and will be defined in the SAP.
Every effort will be made to minimize missing data. Furthermore, the Sponsor has made 
every effort to expedite the implementation of the 12 week extension to the double-blind 
treatment period. If the study is extended by an additional 12 weeks (for a total 
extension of 24 weeks), the number of patients in scenario 1 (who will have missing 
Week 128 efficacy data) will be minimized.
Participants who discontinue early from study treatment will be asked to return for 
collection of safety and limited efficacy data (i.e., the primary and secondary efficacy 
endpoints) until the end of the double-blind treatment period and follow-up visits.
Descriptive summaries of the number of participants with missing data, the number of 
participants in each scenario, the timing, and reasons for discontinuation from the study 
will also be provided by treatment group.
Additional details will be documented in the SAP.
6.4.2
Secondary Efficacy Endpoints
The absolute change from baseline in the continuous secondary efficacy endpoints listed 
in Section 2, Table 2 (including cognition/function endpoints, global endpoints, disease 
pathology biomarkers, and endpoints measuring other AD symptoms and effects) will be 
analysed using an approach similar to that described above for the primary efficacy 
endpoint.
In order to protect the overall type I error rate for the study when incorporating the 
hypothesis testing of the primary endpoint and secondary endpoints into the analysis,
the fixed sequence testing procedure (Westfall and Krishen 2001) will be used to adjust 
for multiple comparisons.  The first endpoint that will be tested is:

Change from baseline to Week 116 in CDR-SOB


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In the case where the double-blind treatment period is extended for an additional 
12 weeks, the primary efficacy outcome measure will be the change in CDR-SOB from 
baseline (Day 1) to Week 128.  
The order of testing for other secondary endpoints will be defined in the SAP.
The treatment difference in the primary endpoint (the change from baseline to Week 116
in the CDR-SOB) will be tested at a two-sided 5% overall significance level.  If this test 
result is statistically significant, the secondary endpoints will be tested for significance in 
the predefined order as specified in the SAP.  If any test result is not statistically 
significant, testing of the subsequent endpoints will not occur.
6.4.3
Exploratory Efficacy Analyses
Subgroup analysis of efficacy results will be performed for subgroups defined by age,
sex, race, stage of disease (prodromal AD vs. mild AD), APOE 4 status, geographic 
region, use and non-use of background therapies for AD, and other clinically relevant 
factors at baseline.
The efficacy endpoints collected during the Study WN39658 open-label treatment phase 
and during Study WN42171 may be combined with data from the Study WN39658
double-blind treatment phase in order to evaluate change from baseline beyond the end 
of the double-blind treatment period and to evaluate the effect of a delayed start of 
treatment with gantenerumab.
6.4.4
Pharmacodynamic and Exploratory Biomarker Analyses
PD and exploratory biomarker endpoints will be analysed using descriptive statistics,
subgroup analysis, or statistical models if appropriate.  For longitudinally measured 
endpoints, the change from baseline and the difference between participants 
randomized to gantenerumab and participants randomized to placebo will be estimated if 
appropriate.  
Prior to the completion of the study, a separate PD cutoff date may be established to 
allow expedient sample analyses and early access by third party vendors.
Exploratory biomarkers may be reported separately.
6.5
SAFETY ANALYSES
The safety-analysis population will include all randomized participants who receive at 
least one dose of study drug, with participants grouped according to the treatment 
actually received, as defined in the SAP.

Incidence, nature, and severity of MRI safety findings:  ARIA-E and ARIA-H

Incidence, nature, severity, and timing of injection-site reactions

Incidence, nature, and severity of serious adverse events

Incidence, nature, and severity of adverse events


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
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 CSSR-S 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 
Prior to completion of the study a separate ADA cutoff date may be established to allow 
expedient samples analyses and early access by third party vendors. The ADA cutoff 
date will be applied when there is sufficient ADA sample data available to adequately 
assess immunogenicity.
6.6
PHARMACOKINETIC ANALYSES 
Plasma concentration data for gantenerumab may be tabulated and summarized.  
Descriptive summary statistics will include the arithmetic mean, median, range, SD, 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 analyse the dose 
concentrationtime data of gantenerumab.  Information from other clinical studies may 
be incorporated to establish the PK model.  The selection of parameters and the 
derivation of individual measures of exposure, such as AUC, Cmax, and trough serum 
concentration, will depend on the final PK model used for this analysis.
The influence of background medication on the pharmacokinetics of gantenerumab will 
be explored and, if appropriate, concentrationeffect relationships may be assessed 
post hoc for PD, efficacy, or safety measures.
The results of this modeling analysis may be reported separately from the clinical study 
report.
CSF concentrations of gantenerumab may be tabulated and summarized as appropriate.
Prior to completion of the study a separate PK cutoff date may be established to allow 
expedient sample analyses and early access by third party vendors. The PK cutoff date 
will be applied when there is sufficient PK sample data available to adequately 
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Additional PK analyses will be conducted as appropriate and may be reported separately 
from the clinical study report.
6.7
INTERIM ANALYSIS
6.7.1
Optional Futility Analysis
The Sponsor may perform an interim analysis for futility approximately 116 weeks after 
50% of the targeted study enrollment has been reached. If the study is extended by an 
additional 12 weeks, the interim analysis will be performed approximately 128 weeks
after 50% of the targeted study enrollment has been reached. The exact timing of an 
interim analysis may be synchronized with Study WN29922.
An independent data coordinating center will be responsible for the interim analyses. 
The study results will only be reviewed by the iDMC and the Sponsor will remain blinded.
Other third party vendors may be involved in data preparation and analyses, as 
appropriate.
The iDMC may recommend stop for futility if the failure criterion is met.  The failure 
criterion will represent a low probability of a positive study outcome given the data 
observed at the time of interim analysis. If the futility criteria are not met, the study 
continues beyond the interim analysis. The failure criterion will be pre-specified in the 
iSAP.
In contrast, the iDMC may “declare the study positive for overwhelming efficacy” if the 
study meets the success criterion on the primary endpoint.  The success criterion is 
defined as the p-value threshold determined by standard Lan and DeMets methodology 
(1983) for group sequential design using the O’Brien-Fleming boundary function.  If the 
study continues beyond the interim analysis, the critical value at the final analysis will be 
adjusted accordingly.
Details of the futility analysis, including the final decision to conduct it, the rationale, 
timing, and statistical details for the analyses (such as the data that would be reviewed 
by the iDMC and futility thresholds) will be documented in the iSAP. This will be 
submitted to relevant health authorities at least 2 months prior to the conduct of the 
interim analysis.
6.7.2
Optional Interim Analyses
Based on availability of information pertaining to gantenerumab or other compounds with 
similar mode of action that may emerge during the course of this study, the Sponsor may 
choose to conduct an additional interim analysis, which may include efficacy, safety and 
biomarker outcomes including amyloid PET SUVr and/or other biomarkers to confirm 
PD effect. This analysis may be done on a whole study population or in a well 
predefined subgroup when approximately 50% of the overall population has reached 


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Week 116. If the study is extended by an additional 12 weeks, the interim analysis will 
be performed once approximately 50% of the overall population has reached Week 128.
An independent data coordinating center will be responsible for the interim analyses. 
The study results will only be reviewed by the iDMC and the Sponsor will remain blinded.
Other third party vendors may be involved in data preparation and analyses, as 
appropriate.
The iDMC may indicate that a pre-specified success criterion has been met. If so, the 
Sponsor may decide to present the data to a health authority. Any interim, unblinded 
data will be strictly firewalled to ensure those involved in the conduct of the ongoing 
trial and the WN42171 OLE trial remain fully blinded. If needed, appropriate measures 
will be taken to control the overall Type I error rate and described in the SAP.
Details of the interim analyses, including the decision to conduct the optional interim 
analyses, the rationale, timing, and statistical details for the analyses (such as the data 
that would be reviewed by the iDMC and efficacy thresholds) will be documented in an
iSAP, and the iSAP will be submitted to relevant health authorities at least 2 months 
prior to the conduct of the interim analysis.
6.8
CHINA EXTENSION ANALYSIS
The objective of the China extension and the China subpopulation analyses is to assess 
the treatment effects of gantenerumab in a population of participants enrolled at sites in
mainland China, Hong Kong, and Taiwan that are recognized by the NMPA and to 
investigate the consistency in treatment effect between the China subpopulation and the 
global population for the purpose of registration in China.
All participants enrolled in the global enrollment phase in China will be included in the 
primary analysis.  The analysis of the China extension will be conducted after the end of 
China extension and will be reported separately from the primary analysis and at a 
subsequent point in time. Details will be provided in the SAP.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  All electronic data from external vendors 


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will be sent directly to the Sponsor, using the Sponsor’s standard procedures to handle 
and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
COA data will be collected through the use of an electronic device (tablet) provided by a 
vendor.  Some COA data may be audio recorded for quality assurance purposes.  The 
device is designed for entry of data in a way that is attributable, secure, and accurate, in 
compliance with U.S. FDA regulations for electronic records (21 CFR, Part 11).  
The electronic data are available for view access only via secure access to an online 
Web portal.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 
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 
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.  
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.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive participant data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC CLINICAL OUTCOME DATA
Participants, study partners, and appropriate site staff will use an electronic device 
(tablet) to capture COA.  For some COA, audio recordings may be used for quality 
assurance purposes.  All data will be transmitted via Web automatically after entry into a 
centralized database maintained by the electronic device vendor.
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 on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.


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7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification 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.
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, 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 COA data, Informed Consent Forms, laboratory test 
results, and medication inventory records, must be retained by the Principal Investigator 
for at least 15 years after completion or discontinuation of the study or for the length of 


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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.
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 laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S.
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed 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.


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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to participate.  The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes.
Participants must be re-consented to the most current version of the Consent Forms (or 
to a significant new information/findings addendum in accordance with applicable laws 
and IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each participant shall document 
the informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the participant or the 
participant’s legally authorized representative.  All signed and dated Consent Forms 
must remain in each participant’s study file or in the site file and must be available for 
verification by study monitors at any time.
For sites in the United States, each Consent Form may also include participant
authorization to allow use and disclosure of personal health information in compliance 
with the U.S. Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the 
site utilizes a separate Authorization Form for participant authorization for use and 
disclosure of personal health information under the HIPAA regulations, the review,
approval, and other processes outlined above apply except that IRB review and approval 
may not be required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the 
participant, and relevant supporting information must be submitted to the IRB/EC by the 
Principal Investigator and reviewed and approved by the IRB/EC before the study is 
initiated.  In addition, any participant recruitment materials must be approved by the 
IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
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 


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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.
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.
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.
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 (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the participant data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on participant safety 
and data integrity to the Sponsor and to the IRB/EC in accordance with established 


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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
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ 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.
9.4
ADMINISTRATIVE STRUCTURE
The overall procedures for quality assurance of clinical study data are described in the 
Roche standard operating procedures.  This study will be sponsored by F. Hoffmann-La 
Roche Ltd. Roche will provide clinical operations oversight, site monitoring and 
management, data management support, and medical monitoring.
Study drug distribution may occur through an IxRS (see Section 4.2).  Central facilities 
may be used for study assessments (i.e., ECG, lumbar puncture, specified laboratory 
tests, PK, rating scales, and MRI and PET imaging, as applicable).
9.5
PUBLICATION OF DATA AND PROTECTION OF 
TRADE SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
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.


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146/Protocol WN39658, Version 5
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.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Schedule of Activities
Table 1:  Week 12 to Week 32; Dose Escalation with Q4W Administration
Assessment/Procedure
Prescreen 
&
Screening
Baseline
Dose Escalation Period
Unsched 
Visit
Weeks
12 to 1
Day 
1
Day 
4
Wk 
4
Wk 
8
Wk
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Dose Number
1 a
2
3
4
5 b
6 b
7 a
8 b
9 b
Dose level in milligrams (mg)
120
120
120
255
255
255
510
510
510
Informed consent(s) c
x
Review of inclusion and exclusion criteria
x
B
Medical history, personal status, and demographics
x
Weight and height t
x
x
x
x
Clinical genotyping samples
x
Clinical RNA samples
x
Urinalysis d
x
Urine sample for drugs of abuse e
x
Coagulation (PT)
x
Viral serology (HIV, hepatitis B, and hepatitis C)
x
FCSRT
P f
12-Lead electrocardiogram g
x
B
B
B
x
PK plasma sample h, v
B
x
B
x
ADA sample
B
B
x
Serum chemistry I and 
hematology j
x
B
B
x
Plasma biomarker sample u
x
B
x 
Complete physical examination (includes 
neurological systems) k
x
x


Appendix 1:  Schedule of Activities (cont.)
Table 1:  Week 12 to Week 32; Dose Escalation with Q4W Administration (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
157/Protocol WN39658, Version 5
Assessment/Procedure
Prescreen 
&
Screening
Baseline
Dose Escalation Period
Unsched 
Visit
Weeks
12 to 1
Day 
1
Day 
4
Wk 
4
Wk 
8
Wk
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Dose Number
1 a
2
3
4
5 b
6 b
7 a
8 b
9 b
Dose level in milligrams (mg)
120
120
120
255
255
255
510
510
510
Limited physical examination l
B
x
MRI scan m, n
x o
B
B
x
CSF and matching serum sampling m, p or PET scan
m, p
x
CDR 
P&SP
P&SP
P&S
P
P&SP
ADAS-Cog13
P
P
P
Verbal Fluency Task
P
P
P
Coding
P
P
P
ADCS-ADL
SP
SP
SP
FAQ
SP
SP
SP
MMSE
P f
P
P
P
EQ-5D
SP
SP
SP
QoL-AD
P&SP
P&S
P
P&SP
ZCI-AD
SP
SP
SP
RUD-Lite
SP
SP
SP
NPI-Q
SP
SP
SP
C-SSRS BL/SLV
P
P
P
Vital signs q
x
B
B
B
B
B
B
B
B
B
B
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
Urine pregnancy test r
x
B
B
B
B
B
B
B
B
B
x
Study drug administration h, s
x
x
x
x
x
x
x
x
x


Appendix 1:  Schedule of Activities (cont.)
Table 1:  Week 12 to Week 32; Dose Escalation with Q4W Administration (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
158/Protocol WN39658, Version 5
ADAS-Cog13Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL Alzheimer Disease Cooperative Study GroupActivities of Daily 
Living; CDR Clinical Dementia Rating; CSF cerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor imaging; EQ-
5D EuroQol-Five Dimensions;  FAQ Functional Activities Questionnaire; FCSRTFree and Cued Selective Reminding Test; MMSE Mini-Mental State 
Examination; MRImagnetic resonance imaging; NPI-Q Neuropsychiatric InventoryQuestionnaire; PETpositron emission tomography; 
PK pharmacokinetic; Prescreen prescreening; Q4W every 4 weeks; QoL-AD Quality of LifeAlzheimer's Disease; RBRResearch Biosample 
Repository; RUD-Lite Resource Utilization in DementiaLite; SC subcutaneous; Unsched unscheduled; Wkweek; ZCI-AD Zarit Caregiver 
InterviewAlzheimer’s Disease.
B before study drug administration; P participant completion; P&SP participant and study partner completion; SPstudy partner completion.
Notes:  The visit window is 7 days for dosing days and 3 days for non-dosing Day 4.  For Q4W injections, the recommended minimum time between doses 
is 3 weeks.  The maximum recommended time between doses should not exceed 6 weeks.  Participants should return to initial planned schedule per 
randomization for subsequent visits.  
In case of rescreening a participant, all screening assessments must be repeated other than the lumbar puncture and amyloid PET testing if performed within 
the previous 12 months for this study and are within the eligible ranges.  In addition, clinical genotyping will not need to be repeated in case of rescreening.  
a
Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first, and within 1 week prior to the first dose at 
baseline.  All safety assessments (e.g., vital signs, blood tests, and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and 
functional assessments should be performed at the visit time points stipulated in the schedule of activities.  However, in exceptional circumstances, for post-
randomization visits, if the caregiver, the primary rater or even the participant cannot perform these assessments as per schedule of activities, they may be 
performed up to 4 weeks out of window. 
b
Visit suitable for home administration of gantenerumab.
c
Participants in the optional prescreening period must provide written consent before any study-specific prescreening assessments are performed.  If 
participant is eligible and decides to participate in the screening assessments, he or she will need to provide new written consent.
d
Performed at the site by dipstick for blood, protein, glucose, and pH.
e
Urine samples will be analyzed for the presence of the following drugs:  amphetamine, benzodiazepines, cannabinoids, opiates, cocaine, barbiturates, 
and methadone.
f
Can be done at prescreening or at screening.  There is no need to repeat the test at screening if performed at prescreening.
g
Electrocardiograph machine equipped with computer-based interval measurements.  Lead placement should be as consistent as possible.  ECG recordings 
must be performed after the participant has been resting in a supine position for at least 5 minutes.  All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws, brain MRI scans, and lumbar puncture).  Circumstances that may induce changes 
in heart rate, including environmental distractions (e.g., television, radio, conversation), should be avoided during the pre-ECG resting period and during 
ECG recording.
h
Accurate recording of the date and time of study drug administration and PK sampling is critical.


Appendix 1:  Schedule of Activities (cont.)
Table 1:  Week 12 to Week 32; Dose Escalation with Q4W Administration (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
159/Protocol WN39658, Version 5
i
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 1 to Week –12), 
hemoglobin A1C, glucose, insulin, total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating 
hormone levels will also be assessed and should ideally be collected at least 4 hours after meals.
j
Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelets, basophils, eosinophils, lymphocytes, monocytes, 
neutrophils, and WBC–other total counts.
k
A complete physical examination includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.
l
Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
m CSF and matching serum sampling, and PET and MRI scans at screening should be performed once all other screening results are available and none 
exclude the participant from the study.
n
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  It is not 
recommended that the MRI be performed on the same day as the IMP administration (especially during uptitration period during which it is recommended to 
do the MRI at least 10 days after the third dose of sing step).  MRI should be performed before or at least 3 days following a lumbar puncture.
o
Includes resting-state functional MRI and DTI outcome measures where available.
p
Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters. For 
post-baseline visits, lumbar puncture as well as serum sampling should be performed prior to dosing.  Only one method (CSF or PET) confirming amyloid is 
necessary for all participants.
q
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.
r
Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded 
only in the source documents.
s
Study drug administration should be performed only after all assessments/rating scales for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by SC injection.  Participants should be observed up to 2 hours after dosing.  After the fourth injection visit, 
the observation time may be reduced to 1 hour.  Study personnel preparing and administering study drug must not be involved with any efficacy 
assessments or safety evaluations.
t
Height measured at screening only.
u
A plasma biomarker sample 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 of the occurrence of ARIA-H meeting discontinuation criteria.
v
A plasma PK sample 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 of the occurrence of ARIA-H meeting discontinuation criteria.


Gantenerumab—F. Hoffmann-La Roche Ltd
160/Protocol WN39658, Version 5
Appendix 1
Schedule of Activities (cont.)
Table 2:  Week 36 to the End of Study:  510 mg Q2W
Assessment/Procedure
Only for 
Participants Who 
Have Completed 
Week 104 when 
the 12 week 
study extension 
is Implemented
Early 
Term
Visit a
Unsched
Visit
Treatment Period
Final Efficacy 
and Safety 
Assessments
Follow-Up Period 
for Participants 
Not Enrolling in 
the OLE
Wk
36
Wk 
38
Wk 
40
Wk 
41
Wk
4250
Wk
52
Wk
5474
Wk 
76
Wk
78102
Wk 
103
Wk 
104 a, b
Wk 
116
Wk 
152
Dose number
10
11
12
1317
c
18 a
1929
c
30 a
3143 c
Dose level in 
milligrams (mg)
510
510
510
510
510
510
510
510
12-Lead ECG
B
B
x
x
x
x
PK plasma sample d
x 
(Site 
visit)
B
B
x
(Site 
visit)
x
x
x
x
ADA sample
B
B
x
x
x
x
Clinical RNA sample
x
x
Serum chemistry e and 
hematology f
B
B
x
x
x
x
x
Plasma biomarker 
sample o
B
x
x
x
Complete physical 
examination (including 
neurological systems) g
x
x
x
Limited physical 
examination h
B
B
x
Weight
x
x
x
x
x
x
x


Appendix 1:  Schedule of Activities (cont.)
Table 2:  Week 36 to the End of Study:  510 mg Q2W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
161/Protocol WN39658, Version 5
Assessment/Procedure
Only for 
Participants Who 
Have Completed 
Week 104 when 
the 12 week 
study extension 
is Implemented
Early 
Term
Visit a
Unsched
Visit
Treatment Period
Final Efficacy 
and Safety 
Assessments
Follow-Up Period 
for Participants 
Not Enrolling in 
the OLE
Wk
36
Wk 
38
Wk 
40
Wk 
41
Wk
4250
Wk
52
Wk
5474
Wk 
76
Wk
78102
Wk 
103
Wk 
104 a, b
Wk 
116
Wk 
152
Dose number
10
11
12
1317
c
18 a
1929
c
30 a
3143 c
Dose level in 
milligrams (mg)
510
510
510
510
510
510
510
510
MRI scan i
B
Wk 
48 j
Wk 
60
B
x j
x j
x
CSF k and matching 
serum sampling (for 
participants enrolled 
based on CSF eligibility 
criteria only)
x
x
x k
CDR
P&S
P
P&S
P
P&SP
P&SP
P&SP
P&SP
ADAS-Cog13
P
P
P
P
P
P
Verbal Fluency Task
P
P
P
P
P
P
Coding
P
P
P
P
P
P
ADCS-ADL
SP
SP
SP
SP
SP
SP
FAQ
SP
SP
SP
SP
SP
SP
MMSE
P
P
P
P
P
P
EQ-5D
SP
SP
SP
SP
SP
QOL-AD
P&S
P
P&S
P
P&SP
P&SP
P&SP
ZCI-AD
SP
SP
SP
SP
SP
RUD-Lite
SP
SP
SP
SP
SP


Appendix 1:  Schedule of Activities (cont.)
Table 2:  Week 36 to the End of Study:  510 mg Q2W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
162/Protocol WN39658, Version 5
Assessment/Procedure
Only for 
Participants Who 
Have Completed 
Week 104 when 
the 12 week 
study extension 
is Implemented
Early 
Term
Visit a
Unsched
Visit
Treatment Period
Final Efficacy 
and Safety 
Assessments
Follow-Up Period 
for Participants 
Not Enrolling in 
the OLE
Wk
36
Wk 
38
Wk 
40
Wk 
41
Wk
4250
Wk
52
Wk
5474
Wk 
76
Wk
78102
Wk 
103
Wk 
104 a, b
Wk 
116
Wk 
152
Dose number
10
11
12
1317
c
18 a
1929
c
30 a
3143 c
Dose level in 
milligrams (mg)
510
510
510
510
510
510
510
510
NPI-Q
SP
SP
SP
SP
SP
C-SSRS BL/SLV
P
P
P
P
P
Vital signs l
B
B
B
B
B
B
B
B
x
x
x
x
x
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine pregnancy test m
B
B
B
B
B
B
B
B
x
x
x
x
Study drug 
administration d, n
x
x
x
x
x
x
x
x
ADAS-Cog13Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL Alzheimer Disease Cooperative Study GroupActivities of Daily 
Living; CDR Clinical Dementia Rating; CSF cerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor imaging; 
EQ-5D EuroQol-Five Dimensions; FAQ Functional Activities Questionnaire; FCSRTFree and Cued Selective Reminding Test; MMSE Mini-Mental State 
Examination; MRImagnetic resonance imaging; NPI-Q Neuropsychiatric InventoryQuestionnaire; OLEopen-label extension; PETpositron emission 
tomography; PKpharmacokinetic; Q2W every 2 weeks; QoL-AD Quality of LifeAlzheimer’s Disease; RBRResearch Biosample Repository;
RUD-Lite Resource Utilization in DementiaLite; SC subcutaneous; Unsched unscheduled; Wk week; ZCI-ADZarit Caregiver InterviewAlzheimer’s 
Disease.
B before study drug administration; P participant completion; P&SPparticipant and study partner completion; SPstudy partner. 


Appendix 1:  Schedule of Activities (cont.)
Table 2:  Week 36 to the End of Study:  510 mg Q2W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
163/Protocol WN39658, Version 5
Notes:  The visit window is 3 days for dosing days and 3 days for Week 41 and Week 103 non-dosing days.  For Q2W injections, the recommendation is not to 
administer more than 1020 mg (i.e., 2 times 510 mg Q2W) within 28 days.  Participants should return to initial planned schedule per randomization for subsequent 
visits. 
a
Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vitals, blood tests, 
and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments should be performed at the visit time points 
stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the primary rater, or even the participant cannot perform these 
assessments as per schedule of activities, they may be performed up to 4 weeks out of window.
b
Transition to OLE study for participants who are eligible to participate.
c
Visit suitable for home administration of gantenerumab.
d
Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtained as soon as is practical (e.g., at 
an unscheduled visit) once the site becomes aware of the occurrence or worsening of ARIA-E or of the occurrence of ARIA-H meeting discontinuation criteria
e
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).  At Week 52 and Week 104, hemoglobin A1C, glucose, insulin, total 
cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed and 
should ideally be collected at least 4 hours after meals.
f
Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and 
WBC–other total counts. 
g
A complete physical examination includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary (optional), and neurological systems.
h
Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI should be 
performed before or at least 3 days following a lumbar puncture.
j
Includes resting-state functional MRI and DTI outcome measures, where available.
k
Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters and should be 
performed prior to dosing.  For participants enrolling based on CSF eligibility criteria, CSF and matching serum samples are optional at Week 76.  Lumbar 
puncture does not have to be performed the same day as the main Week 76 visit or Week 104 visit, but should be performed in a reasonable time around these 
visits.  The need for CSF collection at early termination visit should be determined on a case-by-case basis, based on the participant's condition and the time 
since last lumbar puncture and advice by the Medical Monitor may be sought.


Appendix 1:  Schedule of Activities (cont.)
Table 2:  Week 36 to the End of Study:  510 mg Q2W (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
164/Protocol WN39658, Version 5
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 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 Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in 
the source documents.
n
Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by subcutaneous injection (full details are provided in the pharmacy manual).  Participants should be observed for 
up to 2 hours after dosing.  After the fourth injection visit, this observation time may be reduced to 1 hour.  Study personnel preparing and administering study 
drug must not be involved with any efficacy assessments or safety evaluations. 
o
A plasma biomarker sample 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 of the occurrence of ARIA-H meeting discontinuation criteria.


Gantenerumab—F. Hoffmann-La Roche Ltd
165/Protocol WN39658, Version 5
Appendix 1
Schedule of Activities (cont.)
Table 3:  Scenario 1 / Week 104 to the End of Study:  510 mg Q2W
(3-Month Extension)
Assessment/Procedure
Treatment Period
Final Safety 
and 
Efficacy 
Assessmen
t
Follow-Up Period for 
Participants 
Not Enrolling in the OLE
Early
Term 
Visit a
Unsched 
Visit
Wk
104 a
Wk 
106-114 c
Wk 
115
Wk 
116 a, b
Wk
128
Wk 
164
Dose number
44
45-49
Dose level in 
milligrams (mg)
510
510
12-Lead ECG
x
x
x
x
x
PK plasma sample d
x (site visit)
x
x
x
x
ADA sample
x
x
x
x
Clinical RNA sample
x
x
x
Serum chemistry e and 
hematology f
x
x
x
x
x
x
Plasma biomarker sample o
x
x
x
x
Complete physical examination 
(including neurological systems)
g
x
x
x
Limited physical 
examination h
x
x
Weight
x
x
x
x
x
x
MRI scan i
x j
x j
x j
x


Appendix 1:  Schedule of Activities (cont.)
Table 3:  Scenario 1 / Week 104 to the End of Study:  510 mg Q2W (3-Month Extension)
Gantenerumab—F. Hoffmann-La Roche Ltd
166/Protocol WN39658, Version 5
Assessment/Procedure
Treatment Period
Final Safety 
and 
Efficacy 
Assessmen
t
Follow-Up Period for 
Participants 
Not Enrolling in the OLE
Early
Term 
Visit a
Unsched 
Visit
Wk
104 a
Wk 
106-114 c
Wk 
115
Wk 
116 a, b
Wk
128
Wk 
164
Dose number
44
45-49
Dose level in 
milligrams (mg)
510
510
CSF k and matching serum 
sampling (for participants 
enrolled based on CSF eligibility 
criteria only)
x
x k
CDR
P&SP
P&SP
P&SP
P&SP
P&SP
ADAS-Cog13
P
P
P
P
P
Verbal Fluency Task
P
P
P
P
P
Coding
P
P
P
P
P
ADCS-ADL
SP
SP
SP
SP
SP
FAQ
SP
SP
SP
SP
SP
MMSE
P
P
P
P
P
EQ-5D
SP
SP
SP
SP
QOL-AD
P&SP
P&SP
P&SP
P&SP
ZCI-AD
SP
SP
SP
SP
RUD-Lite
SP
SP
SP
SP
NPI-Q
SP
SP
SP
SP
C-SSRS BL/SLV
P
P
P
P
Vital signs l
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
Urine pregnancy test m
x
x
x
x
x
x
Study drug administration d, n
x
x


Appendix 1:  Schedule of Activities (cont.)
Table 3:  Scenario 1 / Week 104 to the End of Study:  510 mg Q2W (3-Month Extension)
Gantenerumab—F. Hoffmann-La Roche Ltd
167/Protocol WN39658, Version 5
ADAS-Cog13Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL Alzheimer Disease Cooperative Study GroupActivities of Daily 
Living; CDR Clinical Dementia Rating; CSF cerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor imaging; 
EQ-5D EuroQol-Five Dimensions; FAQ Functional Activities Questionnaire; FCSRTFree and Cued Selective Reminding Test; MMSE Mini-Mental State 
Examination; MRImagnetic resonance imaging; NPI-Q Neuropsychiatric InventoryQuestionnaire; OLEopen-label extension; PETpositron emission 
tomography; PKpharmacokinetic; Q2W every 2 weeks; QoL-AD Quality of LifeAlzheimer’s Disease; RBRResearch Biosample Repository;
RUD-Lite Resource Utilization in DementiaLite; SC subcutaneous; Unsched unscheduled; Wk week; ZCI-ADZarit Caregiver InterviewAlzheimer’s 
Disease.
B before study drug administration; P participant completion; P&SPparticipant and study partner completion; SPstudy partner.
Notes:  The visit window is 3 days for dosing days and 3 days for Week 115 non-dosing days.  For Q2W injections, the recommendation is not to administer 
more than 1020 mg (i.e., 2 times 510 mg Q2W) within 28 days.  Participants should return to initial planned schedule per randomization for subsequent visits. 
SoA from Week 12 to Week 103 for scenario 1 is described in Appendix 1, Table 1 and Table 2. 
a
Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vitals, blood tests, 
and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments should be performed at the visit time points 
stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the primary rater, or even the participant cannot perform these 
assessments as per schedule of activities, they may be performed up to 4 weeks out of window.
b
Transition to OLE study for participants who are eligible to participate.
c
Visit suitable for home administration of gantenerumab. 
d
Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtained as soon as is practical (e.g., at an 
unscheduled visit) once the site becomes aware of the occurrence or worsening of ARIA-E or of the occurrence of ARIA-H meeting discontinuation criteria.
e
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).  At Week 104 and Week 116, hemoglobin A1C, glucose, insulin, total 
cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed and 
should ideally be collected at least 4 hours after meals.
f
Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and 
WBC–other total counts. 
g
A complete physical examination includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.
h
Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI should be performed 
before or at least 3 days following a lumbar puncture.
j
Includes resting-state functional MRI and DTI outcome measures, where available.
k
Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters and should be 
performed prior to dosing.  For participants enrolling based on CSF eligibility criteria, CSF and matching serum samples are optional at Week 76 ; lumbar 


Appendix 1:  Schedule of Activities (cont.)
Table 3:  Scenario 1 / Week 104 to the End of Study:  510 mg Q2W (3-Month Extension)
Gantenerumab—F. Hoffmann-La Roche Ltd
168/Protocol WN39658, Version 5
puncture does not have to be performed the day of Week 76 or Week 116 visit, but should be performed in a reasonable time around these visits; the need of 
CSF collection at early termination visit should be determined on a case-by-case basis, based on the participant's condition and the time since last lumbar 
puncture and advice by the Medical Monitor may be sought. 
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 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 Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in 
the source documents.
n
Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by subcutaneous injection (full details are provided in the pharmacy manual).  Participants should be observed for 
about 1 hour after dosing.  Study personnel preparing and administering study drug must not be involved with any efficacy assessments or safety evaluations.
o
A plasma biomarker sample 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 of the occurrence of ARIA-H meeting discontinuation criteria


Gantenerumab—F. Hoffmann-La Roche Ltd
169/Protocol WN39658, Version 5
Appendix 1
Schedule of Activities (cont.)
Table 4:  Scenario 2 / Week 104 to the End of Study:  510 mg Q2W 
(Additional 3-Month Extension)
Assessment/Procedure
Treatment Period
Final Safety 
and Efficacy 
Assessment
Follow-Up Period for 
Participants 
Not Enrolling in the OLE
Early
Term 
Visit a
Unsched 
Visit
Wk
104a
Wk 106-126c
Wk 
127
Wk 
128a, b
Wk
140
Wk 
176
Dose number
44
45-55
Dose level in 
milligrams (mg)
510
510
12-Lead ECG
x
x
x
x
x
PK plasma sample d
x (site 
visit)
x
x
x
x
ADA sample
x
x
x
x
Clinical RNA sample
x
x
x
Serum chemistry e and 
hematology f
x
x
x
x
x
x
Plasma biomarker sample o
x
x
x
x
Complete physical examination 
(including neurological systems) g
x
x
x
Limited physical 
examination h
x
x
Weight
x
x
x
x
x
x
MRI scan i
x j
x j
x j
x
CSF k and matching serum sampling 
(for participants enrolled based on 
CSF eligibility criteria only)
x
x k
CDR
P&SP
P&SP
P&SP
P&SP
P&SP
ADAS-Cog13
P
P
P
P
P


Appendix 1:  Schedule of Activities (cont.)
Table 4:  Scenario 2 Only Week 104 to the End of Study:  510 mg Q2W (Additional 3-Month Extension)
Gantenerumab—F. Hoffmann-La Roche Ltd
170/Protocol WN39658, Version 5
Assessment/Procedure
Treatment Period
Final Safety 
and Efficacy 
Assessment
Follow-Up Period for 
Participants 
Not Enrolling in the OLE
Early
Term 
Visit a
Unsched 
Visit
Wk
104a
Wk 106-126c
Wk 
127
Wk 
128a, b
Wk
140
Wk 
176
Dose number
44
45-55
Dose level in 
milligrams (mg)
510
510
Verbal Fluency Task
P
P
P
P
P
Coding
P
P
P
P
P
ADCS-ADL
SP
SP
SP
SP
SP
FAQ
SP
SP
SP
SP
SP
MMSE
P
P
P
P
P
EQ-5D
SP
SP
SP
SP
QOL-AD
P&SP
P&SP
P&SP
P&SP
ZCI-AD
SP
SP
SP
SP
RUD-Lite
SP
SP
SP
SP
NPI-Q
SP
SP
SP
SP
C-SSRS BL/SLV
P
P
P
P
Vital signs l
x
x
x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
Urine pregnancy test m
x
x
x
x
x
x
Study drug 
administration d, n
x
x
ADAS-Cog13Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL Alzheimer Disease Cooperative Study GroupActivities of Daily 
Living; CDR Clinical Dementia Rating; CSF cerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor imaging; 
EQ-5D EuroQol-Five Dimensions; FAQ Functional Activities Questionnaire; FCSRTFree and Cued Selective Reminding Test; MMSE Mini-Mental State 
Examination; MRImagnetic resonance imaging; NPI-Q Neuropsychiatric InventoryQuestionnaire; OLEopen-label extension; PETpositron emission 
tomography; PKpharmacokinetic; Q2W every 2 weeks; QoL-AD Quality of LifeAlzheimer’s Disease; RBRResearch Biosample Repository;
RUD-Lite Resource Utilization in DementiaLite; SC subcutaneous; Unsched unscheduled; Wk week; ZCI-ADZarit Caregiver InterviewAlzheimer’s 
Disease.


Appendix 1:  Schedule of Activities (cont.)
Table 4:  Scenario 2 Only Week 104 to the End of Study:  510 mg Q2W (Additional 3-Month Extension)
Gantenerumab—F. Hoffmann-La Roche Ltd
171/Protocol WN39658, Version 5
B before study drug administration; P participant completion; P&SPparticipant and study partner completion; SPstudy partner.
Notes:  The visit window is 3 days for dosing days and 3 days for Week 127 non-dosing days.  For Q2W injections, the recommendation is not to administer 
more than 1020 mg (i.e., 2 times 510 mg Q2W) within 28 days.  Participants should return to initial planned schedule per randomization for subsequent visits. 
SoA from Week 12 to Week 103 for scenario 2 is described in Appendix 1, Table 1 and Table 2.
a
Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vitals, blood tests, 
and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments should be performed at the visit time points 
stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the primary rater, or even the participant cannot perform these 
assessments as per schedule of activities, they may be performed up to 4 weeks out of window.
b
Transition to OLE study for participants who are eligible to participate.
c
Visit suitable for home administration of gantenerumab.
d
Accurate recording of the date and time of study drug administration and PK sampling is critical.  A PK sample will be obtained as soon as is practical (e.g., at an 
unscheduled visit) once the site becomes aware of the occurrence or worsening of ARIA-E or of the occurrence of ARIA-H meeting discontinuation criteria
e
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).  At Week 104 and Week 128, hemoglobin A1C, glucose, insulin, total 
cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed and 
should ideally be collected at least 4 hours after meals.
f
Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and 
WBC–other total counts. 
g
A complete physical examination includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.
h
Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
i
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI should be performed 
before or at least 3 days following a lumbar puncture.
j
Includes resting-state functional MRI and DTI outcome measures, where available.
k
Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters and should be 
performed prior to dosing.  For participants enrolling based on CSF eligibility criteria, CSF and matching serum samples are optional at Week 76; lumbar 
puncture does not have to be performed the day of Week 76 or Week 128 visit, but should be performed in a reasonable time around these visits; the need of 
CSF collection at early termination visit should be determined on a case-by-case basis, based on the participant's condition and the time since last lumbar 
puncture and advice by the Medical Monitor may be sought.
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 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 4:  Scenario 2 Only Week 104 to the End of Study:  510 mg Q2W (Additional 3-Month Extension)
Gantenerumab—F. Hoffmann-La Roche Ltd
172/Protocol WN39658, Version 5
m Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in 
the source documents.
n
Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by subcutaneous injection (full details are provided in the pharmacy manual).  Participants should be observed for 
about 1 hour after dosing.  Study personnel preparing and administering study drug must not be involved with any efficacy assessments or safety evaluations.
o
A plasma biomarker sample 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 of the occurrence of ARIA-H meeting discontinuation criteria


Gantenerumab—F. Hoffmann-La Roche Ltd
173/Protocol WN39658, Version 5
Appendix 1
Schedule of Activities (cont.)
Table 5:  Schedule of Activities (OLE Day 1 to Week 22:  Dose Escalation with Q2W Administration)
Assessment/Procedure
Open-Label Extension Treatment Period
OLE 
Early 
Term
Visit m
OLE 
UV
OLE 
Day
1
OLE 
Day 
4
OLE 
Wk
2
OLE 
Wk
4
OLE 
Wk
6
OLE 
Wk
8
OLE 
Wk
10
OLE 
Wk
12
OLE 
Wk
14
OLE 
Wk
16
OLE 
Wk 
18
OLE 
Wk 
20
OLE 
Wk 
22
Dose number
1a
2
3
4
5
6
7
8
9 b
10 b
11 b
12 b
Dose level in 
milligrams (mg) for participants 
previously on placebo
120
120
120
255
255
255
Dose level in 
milligrams (mg) for participants 
previously on active
510
510
510
510
510
510
510
510
510
510
510
510
Informed consent(s)
x
Review of inclusion and 
exclusion criteria
x
Weight
x
x
12-Lead electrocardiogram
B
x
x
PK Plasma Sample c
x
x
x
x
ADA sample
x
x
x
Serum chemistry d and 
hematology e
x
x


Appendix 1:  Schedule of Activities (cont.)
Table 5: Schedule of Activities (OLE Day 1 to Week 22:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
174/Protocol WN39658, Version 5
Assessment/Procedure
Open-Label Extension Treatment Period
OLE 
Early 
Term
Visit m
OLE 
UV
OLE 
Day
1
OLE 
Day 
4
OLE 
Wk
2
OLE 
Wk
4
OLE 
Wk
6
OLE 
Wk
8
OLE 
Wk
10
OLE 
Wk
12
OLE 
Wk
14
OLE 
Wk
16
OLE 
Wk 
18
OLE 
Wk 
20
OLE 
Wk 
22
Dose number
1a
2
3
4
5
6
7
8
9 b
10 b
11 b
12 b
Dose level in 
milligrams (mg) for participants 
previously on placebo
120
120
120
255
255
255
Dose level in 
milligrams (mg) for participants 
previously on active
510
510
510
510
510
510
510
510
510
510
510
510
Plasma biomarker sample l
x
x
Complete physical 
examination (includes 
neurological systems) f
x
x
Limited physical examination g
x
MRI scan h
B
x n
x
CDR
P&SP 
P&SP
ADAS-Cog 13
P
P
MMSE
P
P
Verbal Fluency Test
P
P
Coding
P
P
ADCS-ADL
SP 
SP
FAQ
SP 
SP
EQ-5D
SP  
SP
QOL-AD
P&SP
P&SP
ZCI-AD
SP 
SP


Appendix 1:  Schedule of Activities (cont.)
Table 5: Schedule of Activities (OLE Day 1 to Week 22:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
175/Protocol WN39658, Version 5
Assessment/Procedure
Open-Label Extension Treatment Period
OLE 
Early 
Term
Visit m
OLE 
UV
OLE 
Day
1
OLE 
Day 
4
OLE 
Wk
2
OLE 
Wk
4
OLE 
Wk
6
OLE 
Wk
8
OLE 
Wk
10
OLE 
Wk
12
OLE 
Wk
14
OLE 
Wk
16
OLE 
Wk 
18
OLE 
Wk 
20
OLE 
Wk 
22
Dose number
1a
2
3
4
5
6
7
8
9 b
10 b
11 b
12 b
Dose level in 
milligrams (mg) for participants 
previously on placebo
120
120
120
255
255
255
Dose level in 
milligrams (mg) for participants 
previously on active
510
510
510
510
510
510
510
510
510
510
510
510
RUD-Lite
SP
SP
NPI-Q
SP
SP
C-SSRS/SLV
P
P
CSF and matching serum 
sampling (for participants 
enrolled based on CSF 
eligibility criteria in 
double-blind part only)
x o
Vital Signs i
B
x
B
B
B
B
B
B
B
B
B
B
B
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urine pregnancy test i
B
B
B
B
B
B
B
B
B
B
B
B
x
x
Study drug administration c, k
x
x
x
x
x
x
x
x
x
x
x
x
ADAS-Cog13Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL Alzheimer Disease Cooperative Study GroupActivities of Daily 
Living; CDR Clinical Dementia Rating; CSF cerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor imaging; 
EQ-5D EuroQol-Five Dimensions; FAQ Functional Activities Questionnaire; FCSRTFree and Cued Selective Reminding Test; MMSE Mini-Mental State 
Examination; MRI magnetic resonance imaging; NPI-Q Neuropsychiatric InventoryQuestionnaire; OLEopen-label extension; PET positron emission 


Appendix 1:  Schedule of Activities (cont.)
Table 5: Schedule of Activities (OLE Day 1 to Week 22:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
176/Protocol WN39658, Version 5
tomography; PK pharmacokinetic; Q2W every 2 weeks; QoL-AD Quality of LifeAlzheimer's Disease; RBR Research Biosample Repository; 
RUD-Lite Resource Utilization in DementiaLite; SC subcutaneous; UV unscheduled visit; Wk week; ZCI-AD Zarit Caregiver InterviewAlzheimer’s 
Disease.
B before study drug administration; P participant completion; P&SPparticipant and study partner completion; SPstudy partner.
Notes:  The visit window is 3 days for dosing days and +3 days for OLE non-dosing Day 4.  Participants should return to initial planned schedule per 
randomization for subsequent visits. 
a
OLE Day 1 dosing should take place approximately 2 weeks after final efficacy visit has been completed.
b
Visit suitable for home administration of gantenerumab. 
c
Accurate recording of the date and time of study drug administration and PK sampling is critical. A PK sample will be obtained as soon as is practical (e.g., 
at an unscheduled visit) once the site becomes aware of the occurrence or worsening of ARIA-E or of the occurrence of ARIA-H meeting discontinuation 
criteria
d
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).  At early termination, hemoglobin A1C, glucose, insulin, 
total cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be 
assessed and should ideally be collected at least 4 hours after meals.
e
Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, 
and WBC–other total counts. 
f
A complete physical examination includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.
g
Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
h
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI should be 
performed before or at least 3 days following a lumbar puncture.
i
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.
j
Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded 
only in the source documents.
k
Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by subcutaneous injection (full details are provided in the pharmacy manual).  Participants should be 
observed for up to 2 hours after dosing.  After the 8th injection visit, this observation time may be reduced to 1 hour.  Study personnel preparing and 
administering study drug must not be involved with any efficacy assessments or safety evaluations.


Appendix 1:  Schedule of Activities (cont.)
Table 5: Schedule of Activities (OLE Day 1 to Week 22:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
177/Protocol WN39658, Version 5
l
A plasma biomarker sample 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 of the occurrence of ARIA-H meeting discontinuation criteria
m Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vitals, blood 
tests, and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments should be performed at the visit 
time points stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the primary rater or even the participant cannot 
perform these assessments as per schedule of activities they may be performed up to 4 weeks out of window.  
n
Includes resting-state functional MRI and DTI outcome measures, where available.
o
Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters and should be 
performed prior to dosing.  For patients enrolling based on CSF eligibility criteria, the need of CSF collection at early termination visit during OLE should be 
determined on a case-by-case basis, based on the participant's condition and the time since last lumbar puncture and advice by the Medical Monitor 
may be sought.


Gantenerumab—F. Hoffmann-La Roche Ltd
178/Protocol WN39658, Version 5
Appendix 1
Schedule of Activities (cont.)
Table 6:  Schedule of Activities (OLE Week 24 to Week 35:  Dose Escalation with Q2W Administration)
Assessment/Procedure
Open-Label Extension Treatment Period
Follow-up Period for 
Participants 
Not Enrolling in 
Study WN42171
OLE 
Early 
Term
Visit a
OLE 
Unsched
Visit
OLE 
Wk 24
OLE 
Wk 
26
OLE 
Wk 
28
OLE 
Wk 
30
OLE 
Wk 
32
OLE 
Wk 
34
OLE 
Wk 
35
OLE 
Follow 
Up 1
OLE 
Follow 
Up 2
Dose number
13 a
14 b
15 b
16 b
17 b
18 b
Dose level in milligrams (mg) for participants 
previously on placebo
510
510
510
Dose level in milligrams (mg) for participants 
previously on active
510
510
510
510
510
510
Informed consent(s)
Review of inclusion and exclusion criteria
Weight
x
x
x
x
x
12-Lead electrocardiogram
x
x
x
x
PK plasma sample c
x
x
x
x
x
ADA sample
x
x
x
x
x
Serum chemistry d and hematology e
x
x
x
x
x
Plasma biomarker sample n
x
x
x
Complete physical examination (includes 
neurological systems) f
x
x
Limited physical examination g
x
x


Appendix 1:  Schedule of Activities (cont.)
Table 6:  Schedule of Activities (OLE Week 24 to Week 35:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
179/Protocol WN39658, Version 5
Assessment/Procedure
Open-Label Extension Treatment Period
Follow-up Period for 
Participants 
Not Enrolling in 
Study WN42171
OLE 
Early 
Term
Visit a
OLE 
Unsched
Visit
OLE 
Wk 24
OLE 
Wk 
26
OLE 
Wk 
28
OLE 
Wk 
30
OLE 
Wk 
32
OLE 
Wk 
34
OLE 
Wk 
35
OLE 
Follow 
Up 1
OLE 
Follow 
Up 2
Dose number
13 a
14 b
15 b
16 b
17 b
18 b
Dose level in milligrams (mg) for participants 
previously on placebo
510
510
510
Dose level in milligrams (mg) for participants 
previously on active
510
510
510
510
510
510
MRI scan h
B
x
xi
x
CDR
P&SP
P&SP
P&SP
P&SP
ADAS-Cog 13
P
P
P
P
MMSE
P
P
P
P
Verbal Fluency Test
P
P
P
P
Coding
P
P
P
P
ADCS-ADL
SP
SP
SP
SP
FAQ
SP
SP
SP
SP
EQ-5D
SP
SP
SP
SP
QOL-AD
P&SP
P&SP
P&SP
P&SP
ZCI-AD
SP
SP
SP
SP
RUD-Lite
SP
SP
SP
SP
NPI-Q
SP
SP
SP
SP
C-SSRS/SLV
P
P
P
P


Appendix 1:  Schedule of Activities (cont.)
Table 6:  Schedule of Activities (OLE Week 24 to Week 35:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
180/Protocol WN39658, Version 5
Assessment/Procedure
Open-Label Extension Treatment Period
Follow-up Period for 
Participants 
Not Enrolling in 
Study WN42171
OLE 
Early 
Term
Visit a
OLE 
Unsched
Visit
OLE 
Wk 24
OLE 
Wk 
26
OLE 
Wk 
28
OLE 
Wk 
30
OLE 
Wk 
32
OLE 
Wk 
34
OLE 
Wk 
35
OLE 
Follow 
Up 1
OLE 
Follow 
Up 2
Dose number
13 a
14 b
15 b
16 b
17 b
18 b
Dose level in milligrams (mg) for participants 
previously on placebo
510
510
510
Dose level in milligrams (mg) for participants 
previously on active
510
510
510
510
510
510
CSF and matching serum sampling (for 
participants enrolled based on CSF eligibility 
criteria in double-blind part only)
x j
Vital signs k
B
B
B
B
B
B
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
Urine pregnancy test l
B
B
B
B
B
B
x
x
x
Study drug administration c, m
x
x
x
x
x
x
ADAS-Cog13Alzheimer’s Disease Assessment ScaleCognition, Subscale 13; ADCS-ADL Alzheimer Disease Cooperative Study GroupActivities of Daily 
Living; CDR Clinical Dementia Rating; CSF cerebral spinal fluid; C-SSRSColumbiaSuicide Severity Rating Scale; DTIdiffusion tensor imaging; 
EQ-5D EuroQol-Five Dimensions; FAQ Functional Activities Questionnaire; FCSRTFree and Cued Selective Reminding Test; MMSE Mini-Mental State 
Examination; MRI magnetic resonance imaging; NPI-Q Neuropsychiatric InventoryQuestionnaire; OLEopen-label extension; PET positron emission 
tomography; PK pharmacokinetic; Q2W every 2 weeks; QoL-AD Quality of LifeAlzheimer's Disease; RBR Research Biosample Repository; 
RUD-Lite Resource Utilization in DementiaLite; SC subcutaneous; Unsched unscheduled; Wk week; ZCI-AD Zarit Caregiver InterviewAlzheimer’s 
Disease.
B before study drug administration; P participant completion; P&SPparticipant and study partner completion; SPstudy partner.


Appendix 1:  Schedule of Activities (cont.)
Table 6:  Schedule of Activities (OLE Week 24 to Week 35:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
181/Protocol WN39658, Version 5
Notes:  The visit window is 3 days for dosing days and +3 days for OLE non-dosing Day 4.  Participants should return to initial planned schedule per 
randomization for subsequent visits. 
a
Visit may be split over 2 consecutive days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vitals, blood 
tests, and ECGs) should be completed on the day of dosing.  Whenever possible, cognitive and functional assessments should be performed at the visit time 
points stipulated in the schedule of activities.  However, in exceptional circumstances, if the caregiver, the primary rater or even the participant cannot perform 
these assessments as per schedule of activities they may be performed up to 4 weeks out of window.  
b
Visit suitable for home administration of gantenerumab. 
c
Accurate recording of the date and time of study drug administration and PK sampling is critical. A PK sample will be obtained as soon as is practical (e.g., at 
an unscheduled visit) once the site becomes aware of the occurrence or worsening of ARIA-E or of the occurrence of ARIA-H meeting discontinuation criteria.
d
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).  At early termination, hemoglobin A1C, glucose, insulin, total 
cholesterol, HDL, LDL, triglycerides, C-reactive protein, folic acid, vitamin B-12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed and 
should ideally be collected at least 4 hours after meals.
e
Hematology includes hemoglobin, hematocrit, RBC count (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, 
and WBC–other total counts. 
f
A complete physical examination includes an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.
g
Limited, symptom-directed physical examinations; changes from baseline abnormalities should be recorded in participant notes.  
h
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI should be 
performed before or at least 3 days following a lumbar puncture.
i
Includes resting-state functional MRI and DTI outcome measures, where available.
j
Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters and should be 
performed prior to dosing.  For participants enrolling based on CSF eligibility criteria, the need of CSF collection at early termination visit during OLE should 
be determined on a case-by-case basis, based on the participant's condition and the time since last lumbar puncture and advice by the Medical Monitor 
may be sought.
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.
l
Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only 
in the source documents.


Appendix 1:  Schedule of Activities (cont.)
Table 6:  Schedule of Activities (OLE Week 24 to Week 35:  Dose Escalation with Q2W Administration) (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
182/Protocol WN39658, Version 5
m Study drug administration should be performed only after all assessments and rating scales for the participant are completed (unless indicated otherwise).  
Study drug will be administered to participants by subcutaneous injection (full details are provided in the pharmacy manual).  Participants should be observed 
for up to 2 hours after dosing.  After the 8th injection visit, this observation time may be reduced to 1 hour.  Study personnel preparing and administering study 
drug must not be involved with any efficacy assessments or safety evaluations.
n
A plasma biomarker sample 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 of the occurrence of ARIA-H meeting discontinuation criteria.


Gantenerumab—F. Hoffmann-La Roche Ltd
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Appendix 2
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 neurological disease, or a non-neurological medical comorbidity or use 
of medication that could have a substantial effect on cognition.


Appendix 2:  National Institute on Aging/Alzheimer’s Association Criteria for Mild Alzheimer’s Disease (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
184/Protocol WN39658, Version 5
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
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Appendix 3
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 
patient 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.


Gantenerumab—F. Hoffmann-La Roche Ltd
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Appendix 4
Population PK-PET Response Analysis of 
Gantenerumab Phase III Study WN25203 Data and 
Aducanumab Phase Ib Study PRIME Data
The population pharmacokinetic positron emission tomography (PK-PET) response 
analysis of the gantenerumab Phase III study WN25203 data and aducanumab Phase Ib 
PET study model was built using pooled information from the gantenerumab Phase III 
study WN25203 and the aducanumab Phase Ib PRIME study.  Details about how this 
population analysis was conducted and evaluated are provided herein.
1.
MATERIALS AND METHODS
1.1
MODELING HYPOTHESIS
Based on the high degree of similarity between gantenerumab and aducanumab, it was 
assumed that both compounds share the same PK properties in terms of disposition,
metabolism, elimination, and the same relationship between in serum concentrations 
and reduction in standardized uptake value ratio (SUVr) amyloid PET.
It was also assumed that the SUVr data from aducanumab and gantenerumab could be 
pooled given that they were derived using the same whole cerebellum reference region 
and that the sensorimotor region used only in the composite SUVr of aducanumab was 
having little effect on the SUVr values.
1.2
PHARMACOKINETIC AND PHARMCODYNAMIC DATA
A PK-pharmacodynamic (PD) dataset for PET model was built using information from 
the Phase III gantenerumab study (WN25203) together with information from Phase Ib 
aducanumab trial (PRIME).
2.2.1
Gantenerumab PK and PET Data
2.2.1.1 PK Information
Each patient participating in Study WN25203 provided samples for measurement of their 
PK serum concentrations at the following scheduled timepoints:  Weeks 1, 8, 20, 44, 53,
68, 100, and 101.
The PK data from Study WN25203 were analysed using a population PK model that was 
previously developed on the basis of Phase I studies.
The Phase I PK database comprised data from 235 patients and healthy volunteers for a 
total of 4082 PK observations.  It contained data from both IV and SC administration,
single and multiple repeated doses administered every 4 weeks (Q4W), with dose 
values ranging for the repeated dose administrations from 6 mg to 200 mg for the IV,
105 and 225 mg for the SC, and up to 300 mg SC and 400 mg IV when administered 


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
187/ Protocol WN39658, Version 5
once.  A two-compartment model with a 0 order followed by first-order absorption best 
described the Phase I data.  Population parameter values are reported in Table 1.
Table 1
Population PK Parameters Estimated from Phase I Study Data
The population PK model was used to perform an empirical Bayesian analysis in 
non-linear mixed-effects model (NONMEM) of the PK data collected from 
Study WN25203 and to derive for each patient the individual PK parameters, as well as 
an estimation of the individual average concentrations over the period of observation.
2.2.1.2 PET Information
Among the 799 patients enrolled in Study WN25203, 114 patients participated in the 
amyloid PET substudy (using the AV-45 ligand).  Scans were performed at baseline,
Weeks 20, 60, and 100.  For patients entering the 2-year, double-blinded portion of the 
trial (Part 2), another scan was obtained at Week 156.
PET data up to Week 100 (inclusive) were considered for the PK-PD modeling 
investigations, and the PET database comprised a total of 348 SUVr observations 
determined using the whole cerebellum as the reference region.
2.2.2
Aducanumab PK and PET PD Data
Aducanumab PK and PET data were extracted from a poster (n°ADPD5–2113) and from 
slides that were presented at the 12th International Congress on Alzheimer’s Disease 
and Parkinson’s Disease (ADPD) in March 2015 in Nice, France.
The aducanumab data were collected in the Phase Ib, randomized, double-blind,
placebo-controlled study (PRIME) in patients with prodromal or mild Alzheimer’s 
Parameter
Mean
RSE%
BSV%
RSE%
CL (L/day)
0.336
3.20%
26.1%
6.9%
V2 (L)
3.52
5.60%
31.3%
18.5%
Q (L/day)
0.869
9.50%
55.5%
10.6%
V3 (L)
6.38
4.10%
24.9%
10%
KA (/day)
0.22
8.90%
52.2%
21.1%
D1 (/day)
0.0821
7.10%
96.6%
8.9%
F1 ()
0.494
3.90%
42.8%
10.5%
PROP.ERR
0.196
5.40%
ADD.ERR (g/mL)
0.0121
21.70%
ADD_ERRadditional error; CLclearance; D1zero order rate constant; F1absolute 
bioavailability; KAabsorption rate constant; KeOrate constant for drug transfer from 
serum to effect compartment; PKpharmacokinetic; POW power; 
PROP_ERRproportional error; Q intercompartmental clearance; RSErelative 
standard error; SLOPslope; V2central compartment; V3peripheral volume 3.


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
188/ Protocol WN39658, Version 5
disease.  The study design involved a parallel-group design, with a 54-week treatment 
period.  Patients received 14 IV infusions of aducanumab Q4W; four dose groups were 
evaluated, including the placebo group, and included the 1-mg/kg, 3-mg/kg, 6-mg/kg,
and 10-mg/kg dose groups, respectively.  SUVr measurements were performed at 
baseline, Week 26, and Week 54 and were determined using the whole cerebellum as 
the reference region.
The following figures were used from the aducanumab poster and slides: 

A figure displaying the individual absolute change in SUVr at Week 26 in function of 
the individual cumulative area under the concentration-time curve (AUC) at Week 26 
(see Figure 1)

A table presenting the time course of the mean SUVr up to Week 54 by dose group  
(see Table 2)

A figure displaying the relationship between the individual cumulative AUC at 
Week 26 and the four doses investigated in the PRIME study (see Figure 2)
The individual data, as depicted in Figure 1, were extracted and a database of 
123 patients with their respective cumulative AUC values at Week 26 and the absolute 
change from baseline in SUVr.  The mean data from Figure 2 were used to extrapolate 
the individual aducanumab PET data at Weeks 26 to 54 and, also, to assign a mean 
SUVr baseline value to each aducanumab dose group.  In addition, the data from 
Figure 2 were used to determine from which dose group the individual cumulative AUC 
values at Week 26 from Figure 1 were most likely derived.
Figure 1
Individual Absolute Change in SUVr Observed in Aducanumab 
Data at Week 26 with Respect to Cumulative Exposure 
AUCarea under the concentrationtime curve; SUVr standardized uptake value ratio.
Source:  Hang et al. 2015.


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
189/ Protocol WN39658, Version 5
Table 2
Mean Composite PET SUVr Data Observed in the 
Aducanumab Phase Ib Trial (PRIME) per Dose Group,
Using the Whole Cerebellum as Reference Region
Dose Group
Observed Mean Composite SUVr
Baseline
Week 26
Week 54
Placebo
1.45
1.42
1.42
1 mg/kg
1.45
1.395
1.346
3 mg/kg
1.471
1.365
1.3
6 mg/kg
1.44
1.288

10 mg/kg
1.434
1.223
1.152
SUVrstandardized uptake value ratio.
Source:  Data derived from presented slide at ADPD conference.
Figure 2 Individual DoseExposure Relationship Observed in the 
Aducanumab Phase Ib Trial (PRIME)
AUCarea under the concentrationtime curve.
Note:  Subjects demonstrating low cumulative aducumab exposures were primarily due to 
missed doses.
Source:  Hang et al. 2015.


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
190/ Protocol WN39658, Version 5
2.3
POPULATION PK-PD METHODS
2.3.1
Structural PK-PD Model
Several structural PK-PD models were evaluated to best describe the link between 
exposure and SUVr PET.  The tested models included a direct relationship, as well as 
an indirect relationship, using an effect-compartment model to take into account a time 
delay for the concentrations in serum to reach the effect site.
Furthermore, several types of drug effect were tested, including a linear model, a power 
model, an Emax model, and a sigmoid Emax model.
No placebo models were evaluated because no specific placebo response was noticed 
during the observations period.
An additive error model was used for the residual variability.  The baseline PET SUVr 
values were used as covariate in the model, but with an associated residual error of the 
same magnitude of the additive error model.
Inter-individual variability was tested on the PK-PD parameters by assuming a 
log-normal distribution.
2.3.2
PK-PD Model Selection and Evaluation
Models were selected by means of visual inspection of basic goodness-of-fits plots,
including, but not limited to, plots of the observed data versus population (PRED) and 
individual predictions (IPRED), plots of individual weighted residuals (IWRES) versus 
IPRED, and the distribution of weighted residuals (WRES) over time.  Relative standard 
errors (RSE) of the parameters were also compared to measure parameter precision.  
The NONMEM objective function value (OFV) was used to discriminate between nested 
models.  This discrimination was based on a significance level of 0.05, which 
corresponds to a decrease of 3.84 in OFV (for one degree of freedom), as the 
difference in OFV is approximately 2 distributed.
Additionally, visual predictive check (VPC) was performed to test the model 
appropriateness by means of computing confidence intervals (CIs) derived from 
1000 simulated data sets, using the final model and final parameter estimates, for each 
statistic (i.e., the median, the 5th and the 95th percentiles).  Several VPCs were 
performed, either to test the appropriateness of the model when predicting the 
gantenerumab and aducanumab pooled dataset or to focus separately on the two 
compounds datasets.  Furthermore, they were produced per level of exposure as well as 
per level of doses.
2.3.3
Computer Programs
The analyses were performed in NONMEM Version 7.2, using FOCE INTERACTION 
(Beal and Sheiner 1992).  Graphics and NONMEM datasets were created using 
Version 3.1.2 and/or the SAS system for Windows, Version 9.3.


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
191/ Protocol WN39658, Version 5
2.4
COVARIATE ANALYSIS
Only limited covariate information was available from the aducanumab data, and an 
exploratory graphical analysis of individual post-hoc parameters was conducted only for 
the following covariates:  PET baseline values, compound type, sex, and dose.
3.
RESULTS
3.1 
DATA
The final PK-PD dataset combining aducanumab and gantenerumab data included 
237 patients with a total of 693 PET SUVr observations.
3.2
POPULATION EXPOSURE SUVr PET MODEL
The relationship between exposure and the PET SUVr reduction time course was best 
described by using a power model combined with an effect compartment to account for 
the delay between exposure and PET response.  The model equations are as follows:
PET(time) = Base ∗1 −SLOP ∗(Conc(time)) !
with 
"#$%&'(()*+)
"()*+
= Ke0 ∗(Conc(time) −Conc(time))
with Base the individual PET SUVr baseline value, Conc the predicted concentration at 
effect site, Conc the predicted concentration in serum, Ke0 the rate constant for drug 
transfer from serum to effect compartment, and SLOP and POW the parameters driving 
the drug effect.
Parameter values are reported in Table 3.
Table 3Estimated Population PK-PD Parameters
Parameter
Mean 
(RSE%)
Value Inter-Individual 
Variability (RSE%)
Ke0 (Day -1)
1.7410-3 (38%)
127.3% (14%)
Equilibration half-life 
(weeks)
57
SLOP
0.019 (33%)

POW ()
0.716 (11%)

ADD_ERR
0.0659 (5%)
ADD_ERRadditional error; KeO rate constant for drug transfer from serum to the effect 
compartment; PDpharmacodynamic; PKpharmacokinetic; POW power; 
RSErelative standard error; SLOPslope.
Inspection of the goodness-of-fit plots reported in Figure 3 shows that the final PK-PD 
model describes the data adequately without obvious bias in the population or individual 
predicted PET values.  The VPCs are shown in Figures 57.  The shaded areas indicate 
the 90% CIs (i.e., 5th and 95th percentiles) computed from simulations.  The median and 


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
192/ Protocol WN39658, Version 5
the 5th and 95th percentiles of the observed PK profiles are contained in their respective 
CIs, indicating that the final PK-PD model captures both the central tendency and the 
between-subject variability of both gantenerumab and aducanumab pharmacodynamics 
in the target populations of patients with prodromal and mild Alzheimer’s disease.
3.3
COVARIATE ANALYSIS
The exploratory graphical covariate analysis is reported on Figure 4.  Although a small 
trend between PET baseline values and estimated individual Ke0, this graphical analysis 
did not reveal any relevant covariate relationships that would require further 
investigation.
Figure 3
Goodness-of-Fit Plots for the Final PK-PD Model 


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
193/ Protocol WN39658, Version 5
IWESindividual weighted residual value; PET positron emission tomography; 
PDpharmacodynamic; PK pharmacokinetic.
Note:  The red dots represent the aducanumab compound, and blue dots represent 
gantenerumab compound.  The orange lines correspond to a smoothing of the data.
Figure 4
Exploratory Analysis of Covariates (by Compound Type, Sex, PET 
Baseline Value, and Dose [in milligrams] Value with Respect to 
Estimated Individual Ke0)
KeO rate constant for drug transfer from serum to the effect compartment; PET positron 
emission tomography; PDpharmacodynamic; PKpharmacokinetic.
Note:  Dose was investigated in milligrams, using a mean weight of 70 kg for doses the 
aducanumab PRIME study.  The green line corresponds to a smoothing of the data.


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
194/ Protocol WN39658, Version 5
Figure 5
Visual Predictive Check of the PET Model by Category of Serum 
Concentration Exposure for the Gantenerumab WN25203 Alone
CFBchange from baseline; Conc concentration; KeO rate constant for drug transfer from 
serum to the effect compartment; PET positron emission tomography; PD pharmacodynamic; 
PKpharmacokinetic.


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
195/ Protocol WN39658, Version 5
Figure 6
Visual Predictive Check of the PET Model Per Category of Serum 
Concentration Exposure for the Aducanumab PRIME Study Alone 
KeOrate constant for drug transfer from serum to the effect compartment; PET positron 
emission tomography; PDpharmacodynamic; PKpharmacokinetic.


Appendix 4:  Population PK-PET Response Analysis of Gantenerumab Phase III Study 
WN25203 Data and Aducanumab Phase Ib Study PRIME Data (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
196/ Protocol WN39658, Version 5
Figure 7
Visual Predictive Check of the PET Model by Category of 
Expected Dose Group for the Aducanumab PRIME Trial Alone
KeOrate constant for drug transfer from serum to the effect compartment; PET positron 
emission tomography; PDpharmacodynamic; PKpharmacokinetic.
REFERENCES
Beal S, Sheiner L (editors). NONMEM user guides. NONMEM Project Group,
University of California at San Francisco, San Francisco. 1992.
Hang Y, Chiao P, Sevigny J, et al. Pharmacokinetic and pharmacodynamic (PK-PD)
assessment and covariate analysis of aducanumab (BIIB037) in a randomized,
double-blind, placebo-controlled, Phase 1b study (PRIME) in subjects with 
prodromal or mild Alzheimer’s disease. 12th International Congress on Alzheimer’s 
and Parkinson’s Disease. Poster presentation. March 2015. Nice, France.


Gantenerumab—F. Hoffmann-La Roche Ltd
197/Protocol WN39658, Version 5
Appendix 5
Amyloid-Related Imaging Abnormality Hazard Model
1.
BACKGROUND
Hutmacher et al. (2013) presented a pharmacodynamic (PD) model for bapineuzumab 
addressing the first occurrence of amyloid-related imaging abnormalities, or ARIAs, of 
“vasogenic edema” (ARIA-E) events.  Patients received constant dose regimens of 0.5,
1, and 2 mg/kg given every 13 weeks over 1.5 years.  A total of 2435 patients with 
243 ARIA-E events were analysed.  As shown below, a log hazard model was 
developed that included three elements: 

A baseline value (IBS) reflecting a constant ARIA-E hazard for apolipoprotein E allele 
4 (APOE 4) gene carriers and non-carriers, respectively

Plasma drug concentrations (c) of bapineuzumab modulating the ARIA-E hazard 
through the maximum effect (Emax) of drug and 50% of the effective concentration 
(EC50) parameters

A time component continuously suppressing the ARIA-E hazard by the time (t) since 
first dosing.  ET50 and modulated this effect.
Because no model parameters were reported in Hutmacher et al. 2013, the parameters 
were derived from predicted time-concentration and time-hazard curves presented in 
Hutmacher et al. 2013 after digitizing the respective graphs for 0.5 mg/kg in APOE 4
carriers.  IBS parameters were obtained from the graphs directly, whereas the other 
parameters were calculated from the digitized data using MATLAB (or matrix laboratory)
and maximum likelihood estimation.  Parameter values are shown in Table 1.  
Table 1
Estimated Pharmacodynamic Parameters 
for Bapineuzumab 
IBS
ET50
(day)

Emax
EC50
(g/mL)
8.7E-6 (non-carrier)
3.55E-5 (carrier)
323.441
2.146
6.891
2.64
2.
ARIA EVENTS UNDER CONSTANT DOSING REGIMENS
The above model was applied to the double-blind phase of Study WN25203, in which 
patients received constant dose regimens of 105 and 225 mg of gantenerumab.  Owing 
to paucity of ARIA event data and the assumed independence between time and study 
drugrelated hazard model parameters, IBS, ET50, and were fixed to the bapineuzumab 
values, and only Emax and EC50 were estimated.



t
ET
ET
EC
t
c
t
c
E
I
t
h
BS






50
50
50
max
)
(
)
(
)
(
log


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
198/Protocol WN39658, Version 5
The concentration-time course for gantenerumab in Study WN25203 was derived from a 
population PK model previously developed for Phase I studies.  It covers both 
intravenous (IV) and subcutaneous (SC) administration, as well as single and multiple 
repeated doses every 4 weeks, with a range of dose values for the repeated dose 
administrations from 6 mg to 200 mg for IV administration, 105 mg and 225 mg for SC 
administration, and up to 300 mg SC and 400 mg for IV administration when given only 
once.  The parameters for this model are presented in Table 2.
Table 2 
Pharmacokinetic Parameters for Gantenerumab
CL
(L/day)
Q
(L/day)
V2
(L)
V3
(L)
ka
(1/d)
F1
(1/d)
D
(1/d)
0.336
0.869
3.152
6.38
0.22
0.494
0.0821
An update of the population PK model parameters was not considered as newly 
available drug concentrations were within prediction ranges from the established PK 
model.  The maximum likelihood estimation of the log hazard model parameters Emax
and EC50 was performed using NONMEM software.  ARIA-E events were interval 
censored with a cutoff at 742 days.  A total of 797 patients with 50 ARIA-E events were 
analysed.
Parameter estimates are shown in Table 3.
Table 3
ARIA-E Parameters for Gantenerumab 
IBS
ET50
(day)

Emax
EC50
(g/mL)
8.7E-6 (non-carrier) F
3.55E-5 (carrier) F
323.44 F
2.15 F
6.052.33
8.607.13
amyloid-related imaging abnormalityedema/effusion; Ffixed.
On inspection of the aducanumab PRIME study data (Sevigny et al. 2015), it became 
clear that the PK properties of gantenerumab and aducanumab are very similar.  This 
supported an opportunity to test the hazard PK-PD model applied to gantenerumab on 
IV aducanumab ARIA-E data.  The ARIA–E model, which already provides a good 
description of the gantenerumab ARIA-E data in Study WN25203 after 1 and 2 years of 
treatment, respectively, also predicted the aducanumab Phase Ib ARIA-E data with a 
great degree of accuracy (see Figure 1), including the ARIA rate differences across 
APOE 4 allele groups (see Figure 2), even though this approach is limited based on 
external aggregated data.  This finding indicated that doses much larger than those 
given in Study WN25203 can be described by the hazard model, provided that a 
constant dose regimen is used.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
199/Protocol WN39658, Version 5
Figure 1
ARIA-E Prediction for IV Aducanumab Using Bapineuzumab 
Hazard Model Adapted to SC Gantenerumab 
ARIA amyloid-related imaging abnormality; ARIA-E amyloid-related imaging 
abnormalityedema/effusion; IV intravenous; SC subcutaneous; SD standard deviation.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
200/Protocol WN39658, Version 5
Figure 2
Model-Based Predictions of ARIA-E Occurrence for Aducanumab 
by APOE 4 Carrier and Non-Carrier Status and Dose for a 
Q4W Dosing Regimen:  Comparison to Observed Data in the 
PRIME Study
APOE 4apolipoprotein E, allele 4; ARIA amyloid-related imaging abnormality; ARIA-
E amyloid-related imaging abnormalityedema/effusion; IV intravenous; Q4W every 4 weeks; 
SC subcutaneous.
3.
ARIA EVENTS UNDER DOSE TITRATION REGIMENS
3.1 MODELING DATABASE AS OF 6 DECEMBER 2016 
To check the validity of the model under titration conditions, two patient groups were 
selected from the open-label extension studies of WN25203 and WN28745.  The first 
group comprised 71 patients who received increasing doses of gantenerumab and 
received placebo during the double-blind phase of the study.  The second group 
comprised 417 patients who received a constant dose of gantenerumab and who did not 
have treatment-free intervals of more than 70 days.  The first group is representative for 
the intended Phase III design, and the second group was included to enhance the 
database and link the model to previously established results (see Table 4).


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
201/Protocol WN39658, Version 5
Appendix 5
Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Table 4
Patient Population Included in ARIA-E Model Building 
(Database as of 6 December 2016)
Number of Patients
(Number of Events)
Study
WN25203
Study
WN28745
Total
Comment
Total included in study
797 (63)  
371 (35)
1168 (108)
Placebo treatment 
236 (2)
111 (3)
347 (5)
Excluded from 
model building
Total included in study
on active drug
561 (61)
260 (32)
821 (103)
Total on active drug before
OLE, or treatment gaps 
70 days
125 (11)
108 (23)
333 (44)
Excluded from 
model building
Total included in
model building
436 (50)
52 (9)
488 (59)
Titrated without prior 
treatment
19 (1)
52 (9)
71 (10)
Included in 
model building
Constant dosing, and 
treatment gaps 70  days
417 (49)

417 (49)
Included in 
model building
ARIA-E amyloid-related imaging abnormalityedema/effusion; OLEopen-label extension.
As noted previously, the maximum likelihood estimation was performed using NONMEM 
software.  Estimated model parameters were Emax , EC50 and the baseline risk for 
carriers and non-carriers.  ARIA-E events were observation interval censored.
Parameter estimates are shown in Table 5.
Table 5 
ARIA-E Parameters for Gantenerumab When Applied to 
Titration Data 
IBS
ET50
(day)

Emax
EC50
(g/mL)
5.844.22 E-6 (non-carrier)
11.97.30 E-6 (carrier)
323.44 F
2.15 F
7.121.03
5.162.85
ARIA-E amyloid-related imaging abnormalityedema/effusion; Ffixed.
Visual predictive checks were performed to assess model performance.  As shown in 
Figure 3, the overall model performance was acceptable.  Figure 4 presents a condition 
that was excluded from the model building.  The apparent bias in the prediction might be 
attributable to a SCarlet RoAD study effect, which will be followed up during ongoing 
completion of the database.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
202/Protocol WN39658, Version 5
Figure 3
Visual Predictive Check on Database Used for Model Building
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines:  90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.  
Inserted are the number of model-predicted ARIA-E events at given percentiles (2.5%, 50% 
[median], and 97.5%) and the actual observed number of events.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
203/Protocol WN39658, Version 5
Figure 4
Visual Predictive Checks: Patients in SCarlet RoAD Study with 
Treatment Interruption 70 Days from Time 0 at Start of 
Open-Label Extension WN25203
ARIA-E amyloid-related imaging abnormalityedema/effusion; OLEopen-label extension.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines:  90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.  
Inserted are the number of model-predicted ARIA-E events at given percentiles (2.5%, 50% 
[median], and 97.5%) and the actual observed number of events.
3.2 MODELING DATABASE AS OF 3 MARCH 2017
Table 6 presents an updated ARIA-E model building using data based on the cutoff date 
of 3 March 2017.  In Table 7, ARIA-E parameters for gantenerumab are summarized 
when applied to titration data.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
204/Protocol WN39658, Version 5
Table 6
Patient Population Included in ARIA-E Model Building 
(Database as of 3 March 2017)
Number of Patients 
(Number of Events)
Study
WN25203
Study
WN28745
Total
Comment
Total included in study
797 (69)
371 (60)
1168 (129)
Placebo treatment 
234 (2)
108 (3)
342 (5)
Excluded from 
model building
Database cleaning 
ongoing 
3 (0)

3 (0)
Excluded from 
model building
Total included in study
on active drug
560 (67)
263 (57)
823 (124)
Long-term constant 
dose before titration
64 (9)
83 (17)
147 (26)
Excluded from 
model building
Total included into
model building
496 (58)
180 (40)
676 (98)
Titrated without 
prior treatment
24 (2)
67 [18]
91 (20)
Included in model 
building
Doses always smaller 
or equal to 225 mg 
472 (56)
113 (22)
585 (78)
Included in model 
building
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Table 7
ARIA-E Parameters for Gantenerumab when Applied to 
Titration Data 
IBS
ET50
(day)

Emax
EC50
(g/mL)
2.361.01 E-5 (non-carrier)
3.751.30 E-5 (carrier)
323.44 F
2.15 F
6.070.702
7.752.70
ARIA-E amyloid-related imaging abnormalityedema/effusion; Ffixed.
Figures 57 show visual predictive checks for the final model.  For both patients groups 
selected for model building, the diagnostics look acceptable (see Figures 5 and 6).  For 
the excluded patient group who exhibited constant gantenerumab dosing followed by 
titration, often with 1 to 2 years of treatment gap in between, the diagnostics indicate a 
considerable mismatch.  This could not be corrected by introducing covariates (such 
maximum treatment gap) into the model.  It appears that the hazard model with its time 
component is not flexible enough for such regimens.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
205/Protocol WN39658, Version 5
Figure 5
Visual Predictive Check on Titration Data Used for 
Model Building 
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines:  90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.  
Inserted are the number of model-predicted ARIA-E events (2.5%, 50% [median], and 97.5% 
percentiles), and the actual observed number of events. The apparent mismatch over the first 
12 weeks is because no scan was performed during this period.  Survival refers to the ARIA-E 
event-free proportion.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
206/Protocol WN39658, Version 5
Figure 6
Visual Predictive Check on Data Used for Model Building (Based 
on Data from Patients Enrolled in the Double-Blind WN25203 and 
WN28745 Studies and Dosed with 225 mg)
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines: 90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.  
Inserted are the number of model-predicted ARIA-E events at given percentiles (2.5%, 50% 
(median), and 97.5%) and the actual observed number of events.  Survival refers to the ARIA-E 
event-free proportion.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
207/Protocol WN39658, Version 5
Figure 7
Visual Predictive Check on Excluded Data from Model Building
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines: 90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.
Inserted are the number of model-predicted ARIA-E events at given percentiles (2.5%, 50% 
(median), and 97.5%) and the actual observed number of events.  Survival refers to the ARIA-E 
event-free proportion.
3.3.MODELING DATABASE AS OF 8 JULY 2017
Table 8 presents an updated ARIA-E model building using data based on the cutoff date 
of 8 July 2017.  In Table 9, ARIA-E parameters for gantenerumab are summarized when 
applied to titration data.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
208/Protocol WN39658, Version 5
Table 8
Patient Population Included in ARIA-E Model Building 
(Database as of 7 July 2017)
Number of Patients 
(Number of Events)
Study
WN25203
Study
WN28745
Total
Comment
Total included in study
797 (75)
371 (60)
1168 (135)
Placebo treatment 
227 (2)
108 (3)
335 (5)
Excluded from 
model building
Database cleaning 
ongoing 
2 (0)

2 (0)
Excluded from 
model building
Total included in study
on active drug
568 (73)
263 (57)
831 (130)
Long-term constant 
dose before titration
66 (14)
80 (16)
146 (30)
Excluded from 
model building
Total included into
model building
502 (59)
183 (41)
685 (100)
Titrated without 
prior treatment
36 (3)
70 (19)
106 (22)
Included in model 
building
Doses always smaller 
or equal to 225 mg 
466 (56)
113 (22)
579 (78)
Included in model 
building
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Table 9
ARIA-E Parameters for Gantenerumab when Applied to 
Titration Data 
IBS
ET50
(day)

Emax
EC50
(g/mL)
2.140.9742 E-5 (non-carrier)
3.521.24 E-5 (carrier)
323.44 F
2.15 F
5.920.688
6.782.88
ARIA-E amyloid-related imaging abnormalityedema/effusion; Ffixed.
Figures 810 show visual predictive checks for the final model.  For both patients groups 
selected for model building, the diagnostics look acceptable (see Figures 8 and 9).  For 
the excluded patient group who exhibited constant gantenerumab dosing followed by 
titration, often with 1 to 2 years of treatment gap in between, the diagnostics indicate a 
considerable mismatch.  This could not be corrected by introducing covariates (such 
maximum treatment gap) into the model.  It appears that the hazard model with its time 
component is not flexible enough for such regimens.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
209/Protocol WN39658, Version 5
Figure 8
Visual Predictive Check on Titration Data Used for 
Model Building
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines:  90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.  
Inserted are the number of model-predicted ARIA-E events (2.5%, 50% [median], and 97.5% 
percentiles), and the actual observed number of events.  Survival refers to the ARIA-E event-free 
proportion.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
210/Protocol WN39658, Version 5
Figure 9
Visual Predictive Check on Data Used for Model Building
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines: 90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.  
Inserted are the number of model-predicted ARIA-E events at given percentiles (2.5%, 50% 
(median), and 97.5%) and the actual observed number of events.  Survival refers to the ARIA-E 
event-free proportion.


Appendix 5:  Amyloid-Related Imaging Abnormality Hazard Model (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
211/Protocol WN39658, Version 5
Figure 10 Visual Predictive Check on Excluded Data from Model Building
ARIA-E amyloid-related imaging abnormalityedema/effusion.
Notes:  Kaplan-Meier curves of the data are shown in green (dashed lines: 90% CI).  Simulated 
study data (100 replicated Kaplan-Meier curves) are shown in blue with their mean and 90% CI.
Inserted are the number of model-predicted ARIA-E events at given percentiles (2.5%, 50% 
(median), and 97.5%) and the actual observed number of events.  Survival refers to the ARIA-E 
event-free proportion.
REFERENCES
Hutmacher M, Hu C, Guenzler-Pukall V, et al. Pharmacokinetic-pharmacodynamic 
modeling of amyloid-related imaging abnormalities of edema following 
administration of bapineuzumab to subjects with mild to moderate Alzheimer’s 
disease [poster]. Presented at the American Conference on Pharmacometrics 2013.
Sevigny J, Chiao P, Williams L, et al. Randomized, double-blind, Phase 1b study of 
BIIB037 in patients with prodromal or mild Alzheimer’s disease. 12th International 
Congress on Alzheimer’s and Parkinson’s Disease. Symposium 26 March 2015.
Nice, France.


Gantenerumab—F. Hoffmann-La Roche Ltd
212/Protocol WN39658, Version 5
Appendix 6
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.
–
As long as BGTS is 4 and 1, continue study drug at 
the same dose level and repeat MRI 4 weeks later.
–
Once ARIA resolves, resume uptitration and obtain an
MRI scan per the titration schedule.  For participants 
randomized to the Q2W regimen, perform another MRI 
scan 3 months after ARIA resolution.
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 an MRI scan before next scheduled dose for 
participants randomized to the Q4W regimen or after 
the second dose for participant randomized to the Q2W 
regimen.
–
If no new ARIA-E is detected, resume uptitration and 
obtain an MRI per titration schedule.  For participants 
randomized to the Q2W regimen, 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
15 ARIA-H cumulatively (should not 
include any disseminated LH)

Discontinue study drug.


Appendix 6:  Management Rules for Amyloid-Related Imaging Abnormalities (cont.)
Gantenerumab—F. Hoffmann-La Roche Ltd
213/Protocol WN39658, Version 5
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;Q2Wevery 2 weeks.
In exceptional cases of (1) an ARIA-E that is asymptomatic with BGTS <4 and considered stable over consecutive MRI images by the Sponsor and 
investigator; or (2) symptomatic ARIA-E for which the imaging evidence of ARIA-E has resolved but the CNS symptoms continue, study drug can 
be either reintroduced or uptitrated, as applicable, and 4-weekly MRI monitoring may no longer be necessary, as determined by the Sponsor and 
investigator.
Symptomatic ARIA-E is defined as onset or worsening of CNS symptom(s) that is/are temporally associated with ARIA-E MRI findings
A PK and a plasma biomarker sample 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 of the occurrence of ARIA-H meeting discontinuation criteria

SAP_003.pdf: 
Official Title: 
A Phase III, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group, Efficacy, and Safety Study of 
Gantenerumab in Patients With Early (Prodromal to Mild) Alzheimer's 
Disease 
NCT Number: 
NCT03443973 (WN39658)  
Document Date: 
SAP Version 3: 05-October-2022 


STATISTICAL ANALYSIS PLAN AMENDMENT 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, WN29922, WN39658 
STATISTICAL ANALYSIS PLAN 
STUDY 
TITLE: 
TWO PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP EFFICACY AND 
SAFETY STUDIES OF GANTENERUMAB IN PATIENTS WITH 
EARLY (PRODROMAL TO MILD) ALZHEIMER’S DISEASE 
STUDY NUMBER: 
STUDY NAME:  
VERSION NUMBER: 
ROCHE COMPOUND(S): 
EUDRACT NUMBER: 
IND NUMBER: 
NCT NUMBER: 
WN29922, WN39658 
GRADUATE I, GRADUATE II 
3 
Gantenerumab (RO4909832) 
2017-001364-38 (WN29922) 
2017-001365-24 (WN39658) 
102,266 
NCT03443973 (WN39658) 
PLAN PREPARED BY: 


Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan, WN29922, WN39658 
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) 
3 
see electronic date stamp 
on last page of the 
document 
Version 5.0, 2 August 2021 
2 
29 July 2022 
Version 5.0, 2 August 2021 
1 
12 October 2021 
Version 5.0, 2 August 2021 


Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan, WN29922, WN39658 
3 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
Key changes to the SAP version 2.0, along with the rationale(s) for each change, are 
summarized below.  
Section 
Description of Change 
Rationale for Change 
Section 4 
In Table 2, Neurogranin has been 
added to the definition of the CSF-
longitudinal analysis set 
It was a typo not including 
Neurogranin it in the previous 
version of the SAP. 
Section 5.3.3 
In the ‘analysis step of the ‘description if 
the primary estimator’ the percent 
relative difference was updated to be 
defined as 100 times the estimated 
treatment effect divided by the absolute 
value of the placebo arm estimate 
It was a typo not to 
considering the ‘absolute 
value’ for the denominator in 
the previous version of the 
SAP.  
Section 5.3.5.2 
A new supplementary analysis has 
been added, ‘Treatment effect in 
relationship to a post-baseline 
timepoint‘, to estimate the percent 
relative difference in CDR-SB between 
week 52 and week 116, as well 
between week 24 and week 116 and  
week 76 and week 116 
In order to assess the 
treatment effect using 
different starting points 
relative to the scheduled start 
of the target dose (with 
Weeks 24, 52 and 76 being 
respectively 12 weeks before, 
16 weeks after and 40 weeks 
after the scheduled start of 
the target dose). This 
analysis may help to better 
understand the time 
dynamics of a treatment 
effect. 
Section 5.3.6 
A new section was added to describe 
what to do in case of the rare 
circumstances that the imputation 
model (see step 1, imputation model, in 
Section 5.3.3) would fail to converge. 
To add clarity 
Section 5.4 
More details have been added to 
describe the estimator used for the 
secondary efficacy endpoints. 
To add clarity 
Section 5.4.1 
Given that the ‘confirmatory secondary 
endpoints’ are a subset of the 
secondary endpoints, now the SAP is 
referencing to the secondary endpoints 
for the details of the estimand’s 
strategy, 
To add clarity 
Section 5.5 
More details have been added to 
describe the estimator used for the 
exploratory efficacy endpoints. 
To add clarity 
Section 5.7.7 
The CSF biomarkers analysis plan has 
been updated to now use two different 
Although those two models 
will provide the same exact p-


 
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Additional minor changes have been made throughout the document to improve clarity 
and consistency.  
 
ANCOVA models: one based on the 
change from baseline and the other one 
based on the value at visit 
value in characterizing the 
treatment effect, they also 
allow to estimate 
complementary summary 
statistics. 
Section 5.7.8 
The plasma biomarkers analysis plan 
has been updated to now use two 
different MMRM models: one based on 
the change from baseline and the other 
one based on the value at visit 
Although those two models 
will provide the same exact p-
value in characterizing the 
treatment effect, they also 
allow to estimate 
complementary summary 
statistics. 


 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1. 
INTRODUCTION ........................................................................... 11 
1.1 
Objectives ................................................................................ 11 
1.2 
Study Design ........................................................................... 14 
1.2.1 
Treatment Assignment and Blinding ........................................ 16 
1.2.2 
Independent Review Facility .................................................... 17 
1.2.3 
Data Monitoring Committee ..................................................... 17 
2. 
STATISTICAL HYPOTHESES ...................................................... 17 
3. 
SAMPLE SIZE DETERMINATION ................................................ 17 
4. 
ANALYSIS SETS .......................................................................... 18 
5. 
STATISTICAL ANALYSES ........................................................... 20 
5.1 
General Considerations ........................................................... 20 
5.2 
Participant Disposition ............................................................. 22 
5.3 
Endpoint Analysis .................................................................... 22 
5.3.1 
Definition of Primary Endpoint ................................................. 22 
5.3.2 
Definition of Primary Estimand ................................................. 23 
5.3.3 
Main Analytical Approach for Primary Estimand and 
Primary Endpoint ..................................................................... 26 
5.3.3.1 
Software Implementation and Validation ................................. 30 
5.3.4 
Sensitivity Analyses for Primary Endpoint ............................... 31 
5.3.5 
Supplementary Analyses for Primary Endpoint........................ 32 
5.3.5.1 
Subgroup Analyses for Primary Endpoint ................................ 32 
5.3.5.2 
Other Supplementary Analyses for Primary Endpoint(s) ......... 33 
5.3.6 
Convergence Considerations for RBMI-Based Analyses ......... 35 
5.4 
Secondary Endpoints Analyses ............................................... 36 
5.4.1 
Confirmatory Secondary Endpoints ......................................... 37 
5.4.1.1 
Alzheimer’s Disease Assessment Scale, Cognitive 
Subscale, 11- item and 13-Item (ADAS-Cog 11/ ADAS-
Cog 13) .................................................................................... 37 
5.4.1.2 
Alzheimer’s Disease Cooperative Study, Activities of Daily 
Living Scale (ADCS-ADL), Total Score .................................... 38 




 
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5.7.4 
Summaries of COVID-19 Impact on the Trials ......................... 49 
5.7.5 
Amyloid PET Substudy ............................................................ 49 
5.7.5.1 
General considerations on Amyloid PET statistical 
analyses .................................................................................. 49 
5.7.5.2 
Summaries of Treatment Group Comparability ........................ 50 
5.7.5.3 
Visit Windowing ....................................................................... 50 
5.7.5.4 
Definition of the Estimand for Amyloid PET ............................. 51 
5.7.5.5 
Main Analytical Approach ........................................................ 52 
5.7.5.6 
Supplementary analyses ......................................................... 53 
5.7.6 
Tau PET Substudy ................................................................... 53 
5.7.6.1 
Summaries of Treatment Group Comparability ........................ 54 
5.7.6.2 
Definition of the Estimand ........................................................ 54 
5.7.6.3 
Main Analytical Approach ........................................................ 55 
5.7.6.4 
Visit Windowing ....................................................................... 55 
5.7.7 
Cerebrospinal Fluid (CSF) Analyses ........................................ 56 
5.7.8 
Plasma Biomarker Analyses .................................................... 58 
5.7.9 
Volumetric MRI Analyses ......................................................... 60 
5.8 
Interim Analyses ...................................................................... 62 
6. 
SUPPORTING DOCUMENTATION .............................................. 63 
7. 
REFERENCES.............................................................................. 64 
 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 12 
Table 2 
Analysis Sets .............................................................................. 19 
Table 3 
Intercurrent Events Impacting Primary Analysis .......................... 25 
Table 4 
Time windows for clinical endpoint assessments ........................ 26 
Table 5 
Secondary Endpoints .................................................................. 37 
Table 6 
Exploratory Endpoints ................................................................. 41 
Table 7 
Time Windows for Amyloid PET Assessments ........................... 50 
Table 8 
Primary Centiloid Equation Parameters ...................................... 52 
Table 9 
Time Windows for tau PET Assessments ................................... 56 
Table 10 
Time Windows for CSF Assessments ......................................... 58 
Table 11 
Time windows for Plasma assessments ..................................... 60 
Table 12 
Time windows for Volumetric MRI assessments ......................... 62 
 


 
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LIST OF FIGURES 
Figure 1 
Overall Study Design .................................................................. 15 
 
 
LIST OF APPENDICES 
Appendix 1 
Type I Error Control Considerations for Reference-Based 
Conditional Mean Imputation Combined with the Jackknife 
for Inference ................................................................................ 68 
Appendix 2 
ADCS-ADL Dependence Scale Algorithm Version 2.1 ............... 76 
Appendix 3 
Charter for Adjudication Committee for Intercurrent Events ........ 78 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term Description 
Aβ amyloid-beta 
AD Alzheimer’s disease 
ADA anti-drug antibody 
ADAS-Cog11 / Cog13 Alzheimer disease assessment scale – cognition, 
subscale 11 / 13 
ADCS-ADL Alzheimer disease cooperative study - activities of daily 
living 
ADL activities of daily living 
AE adverse event 
AESI adverse event of special interest 
ANCOVA analysis of covariance 
APOE apolipoprotein ε 
ARIA-E amyloid-related imaging abnormalities – edema/effusion 
ARIA-H amyloid-related imaging abnormalities – hemosiderin 
deposition 
CDR-GS clinical dementia rating – global score 
CDR-SB clinical dementia rating – sum of boxes 
CIR copy increments from reference 
CNS central nervous system 
COVID-19 coronavirus disease 2019 
CSF cerebrospinal fluid 
CSR Clinical Study Report 
C-SSRS Columbia-suicide severity rating scale 
DTI diffusion tensor imaging 
ECG Electrocardiogram 
eCRF electronic case report form 
EMA European Medicines Agency 
EQ-5D EuroQol-Five Dimensions 
FAQ functional activities questionnaire 
FDA (U.S.) Food and Drug Administration 
ICE intercurrent event 
ICH International Council on Harmonization 
iDMC independent Data Monitoring Committee 
IRC independent review charter 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (Cont’d) 
Abbreviation or Term Description 
ISR injection-site reaction 
ITT intent to treat 
IxRS interactive voice/web-based response system 
MAR missing at random 
MedDRA Medical Dictionary for Regulatory Activities 
mITT modified intent to treat 
MMRM mixed effects model repeated measures 
MMSE mini-mental state examination 
MNAR Missing not at random 
MRI magnetic resonance imaging 
NMPA National Medical Products Administration 
NPI-Q neuropsychiatric inventory-questionnaire 
NSDCR not study drug or condition related 
OLE open-label extension 
PET Positron emission tomography 
PK Pharmacokinetic 
pTau phosphorylated tau 
Q2W every 2 weeks 
Q4W every 4 weeks 
QoL quality of life 
QoL-AD quality of life – Alzheimer’s disease 
RUD-Lite resource utilization in dementia - lite 
SAE serious adverse events 
SAP Statistical Analysis Plan 
SC Subcutaneous 
SDCR study drug or condition related 
SUV standard uptake value 
SUVR standard uptake value ratio 
tTau total tau 
ZCI-AD Zarit caregiver interview – Alzheimer’s disease 


 
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1. 
INTRODUCTION 
This document describes the statistical analyses that will be reported in the primary 
Clinical Study Reports (CSR) of Studies WN29922 (hereafter referred to as 
“GRADUATE I”) and WN39658 (hereafter referred to as “GRADUATE II”).  The 
descriptions, methodology, and analyses presented in this document applies to both 
studies unless otherwise specified.  The efficacy estimands and safety endpoints that 
will be the basis for comparing the two treatment arms will be defined in full in this 
document along with the populations of participants that are to be used in the analyses.  
This Statistical Analysis Plan (SAP) covers analyses planned for the double-blind 
treatment period and the safety follow-up across both studies.  Analyses for the OLE 
phase will focus on safety and will be listed directly in the corresponding List of Planned 
Outputs (LoPO).  Pharmacokinetic (PK) data will be reported in a separate population 
PK report and thus is not covered in this document.  Similarly, health economic data 
(such as utility values derived from the EQ-5D-5L and the RUD-lite) will be analyzed and 
reported separately from the Clinical Study Report and are therefore not covered in this 
document.   
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, i.e., 
Data Analysis Plan Module 2 and 3. 
The language used in this SAP supersedes that in the protocol and protocol synopsis.  
An early draft of this SAP was presented to U.S. Food and Drug Administration (FDA) in 
the context of a Type C meeting (Written Response Only procedure, 
December 21, 2020, Ref ID: 4720726) and to the European Medicines Agency (EMA) in 
the context of Scientific Advice procedure (EMA Written Advice received on 29 January 
2020; EMA//SA/0000046418).  These procedures focused on the proposed primary 
estimand, the estimator and other aspects of the analysis plan.  Both agencies in 
principle agreed on the primary question of interest in the context of the estimand 
framework (ICH E9[R1]).  There was also agreement on the proposed hierarchy of 
secondary endpoints.   
A more advanced version of the SAP was submitted to the FDA for their review in 
December 2021.  The feedback received during these health authority interactions was 
duly considered and informed the current version of this SAP. 
1.1 
OBJECTIVES  
This study will evaluate the efficacy and safety of gantenerumab compared with placebo 
in participants with early (prodromal to mild) AD. 


 
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Table 1 
Objectives and Corresponding Endpoints 
Primary Objective(s) 
Corresponding Endpoint(s) 
 
To evaluate the efficacy of 
gantenerumab administered by 
SC injection compared with 
placebo 
 
The change in global outcome from baseline 
(Day 1) to Week 116, as measured by the CDR-
SB 
Secondary Objective(s) 
Corresponding Endpoints 
 
To evaluate the efficacy of 
gantenerumab versus placebo on 
cognition and/or function 
The change from baseline to Week 116 in cognition 
and/or function, as measured by: 
 
MMSE total score 
 
ADAS-Cog11 and ADAS-Cog13 
 
Verbal Fluency Task 
 
Coding 
 
FAQ 
 
ADCS-ADL total score and instrumental score 
Exploratory Objective(s) 
Corresponding Endpoints 
 
To evaluate the efficacy of 
gantenerumab versus placebo 
The change from baseline to Week 116 in the 
following: 
 
Clinically evident decline as measured using the 
CDR 
 
Severity, as assessed by the CDR Global Score 
 
Dependence level, as derived from the 
ADCS‑ADL score 
 
Health-related quality of life, as assessed by the 
QoL-AD scale 
 
Behavioral and neuropsychiatric symptoms of 
AD, as measured by the NPI-Q 
 
Study partner burden, as assessed by the 
ZCI‑AD scale 
 
Elements of resource utilization, as assessed by 
the RUD-Lite 
 
Health outcomes in participant and study 
partner, as measured by EQ-5D questionnaire 
 


 
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Table 1 Objectives and Corresponding Endpoints (cont.) 
Safety Objective(s) 
Corresponding Endpoints 
 
To evaluate the safety of 
gantenerumab compared with 
placebo 
 
Nature, frequency, severity, and timing of 
adverse events and serious adverse events 
 
Physical examinations (including neurological 
systems), vital signs, blood tests, ECGs, and 
C‑SSRS 
 
Nature, frequency, severity, and timing of MRI 
findings:  ARIA-E and ARIA-H 
 
Nature, frequency, severity, and timing of 
injection-site reactions 
 
Presence of ADAs during the study relative to 
the presence of ADAs at baseline (in active 
drug group only) 
Pharmacodynamic Biomarker 
Objective 
Corresponding Endpoints 
 
To evaluate the effect of 
gantenerumab compared with 
placebo  
 
Change from baseline to Week 116 in brain 
amyloid load, as measured by amyloid PET 
scan in a subset of participants 
 
Change from baseline to Week 116 in brain tau 
load, as measured by tau PET scan in a subset 
of participants 
 
Change from baseline to Week 116 in 
cerebrospinal fluid markers of disease in a 
subset of participants, including, but not limited 
to total tau, and phosphorylated tau 
Exploratory Biomarker 
Objective 
Corresponding Endpoints 
 
To evaluate the effect of 
gantenerumab compared with 
placebo  
 
Change over time in plasma and other CSF 
biomarkers 
 
Change from baseline to Week 116 in functional 
brain connectivity, as measured by resting-state 
functional MRI (where available) 
 
Change from baseline to Week 116 in integrity 
of white matter, as measured by DTI-MRI 
(where available) 
 
Change in MRI-derived measurements over 
time, such as volumetric changes in whole 
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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-SB  Clinical Dementia Rating-
Sum of Boxes; CSF  cerebrospinal fluid; C-SSRS  Columbia-Suicide Severity Rating Scale; 
DTI  diffusion tensor imaging; EQ-5D  EuroQol-Five Dimensions; FAQ  Functional Activities 
Questionnaire; MMSE  Mini-Mental State Examination; MRI  magnetic resonance imaging; 
NPI-Q  Neuropsychiatric Inventory-Questionnaire; PET  positron emission tomography; QoL-
AD = Quality of Life-Alzheimer's Disease; RUD-Lite  Resource Utilization in Dementia-Lite; 
SC  subcutaneous; ZCI-AD  Zarit Caregiver Interview-Alzheimer's Disease. 
  
1.2 
STUDY DESIGN 
GRADUATE I and GRADUATE II are two identical Phase III, multicenter, randomized, 
double-blind, placebo‑controlled, parallel-group studies designed to evaluate the efficacy 
and safety of gantenerumab in participants with early (prodromal to mild) AD. 
The planned number of participants for the global enrollment phase for each study is 
approximately 1016 participants randomized in a 1:1 ratio to receive active drug or 
placebo (508 participants randomized to active drug and 508 randomized to placebo; 
see Section 3).  To maintain a balanced number of participants enrolled in each 
treatment arm and to ensure that the arms are comparable, randomization will be 
stratified by stage of the disease (prodromal AD vs. mild AD), apolipoprotein 4 (APOE) 
allele status (presence vs. absence of the ε4 allele), use of AD medication (presence vs. 
absence), geographic region (Western Europe and Australia vs. Rest of the World vs. 
North America), and participation in the longitudinal amyloid and tau PET substudies.  
Approximately 175 centers in approximately 15 countries worldwide will participate in 
these studies. 
Due to the global impact of the coronavirus disease (COVID-19) pandemic and the 
resulting disruption in study drug administration, the duration of the double-blind 
treatment period was extended by 12 weeks, with Protocol Amendment 4.  The optional 
scenario of a further extension of 12 weeks – resulting in a final efficacy and safety visit 
at Week 128 – was not implemented.  An overview of the study design is provided in 
Figure 1. 


 
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Figure 1 Overall Study Design 
Each study consists of three distinct periods:   
Screening (including an optional prescreening): The screening period may last up to 
12 weeks for each eligible participant. 
Double-blind treatment period: After screening, participants who meet all eligibility 
criteria will be randomly assigned to one of two arms (active drug or placebo) in a 
1:1 ratio.  Following baseline assessments, each participant will receive a minimum of 
9 subcutaneous (SC) administrations every 4 weeks (Q4W) of study drug (uptitration 
period), followed by up to 40 administrations every 2 weeks (Q2W) of study drug at 
target dose in the double-blind treatment period.  The last dose of study drug will be 
administered at Week 114.  At the end of the double-blind treatment period, 2 weeks 
after the last dose, all participants will undergo the final efficacy and safety study visit.  
Participants who have already completed the double-blind treatment period prior to 
implementation of Protocol Version 4 will have received up to 34 SC Q2W 
administrations of study drug during the double-blind treatment period.  The last dose 
will have been administered at Week 102, and their final efficacy and safety visit will be 
at Week 104.   
The Sponsor will emphasize to Investigators the importance of collecting data for the 
primary endpoint through Week 116, even if participants withdraw from treatment but do 
not withdraw from the study. 
Post-double-blind treatment period: After the final efficacy and safety study visit for 
the double-blind treatment period, all participants will be asked to come back for the 
long‑term follow-up visits or to continue in the open-label extension (OLE).  Participants 
will either directly enter the separate WN42171 (hereafter referred to as 
“POSTGRADUATE”) OLE study or enter a parent study OLE period.  If entering the 
parent study OLE period, they will be required to complete the uptitration period (a 
minimum 36 weeks) following which they will then be able to roll over to the 


 
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POSTGRADUATE OLE study.  This second option is for participants at sites where 
POSTGRADUATE is not yet approved when they have reached the end of the double-
blind treatment period. 
China Enrollment Plan 
Based on historical data, participant recruitment is expected to take longer in China and 
therefore, a specific China enrollment plan has been established.  Thus, if at least 
1 participant is enrolled at sites in mainland China, Hong Kong, and Taiwan that are 
recognized by the National Medical Products Administration (NMPA) during the global 
enrollment phase, additional participants may be enrolled in a China extension to ensure 
a total enrollment that is sufficient to support registration in China.  Only participants 
enrolled at NMPA-recognized sites, during the global enrollment phase, will be included 
in the primary analysis.  All participants enrolled at NMPA-recognized sites, either during 
the global enrollment phase or the China extension phases, will be included in a 
China‑specific analysis. 
The China-specific analysis will be described in a separate SAP and therefore is not 
covered in this document. 
1.2.1 
Treatment Assignment and Blinding 
Randomization will be performed centrally using an interactive voice or Web‑based 
response system (IxRS).  After screening, participants who meet all eligibility criteria will 
be randomly assigned to one of two treatment groups (active drug or placebo).  The ratio 
will be 1:1; one active to one placebo.  The randomization method will be stratified 
block‑randomization.  Randomization to treatment allocation will be stratified by 
geographic region (Western Europe and Australia vs. Rest of the World vs. North 
America), participant APOE ε4 status (carrier vs. non-carrier), participant stage of 
disease (prodromal vs. mild AD), use of AD medication (presence vs. absence), and 
participation in the longitudinal amyloid and tau PET substudies.  Except in 
circumstances in which a Health Authority, Ethics Committee, or Institutional Review 
Board requires it, a participant will not be told of his or her APOE ε4 status.  Individual 
participant APOE ε4 genotype results will be blinded to participants, Investigators, and 
the Sponsor.  APOE ε4 status information will be supplied directly to the IxRS vendor by 
the central testing laboratory so that the information can be incorporated at the time of 
randomization.  For participants for whom APOE ε4 status is already known, the results 
will be blinded to the Sponsor and, as much as possible, to the site and central MRI 
reader.   
The study is to be conducted in a double-blind manner to minimize potential bias from 
Investigators and participants.  The Sponsor will be blinded to study treatment.  In the 
OLE phase, the Sponsor, participants, and site staff will remain blinded to previous 
treatment allocation.  


 
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The randomization method implemented in the China extension cohort will be the same 
as that implemented in the global population. 
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. 
Central facilities will be used for PET assessments (see Independent Review Charter 
[IRC]). 
1.2.3 
Data Monitoring Committee 
The iDMC will evaluate participant safety and efficacy on a regular basis.  In addition to 
the data defined in the iDMC Charter (e.g., the incidence and nature of adverse events 
[AE], serious adverse events [SAE], adverse events of special interest [AESI], 
amyloid‑related imaging abnormalities‑edema/effusion [ARIA-E], amyloid‑related 
imaging abnormalities‑hemosiderin deposition [ARIA‑H], and injection‑site reactions 
[ISR]), the iDMC will review all necessary cumulative data at regular intervals during the 
study, including efficacy when needed.  It is anticipated that these assessments will 
occur approximately every 3 months.  At the time of each review, the iDMC will make 
appropriate recommendations (e.g., the study should continue as planned, enrollment in 
a specific arm should be discontinued, the treatment regimen should be modified, the 
protocol should be amended, enrollment should be held pending further safety 
evaluations).  The iDMC will also evaluate planned or unplanned interim analyses for 
efficacy or futility. 
2. 
STATISTICAL HYPOTHESES 
The primary efficacy analysis will compare the active drug arm to the placebo arm at 
Week 116 with a two-sided test corresponding to the following null hypothesis, H0, and 
alternative hypothesis, H1: 
H0: µ active = µ placebo 
H1: µ active ≠ µ placebo 
Where  active and  placebo are the mean change from baseline to Week 116 in the 
CDR‑SB score for each arm. 
 
3. 
SAMPLE SIZE DETERMINATION 
Determination of sample size is based on participants enrolled in the global enrollment 
phase.  In each study, approximately 1016 participants will be enrolled and randomized 
in 1:1 ratio to each treatment arm (active drug or placebo) during the global enrollment 
phase.  The original planned sample size was of 760 participants, but it was increased to 
1016 participants based on considerations from external studies (in protocol version 3). 


 
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Additional participants may be randomized during the China extension if at least 
1 participant is enrolled at sites in mainland China, Hong Kong, or Taiwan that are 
recognized by the NMPA during the global enrollment phase. 
The estimated sample size required to demonstrate efficacy with regard to Clinical 
Dementia Rating-Sum of Boxes (CDR-SB) is based on the following assumptions:   
 
the mean change in the CDR-SB from baseline to Week 104 is 2.5 points in the 
placebo arm 
 
a common standard deviation across treatment arms for change of approximately 
2.97 from baseline to Week 104 in the CDR-SB 
 
active drug has a true effect of a 30% relative reduction in deterioration of CDR-SB 
 
Based on these assumptions, and using a student’s T‑test with equal variance, a sample 
size was calculated for 90% power to detect a true treatment effect of 30% relative 
reduction in deterioration of CDR-SB at a two-sided  of 0.05. 
Uncertainties on parameters affecting the power (e.g., dropout rate, study drug 
discontinuation rate, standard deviation, and placebo decline) were assumed to be 
equivalent to a drop in sample size of up to around 35% and were corrected for 
accordingly.  This calculation leads to a total of 1016 participants in the study. 
At the date of writing Protocol Version 4, it was expected that participants would miss an 
average of 8 weeks of study drug administration over the course of the original two-year 
study due to the COVID-19 pandemic.  This had the potential to decrease the power of 
the study from ~90% to ~80%.  To mitigate the impact of missed administrations, the 
double-blind treatment period has been extended by 12 weeks.  Under current 
assumptions, this brings the study power back to the originally planned ~90%. 
4. 
ANALYSIS SETS 
The following analysis sets are defined: 
 


 
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Table 2 
Analysis Sets 
Analysis set 
Definition 
Scope 
All enrolled 
participants 
All participants randomized during the global 
enrollment phase whether or not the participant 
received the assigned treatment. 
Analysis using this analysis set will be performed 
by randomized treatment. 
Participant disposition report 
will be based on this analysis 
set 
Intent-to-treat (ITT) 
All participants randomized during the global 
enrollment phase, who received at least one 
dose of study drug. 
Analysis using this analysis set will be performed 
by randomized treatment. 
All efficacy analyses, 
including the primary 
estimand, will be based on 
this analysis set. 
CSF modified intent-
to-treat (CSF-mITT) 
All participants in the ITT analysis set who had at 
least one valid quantitative cerebrospinal fluid 
(CSF) measurement  
Analysis using this analysis set will be performed 
by randomized treatment. 
All analyses of CSF 
biomarkers will be based on 
this analysis set 
CSF-longitudinal 
All participants in the CSF-mITT who had at 
least one valid quantitative Week 116 CSF 
measurement of phosphorylated tau (pTau-181), 
tTau, Neurogranin or NFL. 
Summary of treatment group 
comparability will also be 
repeated on this analysis set. 
Plasma-longitudinal 
All participants in the ITT analysis set who had at 
least one valid quantitative post-baseline plasma 
measurement of Amyloid beta (1-42) (Abeta-42) 
or phosphorylated tau (pTau-181) 
Summary of treatment group 
comparability will also be 
repeated on this analysis set. 
MRI modified intent-
to-treat  
(MRI-mITT) 
All participants in the ITT analysis set who had at 
least one valid volumetric MRI quantitative 
measurement.  
Analysis using this analysis set will be performed 
by randomized treatment. 
All analyses of volumetric 
MRI parameters will be based 
on this analysis set. 
MRI-longitudinal 
All participants in the MRI-mITT with at least one 
valid post-baseline volumetric MRI quantitative 
measurement. 
Summary of treatment group 
comparability will also be 
repeated on this analysis set. 
Tau PET modified 
intent-to-treat (Tau-
PET-mITT) 
All participants in the ITT analysis set who 
participated in the Tau PET sub-study and who 
had at least one Tau PET scan with a valid 
quantitative measurement and who did not 
withdraw from the Tau PET substudy before 
randomization 
Analysis using this analysis set will be performed 
by randomized treatment. 
All analyses of Tau PET 
parameters will be based on 
this analysis set. 
Tau-PET-longitudinal 
All participants in the Tau-PET-mITT with a valid 
post-baseline quantitative Tau PET 
measurement. 
Summary of treatment group 
comparability will also be 
repeated on this analysis set. 


 
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Table 2  
Analysis Sets (cont.) 
Analysis set 
Definition 
Scope 
Amyloid PET 
modified intent-to-
treat (Amyloid-PET-
mITT) 
All participants in the ITT analysis set who 
participated in the Amyloid PET sub-study and 
who had at least one Amyloid PET scan with a 
valid quantitative measurement performed with 
either florbetaben or flutemetamol and who did 
not withdraw from the Amyloid PET substudy 
before randomization.  
 
Analysis using this analysis set will be performed 
by randomized treatment. 
All analyses of Amyloid PET 
parameters will be based on 
this analysis set 
Amyloid-PET-
longitudinal 
All participants in the Amyloid-PET-mITT with a 
valid post-baseline quantitative amyloid PET 
measurement performed with either florbetaben 
or flutemetamol.  
Summary of treatment group 
comparability will also be 
repeated on this analysis set. 
Safety-evaluable 
All participants randomized during the global 
enrollment phase who received at least one 
dose of study drug.  Any participant randomized 
to placebo who received at least one dose (any 
dose) of active drug will be summarized as 
having received the active drug. 
Analysis using this analysis set will be performed 
by treatment actually received. 
All safety analyses (with the 
exception of Safety MRI) will 
be based on this analysis set. 
MRI Safety-
evaluable  
All participants in the Safety-evaluable analysis 
set who had at least one post-baseline safety 
MRI scan. 
Analysis using this analysis set will be performed 
by treatment actually received 
All analyses of safety MRI will 
be based on this analysis set. 
Amyloid-PET Safety 
Evaluable 
All participants in the Safety-evaluable analysis 
set who received at least one dose of radioligand 
Analysis using this analysis set will be performed 
by treatment actually received 
All safety analysis for the 
amyloid-PET sub-study will 
be based on this analysis set. 
Tau-PET Safety 
Evaluable 
All participants in the Safety-evaluable analysis 
set who received at least one dose of 
radioligand. 
Analysis using this analysis set will be performed 
by treatment actually received 
All safety analysis for the 
tau-PET sub-study will be 
based on this analysis set. 
  
5. 
STATISTICAL ANALYSES 
5.1 
GENERAL CONSIDERATIONS 
The clinical cutoff date for the primary analysis is defined by the date of the last 
randomized participant plus 116 weeks.  
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 


 
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(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 clinical endpoints and biomarkers assessments, the baseline is defined as the 
assessment taken at the baseline visit (Day 1) up to and including the day of first study 
drug intake.  If no assessment is reported at the baseline visit up to the day of first study 
drug intake, the earliest assessment reported after Day 1 and up to the day of second 
dose or Day 35, whichever is earlier, will be used as baseline.  If no assessment is 
reported either at baseline visit or up to Day 35, an assessment reported at screening 
will be used as baseline.  Day 35 is the latest timepoint allowed for Week 4 visit as per 
protocol. 
For all other assessments, the baseline is defined as the last available assessment prior 
to first study drug intake, unless specified otherwise.  
For biomarkers (CFS and plasma), values below the lower limit of quantification (LLOQ) 
will be set to 0.5*LLOQ, while values above the upper limit of quantification (ULOQ) will 
be set to ULOQ.  A summary table will be provided to summarize the values below 
LLOQ and above ULOQ for each treatment arm. 
The efficacy analyses will be based on the ITT analysis set (see Table 2) and will 
compare the active drug arm against the placebo arm with regards to mean change from 
baseline to Week 116.  Two-sided test hypotheses will be defined in the following 
sections and the type I error level will be 5%.  There are two identical Phase III studies, 
for each respective study the type I error level will be 5%.  In order to protect the overall 
type I error rate (i.e., at each study level) when incorporating the hypothesis testing of 
multiple endpoints into the analysis, a fixed sequence testing procedure (Westfall and 
Krishen 2001) will be used to adjust for multiple comparisons.  Testing of each 
hypothesis will follow a pre-specified order such that an endpoint would only be tested if 
the preceding one in the hierarchy was significant at 5% alpha level.  The endpoint 
hierarchy, starting with the primary endpoint and including only confirmatory secondary 
endpoints, is the following:   
1. 
CDR-SB (Clinical Dementia Rating, Sum of Boxes) 
2. 
ADAS-Cog 13 (Alzheimer’s Disease Assessment Scale, Cognitive subscale, 
13-item) 
3. 
ADCS-ADL (Alzheimer’s Disease Cooperative Study, Activities of Daily Living 
scale) total score 
4. 
FAQ (Functional Activities Questionnaire) 
 
Missing outcome data will be handled using data imputation aligned with the estimand, 
see Section 5.3.3 for a detailed description of the analysis strategy. 


 
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When using a statistical model with baseline covariate adjustment, missing baseline 
covariate data other than the baseline outcome measure will be imputed to the overall 
median value for continuous covariates, or will be imputed to the most frequent category 
for categorical variables.  In addition, baseline covariates will be derived from information 
collected into the eCRF, unless otherwise specified. 
In statistical models using change from baseline of a given outcome measure as the 
dependent variable, there will be no imputation of the baseline outcome value, with the 
consequence that participants missing the baseline outcome measure will not contribute 
to the analysis. 
The impact of the COVID-19 pandemic on the study and its conduct will be monitored 
and the overall impact will be assessed and described in the Clinical Study Reports.  
 
5.2 
PARTICIPANT DISPOSITION 
The analysis of participant disposition will be based on all enrolled participants (see 
Analysis sets in Table 2).  The number of participants enrolled will be tabulated by 
country, site, and treatment arm.  Participant disposition (the number of participants 
randomized and completing the different study periods) will be tabulated by treatment 
arm.  Premature study drug discontinuation and study discontinuation, as well as 
reasons for discontinuations, will be summarized.  
Major protocol deviations, including major deviations with regard to the inclusion and 
exclusion criteria, will be summarized by treatment arm.  Separate tables will be 
provided for COVID-19-related major protocol deviations and reasons for 
COVID-19-related major protocol deviations. 
5.3 
ENDPOINT ANALYSIS 
5.3.1 
Definition of Primary Endpoint 
As detailed in the study protocols, the primary endpoint is the change from baseline to 
Week 116 in the CDR-SB which is a global scale covering both functional and cognitive 
domains. 
The CDR-SB is a detailed quantitative general index that 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 patient and a reliable informant or collateral 
source (e.g., a study partner). 


 
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5.3.2 
Definition of Primary Estimand 
The clinical question of interest is to assess the effect of the active drug on disease 
progression at Week 116, irrespective of use or initiation of symptomatic treatments for 
AD, in the absence of a substantial impact of the COVID-19 pandemic.  
In alignment with the Addendum to ICH E9, the primary efficacy estimand is described 
by the following attributes:   
 
Target Population: 
Early (prodromal to mild) AD population as identified by the inclusion and exclusion 
criteria, see Sections 4.1.1 and 4.1.2 of the study protocols  
 
Variable: 
Change from baseline to Week 116 in Clinical Dementia Rating – Sum of Boxes 
(CDR-SB) 
 
Treatment: 
Prescribed study drug including uptitration to the target dose and safety-related 
dose modifications, irrespective of use or initiation of symptomatic treatment for AD  
 
Population-level summary: 
Difference in variable means between treatment arms 
Intercurrent events (ICE): 
The ICEs are classified into two categories: those that are Study Drug or Condition 
Related (SDCR) and those that are not (NSDCR).  The list of main anticipated ICEs, and 
their classification as SDCR or NSDCSR, is presented below (Table 3).  The final list of 
ICEs may need to be adapted in case unanticipated ICEs emerge during the study 
conduct.  The classification of each ICE into SDCR or NSDCR will be completed and 
documented prior to the unblinding. 
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, not necessarily consecutive) of 
treatment missed due to COVID-19-related reasons.  This definition will be equally 
applied to placebo and active arms.  One dose-month is defined as 4 weeks of dosing, 
i.e., one dose with a Q4W dosing frequency (mostly during uptitration) or two doses with 
a Q2W dosing frequency (at target dose).  The threshold of four missed dose-months 
was determined based on the following reasons:   
– 
A 12-week extension to the study was implemented (in protocol amendment 
version 4) to mitigate the impact of the COVID-19 pandemic.  Therefore, treatment 
interruptions up to 3 dose-months (i.e., 12 weeks) are already accounted for in the 
study design.  
– 
Based on the half-life of approximately 24 days of gantenerumab, plasma 
concentration after a 4 months’ interruption at the target dose is expected to 
be below the observed concentration with the dose of 225 mg Q4W which was 


 
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shown to be ineffective in Studies WN25203 (SCarlet RoAD) and WN28745 
(Marguerite RoAD). 
– 
A 20% difference is the usual acceptability threshold to establish PK bioequivalence.  
The protocol includes 20 dose-months (80 weeks) at target dose after the 
up-titration period.  Missing less than 4 dose-months results in an overall reduction 
in drug exposure of less than 20% of the total planned dose. 
As a conservative approach, all withdrawals from study treatment due to an AE will be 
classified as SDCR for the purpose of the primary analysis.  This includes withdrawal 
from study treatment due to suspected or confirmed COVID-19 infection AE, because 
the relationship of these events to the participant condition may be ambiguous. 
All SDCR ICEs will be handled with a treatment policy strategy, while NSDCR ICEs will 
be handled with a hypothetical strategy.  The frequencies of ICE will be summarized by 
treatment arm. 
In this study, given the disease stage at baseline of the target population, death is 
expected to be a rare event and mostly not considered related to treatment or disease 
progression, and as such the corresponding ICE of death will be handled with a 
hypothetical strategy for the primary estimand.  Of note, a supplementary estimand 
which defines all ICEs, including death, as SDCR (and thus using the same imputation 
strategy as for the other SDCR ICEs; see Section 5.3.3), is described in Section 5.3.5.


 
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Table 3 
Intercurrent Events Impacting Primary Analysis 
Intercurrent Event 
SDCR/NSDCR 
Estimand Approach 
Withdrawal from study treatment due to lack of 
efficacy  
SDCR 
Treatment Policy 
Withdrawal from study treatment due to safety or 
tolerability reason  
(NOTE: This will include discontinuation due to AE, 
incl. suspected or confirmed COVID-19 AEs) 
SDCR 
Treatment Policy 
Withdrawal from study treatment with no informative 
reason given 
SDCR 
Treatment Policy 
Withdrawal from study treatment due to the 
COVID-19 pandemic 
NSDCR 
Hypothetical Strategy 
Substantial reduction in drug exposure due to the 
COVID-19 pandemic (defined as    4 missed 
dose-months) 
NSDCR 
Hypothetical Strategy 
Withdrawal from study treatment due to purely 
administrative reason 
NSDCR 
Hypothetical Strategy 
Death  
NSDCR 
Hypothetical Strategy 
Withdrawal from study treatment due to use or 
initiation of protocol prohibited medication 
SDCR 
Treatment Policy 
Withdrawal from study treatment due to other SDCR 
ICEs 
SDCR 
Treatment Policy 
AE   adverse event; COVID-19   coronavirus disease 2019; NSDCR   Non Study Drug or 
Condition Related; SDCR   Study Drug or Condition Related 
 
ICE Derivation 
Identification and categorization of the ICEs will be done based on fully blinded data only 
and will be finalized before database lock.  
The number of missed dose-months due to the COVID-19 pandemic will be derived from 
the standardized eCRF data fields.  More specifically, any Q4W missed dose due to 
COVID will count as 1 missed dose-months, while any Q2W missed dose due to COVID 
will count as 0.5 missed dose-months.  The information whether a dose was missed due 
to COVID will be derived from the corresponding “reason for missed visit” and “reason 
for missed dose” fields in the eCRF. 
All occurrences of “withdrawal from study treatment” ICE, as per Table 3, will be 
identified and categorized as SDCR/NSDCR based on the standardized reason reported 
in the eCRF “Study Drug Completion/Early Discontinuation” form.  In case of ambiguity 
(i.e., if the reason for study drug discontinuation as reported in the eCRF is either 
“Protocol deviation”, “Withdrawal by subject”, “Physician decision” or “Other”), an 
adjudication committee will review the dedicated eCRF free text field and assign the 
withdrawal to a pre-specified ICE and a corresponding SDCR or NSDCR category.  The 


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adjudication committee may also introduce additional ICEs to the list, in case where no 
appropriate fit is found in Table 3 or Appendix 2 .  The adjudication committee members 
must not have been involved in the conduct of Studies GRADUATE I and GRADUATE II 
and must not have been exposed to unblinding data from these studies.  The members 
of the adjudication committee must have signed the charter of the adjudication 
committee, in Appendix 3.  
5.3.3 
Main Analytical Approach for Primary Estimand and Primary 
Endpoint 
Primary study hypothesis 
The primary efficacy analysis for this study will test the superiority of the active drug over 
the placebo at Week 116 with a two-sided test corresponding to the following null 
hypothesis, H0, and alternative hypothesis, H1:   
H0: µ active = µ placebo 
H1: µ active ≠ µ placebo
Where  active and  placebo are the mean changes from baseline to Week 116 in the 
CDR-SB score for each arm. 
Time Windowing 
For the primary endpoint (and in general for clinical efficacy endpoints) the following time 
windows will be used for analyses (see Table 4), based on study days.  Study days are 
defined based on days on study since the date of the first dose, with the day of the first 
dose being study day 1. 
Table 4 
Time windows for clinical endpoint assessments 
Visit 
Target day 
Time window (in study 
days*) 
Baseline 
1 
Up to Day 35 
Week 24 
169 
72, 266 
Week 52 
365 
267, 448 
Week 76 
533 
449, 630 
Week 104 
729 
631, 770 
Week 116 
813 
771, earliest between 897 or 
first dose of OLE 
In cases where more than one assessment falls within a time window, the assessment 
with the date closest to the target day is selected whether it’s a scheduled, unscheduled 
or an early termination visit. 


 
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With regards to an ICE of withdrawal from study treatment, an assessment will be 
regarded as having happened after the ICE of withdrawal from study treatment if it is 
collected   28 days since the last dose. 
General strategy to address the ICEs 
For the primary estimand, a treatment policy approach will be used for all SDCR ICEs.  
In line with the clinical question of interest, the aim is to estimate a treatment effect 
irrespective of the occurrence of these ICEs.  This approach is largely in line with the 
EMA guideline on the clinical investigation of medicines for the treatment of AD (EMA 
2018).  
All NSDCR ICEs will be handled using a hypothetical approach.  The aim is to estimate 
a treatment effect “as if” the ICE had not happened.  Post-ICE outcome values 
compatible with a hypothetical strategy are not directly observable.  Consequently, any 
observed outcome values after NSDCR ICEs will be removed and treated as missing 
data for analysis purposes.   
For participants with multiple ICEs, the type of the first ICE will determine the strategy to 
be considered.   
Missing data assumptions for the primary estimator 
For intermittent missing data (i.e., for participants with non-missing Week 116 data but 
missing data at other visits), missing data not associated with an ICE (e.g., for 
participants who had completed Week 104 visit before protocol v4 was implemented), 
and for missing data after NSDCR ICEs (handled with a hypothetical strategy), the 
missing data are assumed to be similar to those from the other participants in the same 
treatment group with no such missing data.  This is compatible with a missing-at-random 
(MAR) assumption. 
All observed data after SDCR ICEs will be included in the analysis.  If data after SDCR 
ICEs are missing, they will be assumed to be similar to those in the placebo group for 
both study arms.  Specifically, data will be imputed based on the placebo arm using 
reference based imputation with a Copy Increments from Reference (CIR) assumption 
(Carpenter et al, 2013 and Cro et al, 2020).  This approach appears conservative yet 
plausible for the study drug.  CIR assumes that changes in the primary endpoint after the 
ICE in a participant randomized to active drug can be represented by, i.e., imputed from, 
that of participants randomized to placebo.  It therefore assumes no treatment effect 
after the ICE.  In the placebo arm, this is compatible with a MAR assumption whereas in 
the active drug arm, the imputation is under a Missing Not At Random (MNAR) 
assumption. 


 
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Further details about the implementation of the missing data imputation are provided 
below.  Sensitivity analyses for the missing data assumptions are discussed in 
Section 5.3.4.  
Description of the primary estimator 
The primary estimator will be applied to the ITT analysis set (see Table 2) and it will be 
implemented using four steps.  First, an imputation model will be fitted to the data.  
Second, imputation of missing data will be performed based on the parameter estimates 
from the imputation model.  Third, the completed data will be analyzed using an analysis 
of covariance (ANCOVA) model.  Finally, inference will be performed based on 
resampling techniques.  All four steps are described and justified in a published 
manuscript (Wolbers et al. 2022) which provides a more detailed justification of the 
statistical methodology and supportive simulations.  Considerations about the control of 
type-I error for the primary estimator and supportive simulations, mimicking the setting of 
the GRADUATE I and GRADUATE II studies and exploring an extended range of 
plausible scenarios for missing data, are provided in the Appendix 1.   
1. Imputation model 
The imputation model is a mixed effects model for repeated measures (MMRM) with the 
longitudinally assessed change from baseline in CDR-SB as the dependent variable.  Its 
purpose is to estimate mean trajectories and covariance matrices of longitudinal 
outcomes in the placebo and active drug arms, respectively, while subjects remain on 
their randomized treatment.  Therefore, all data after withdrawal from study treatment 
will be removed and considered as missing for the purpose of estimating the imputation 
model, and for this purpose only.  If these data were not excluded, then the imputation 
model would estimate mean trajectories based on a mixture of observed pre- and 
post-discontinuation data.  These would not be compatible with the CIR assumption 
employed in the subsequent imputation step, which requires combining mean 
trajectories while on active drug up to the ICE with increments while on placebo 
thereafter, respectively. 
The imputation model includes the following covariates: treatment group, visit, and 
treatment-by-visit interaction, baseline CDR-SB score and baseline 
CDR-SB score-by-visit interaction, baseline ADAS-Cog 13 total score, baseline 
ADCS-ADL total score and the randomization stratification factors, namely: disease 
stage (from the eCRF), geographic region (from the IxRS), the use of AD medication at 
baseline (derived from the eCRF based on a search of medications; see below for more 
details) and the APOE ε4 status (from the Vendor).  For geographic region, IxRS is 
preferred over the eCRF source, to keep the “starting” region for analysis, in case a 
participant moved to a different region during the study (the eCRF would otherwise 
reflect the “final” region).  AD medication at baseline will be defined as any use of 
donepezil, galantamine, memantine or rivastigmine prior to randomization and with an 


 
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end date not before the randomization date.  An unstructured variance-covariance 
structure will be applied to model the within-subject errors across visits.  If the model 
fails to converge, then a heterogeneous Toeplitz covariance structure will be used 
instead and if this still fails, then a compound symmetry covariance structure will be 
used.  
Imputations will be based on restricted maximum likelihood (REML) estimation of the 
regression and covariance parameters from the imputation model (von Hippel and 
Bartlett 2021; Wang and Robins 1998).  
2. Imputation step 
The imputation model implies a marginal multivariate normal distribution of the 
longitudinal outcome values across all visits based on a participant’s assigned treatment 
arm and covariate values.  This marginal imputation distribution will be used for all 
participants in the placebo arm and all participants in the active drug arm without an 
SDCR ICE.  For participants in the active drug arm with an SDCR ICE, the mean of the 
marginal imputation distribution for outcomes after the SDCR ICE will be modified as per 
the CIR assumption (Carpenter et al. 2013). 
For each participant, the conditional imputation distribution of their missing outcome 
values is defined as the marginal imputation distribution conditional on the participant’s 
observed outcomes (including observed post-SDCR ICE outcome assessments).  A 
single deterministic imputation using the conditional mean from the conditional 
imputation distribution for each participant with missing outcomes will be used.  
3. Analysis step 
The completed data (using conditional mean imputation as described above) will be 
analyzed using an ANCOVA model with the change from baseline in CDR-SB at the 
Week 116 visit as the dependent variable.  This analysis model includes treatment group 
as the primary covariate with adjustment for the same set of covariates as for the 
imputation model described above, namely baseline CDR-SB score, baseline 
ADAS-Cog 13 total score, baseline ADCS-ADL total score and the randomization 
stratification factors namely: disease stage (from eCRF), geographic region (from the 
IxRS), the use of AD medication at baseline (derived from eCRF based on a search of 
medications; see below for more details) and the APOE ε4 status (from the Vendor).  For 
geographic region, IxRS is preferred over the eCRF source, to keep the “starting” region 
for analysis, in case a participant moved to a different region during the study (the eCRF 
would otherwise reflect the “final” region).  AD medication at baseline will be defined as 
any use of donepezil, galantamine, memantine or rivastigmine prior to randomization 
and with an end date not before the randomization date.  The primary treatment effect 
estimator is defined as the regression coefficient associated with the treatment group.  
The treatment effect will be reported as a difference in adjusted means.  The treatment 


 
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effect at the other visits will be estimated in the same way and will be reported as 
supplementary analyses of the primary endpoint (see Section 5.3.5).  
Percent relative difference, defined as 100 times the estimated treatment effect divided 
by the absolute value of the placebo arm estimate, will also be reported, for all visits, as 
a point estimate for descriptive purposes.  Importantly, ANCOVA is applied to a 
complete dataset after appropriate missing data imputation.  For complete data, 
ANCOVA applied to outcomes from a single visit is equivalent to a more complex 
MMRM model.  It can be demonstrated that it leads to identical parameter estimates as 
a corresponding MMRM model with an arbitrary covariance structure if separate 
regression coefficients are estimated at different visits for all covariates (Amemiya 1985, 
p. 197).  
4. Inference step 
Inference will be based on resampling techniques as recommended by von Hippel and 
Bartlett 2021.  Specifically, the jackknife (Efron and Tibshirani, 1994) will be used to 
estimate the standard error of the primary treatment effect estimator and the test of the 
primary statistical hypothesis will be based on the corresponding Z-score.  Compared to 
other resampling techniques, the jackknife has the advantage of providing a 
deterministic standard error estimate and, hence, removing any simulation randomness 
from the procedure.  
 
5.3.3.1 
Software Implementation and Validation 
The reference based imputation methodology will be implemented by an internally 
developed R package “rbmi” (“reference-based multiple imputation”).  The package will 
comply with the ICH guidance document “ICH E 9: Statistical principles for clinical trials” 
which states that:  “The computer software used for data management and statistical 
analysis should be reliable, and documentation of appropriate software testing 
procedures should be available.” 
The testing strategy for the package consists of defining and documenting the expected 
input and output of each function and implementing unit tests to prove that the package 
performs as expected.  All implemented methods will be recorded and referenced 
against the literature with unit tests and simulations put in place to show that known 
values can be recovered as well as showing consistency with similar software from other 
languages (most notably the “5-Macros” implemented by the Drug Information 
Association Scientific Working Group on Estimands and Missing Data in SAS). 
The package, including all documentation and testing materials, is available on 
GitHub.com (https://github.com/insightsengineering/rbmi) and on CRAN repository 
(https://cran.r-project.org/package=rbmi) to allow for unrestricted access and enable 
public scrutiny of the code and methods.  Description of the rbmi package is also 
available on a published manuscript (Gower-Page et al. 2022). 


 
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The rbmi R package was validated by the in-house tool, Autovalidate R, which performs 
general R package quality checks and performs testing for expected behaviors.  
5.3.4 
Sensitivity Analyses for Primary Endpoint 
Impact of COVID-19 pandemic 
The following sensitivity analyses will be performed to evaluate the impact of the 
COVID-19 pandemic: 
– 
Vary threshold on number of missed dose-months 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    4 dose-months (not necessarily 
consecutive).  A sensitivity analysis will be performed using different thresholds:  1, 
2, 3, 5 and 6 dose-months.  All other aspects of the primary estimator will remain the 
same. 
– 
Exclude participants based on site closure information and apply a treatment policy 
strategy to all other COVID-19 related ICEs. In this analysis, all participants enrolled 
before a site closure due to the pandemic will be removed from the analysis set.  In 
alignment with the primary estimand, only a site closure of 16 weeks or more during 
the double-blind treatment period and without any access to study drug (no home 
nursing) will be considered. In accordance with the FDA’s guidance for Industry 
“Statistical Consideration for Clinical Trial During the COVID-19 Public Health 
Emergency (June 2020)”, participants excluded from this analysis can be identified 
using baseline data only: randomization date and site number.  The site closure 
information is an administrative site level information, independent of the conduct of 
the trial, collected using the eCRF for the purpose of this study and analysis.  The 
substantial reduction in drug exposure due to the COVID-19 pandemic (defined 
as    4 missed dose-months) will not be considered as an ICE.  All other aspects of 
the primary estimator will remain the same. 
– 
Remote scale administration.  Remote scale administration was authorized in 
exceptional cases at Weeks 104 and 116 visits due to COVID-19 related 
restrictions.  In this analysis, all CDR-SB assessments performed remotely will be 
excluded from the analysis and treated as missing data.  All other aspects of the 
primary estimator will remain the same. 
– 
A subgroup analysis based on the date of randomization.  This will allow estimating 
the treatment effect for subgroups of participants randomized at least 12 months 
before the onset of the global COVID pandemic (11 March 2020 according to the 
World Health Organization (WHO) opening remarks), in   5 to 12 months prior to the 
onset of the global COVID pandemic and within less than 5 months from the onset 
of the global COVID pandemic (see Section 5.3.5.1 for an exact definition of each 
subgroup). 


 
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Impact of missing data handling methods  
The following sensitivity analyses will be performed to evaluate the impact of missing 
data handling method:   
– 
Tipping point analysis  
This analysis stress tests the CIR assumption by imputing worse outcomes after 
SDRC ICEs in the active drug arm than predicted by the CIR assumption.  This will 
be implemented via a marginal -approach as described in the ‘rbmi: advanced 
functionality’ vignette of the rbmi’s package  and in Cro et al, 2020.  Specifically, the 
imputation step will be performed as for the primary estimator and, after imputation 
is completed, a constant  will be added to the imputed week 116 outcomes 
occurring after SDCR ICEs in the active drug arm.  The subsequent analysis step of 
these -adjusted imputed datasets is as for the primary estimator.   
To determine the tipping point, the constant  will be increased in small steps 
starting from a value of 0 (corresponding to the primary estimator).  The tipping point 
will then be defined as the value of  at which the p-value for the treatment effect 
estimator first becomes greater than 5%.   
 
Impact of potential outliers or extreme observations 
In order to assess the impact of a potentially small number of “extreme observations” or 
“outlier points” (e.g., rapid progressors) on the treatment effect, the ANCOVA analysis 
model will be replaced by a robust linear regression.  Robust regression will produce 
treatment effect estimates less contaminated by highly influential observations.  
Specifically, robust regression using M estimation will be used.  Standard errors and 
confidence intervals will be based on jackknife as described previously.  
 
5.3.5 
Supplementary Analyses for Primary Endpoint 
5.3.5.1 
Subgroup Analyses for Primary Endpoint 
The generalizability of the CDR-SB results when comparing the active drug arm to the 
placebo arm will be investigated by estimating the treatment effect in the following 
subgroups:   
 
Demographics: 
 
Age, two age categories cut by the median 
 
Sex  
 
Geographic Region, as per IxRS 
 
Baseline disease severity: 
CDR-GS = 0.5 vs CDR-GS > 0.5 
 
Prodromal vs Mild (as per eCRF) 


 
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 
APOE ε4 genotype  
 
Carrier/Non Carrier  
 
Use of symptomatic AD medication at baseline Yes/No (derived from eCRF based 
on the search below) 
 
Symptomatic AD medication is defined as any one of: donepezil, galantamine, 
memantine or rivastigmine  
 
Randomization date, three subgroups defined by the following dates: 
 
before 11 March 2019 
 
in between (and including) 11 March 2019 and 1 October 2019  
 
after 1 October 2019 
 
Summaries of the treatment effect for the change in CDR-SB from baseline to Week 116 
by these subgroups will be provided in forest plots. 
5.3.5.2 
Other Supplementary Analyses for Primary Endpoint(s)  
Treatment effect estimates before Week 116 
In this supplementary analysis, the same analysis strategy as described for the primary 
estimator will be used to estimate the effect of the active drug on disease progression 
defined as a change in CDR-SB at other time points, other than Week 116.  
The treatment effect on the adjusted mean change in CDR-SB from baseline to 
Week 24, 52, 76 and 104 will be provided. 
Treatment effect in relationship to a post-baseline timepoint 
In this supplementary analysis, the same analysis strategy as described for the primary 
estimator will be used to estimate the percent relative difference between Week 52 and 
Week 116 as well as between Week 24 and Week 116, and between Week 76 and 
Week 116. 
The relative difference between e.g., Week 52 and Week 116 (and similarly for the other 
considered post-baseline timepoints) will be defined as: 
[(Delta_wk_116 - Delta_wk_52) / (Placebo_wk_116 - Placebo_wk_52)] *100 
where Delta_wk_x is the estimated treatment effect at Week x, and Placebo_wk_x is the 
estimated change from baseline for the placebo arm at Week x.  All those quantities will 
be obtained from the same model used for the primary estimand. 


 
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Treatment policy estimand 
All ICEs will be handled with a treatment policy strategy regardless of whether being 
SDCR or NSDCR.  All observed data will be included regardless of occurrence of any 
ICE.  Missing values following all ICEs will be imputed with the method used in the 
primary estimator for missing data following an SDCR ICE, see Section 5.3.3.  Missing 
values, not following an ICE, will be imputed under MAR (similarly to the primary 
estimands analysis, see “Missing data assumptions for the primary estimator” in 
Section 5.3.3).  Note that the attributes of population, variables, treatment, and 
population level summary will remain the same as for the primary estimand. 
Concomitant AD treatment estimand  
In this supplementary analysis, the treatment effect will be evaluated in the hypothetical 
scenario that no post-baseline initiation or modification of the use of other approved AD 
medication has happened.  
All attributes of this estimand except Treatment will be identical as for the primary 
estimator.  The treatment attribute will be: “Prescribed study drug including uptitration to 
the target dose, irrespective of concomitant use of symptomatic treatment for AD at 
baseline, but assuming no initiation or change in symptomatic treatment after baseline”.  
In this supplementary analysis, all data following ICEs “Starting another treatment for 
AD” and “Changing the dose of a symptomatic treatment for AD” will be set to missing 
and imputed under a MAR assumption, in line with a hypothetical strategy.  The analysis 
methods will be the same as described for the primary estimand.  
MMRM  
This analysis aims to provide a reference point analysis method described in early 
versions of the protocol (up to version 4) and to other external analyses where MMRM 
was considered the default and primary analysis.  All available data will be used in the 
analysis.  There will be no missing data imputation or consideration for any intercurrent 
events.  The model will include the following covariates: treatment group, visit, and 
treatment-by-visit interaction, baseline CDR-SB score and baseline CDR-SB 
score-by-visit interaction, baseline ADAS-Cog 13 total score, baseline ADCS-ADL total 
score and the randomization stratification factors, namely: disease stage (from eCRF), 
geographic region (from the IxRS), the use of AD medication at baseline (from eCRF) 
and the APOE ε4 status (from the Vendor).  An unstructured variance-covariance 
structure will be applied to model the within-subject errors across visits. In the case of 
non-convergence, compound symmetry will be used, together with a robust estimator of 
standard error (“sandwich” estimator). 


 
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Clinically evident decline: a progressor analysis 
In this supplementary analysis, CDR-SB progression will be defined as a change from 
baseline in CDR-SB greater than or equal to a threshold x.  The primary threshold of 
interest is x  2.5.  The work justifying the threshold will be presented, as an oral 
presentation, at the Alzheimer’s Association International Conference (AAIC), 
31 July4 Aug 2022; San Diego, CA and online (title of the oral presentation: Selecting 
appropriate meaningful change thresholds for trials of early (prodromal-to-mild) AD: A 
caregiver-rated, anchor-based analysis based on the Tauriel Study). 
The CDR-SB progression endpoint will be analyzed using the same conditional mean 
imputed dataset as for the primary estimator of the primary estimand (Section 5.3.3).   
The probability of CDR-SB progression by Week 116, in each treatment arm, will be 
estimated by the proportion of participants with a progression at any time during the 
double blinded period.  The probability of progression by Week 116 will be obtained for 
different values of the progression threshold x.  A plot of the probability of CDR-SB 
progression by Week 116 versus threshold values x will be generated.  
In addition, a Cox proportional hazard model to estimate the treatment effect on time to 
first CDR-SB progression (based on the primary threshold of interest), may also be 
considered. In this case, the same baseline covariates as for the primary estimator of the 
primary estimand will be used (Section 5.3.3).  An unadjusted model or a stratified 
analysis may be considered as well.  Corresponding standard errors and confidence 
intervals will be calculated using the jackknife as previously described. 
Impact of ARIA-E MRI finding on the primary outcome 
In this supplementary analysis, the objective is to estimate the treatment effect, in the 
hypothetical scenario where ARIA-E would not have occurred.  This analysis aims at 
removing the potential impact of ARIA-E on the primary endpoint. 
All the attributes from the primary estimand will remain the same, but an ICE of ‘ARIA-E 
occurrence’ will be added.  The ‘ARIA-E occurrence’ will be handled with hypothetical 
strategy.  All data collected after the occurrence of an ARIA-E will be removed and 
treated as missing for this data analysis purpose.  Post- ARIA-E data will then be 
imputed under the Missing at Random assumption unless ARIA-E is not the first ICE.  In 
this case, the imputation will be determined by the strategy for the first ICE as described 
for the main estimator.  
5.3.6 
Convergence Considerations for RBMI-Based Analyses 
In the rare situation that the imputation model (see step 1, imputation model, in Section 
5.3.3) would fail to converge despite the attempt to simplify the variance-covariance 


 
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matrix, it will be investigated whether removing some covariates and/or pooling factor 
levels of categorical covariates would solve the issue.  
In case the root cause of the problem could not be attributed to the choice of covariates, 
the following approaches will be tried in sequence: 
 
Replace jackknife with bootstrap, and accept up to a maximum of 5% failed runs 
(out of the total number of bootstrap runs). Runs that did fail would be discarded. 
 
Derive only a point estimate based on the conditional mean imputation, but no 
standard error (as jackknife and bootstrap did not work) 
 
5.4 
SECONDARY ENDPOINTS ANALYSES 
The same primary estimand’s analysis strategy (see Section 5.3.2) will be applied to 
secondary endpoints listed in Table 5, with the following exceptions for the 
corresponding estimator: 
 
.  the imputation model will not include, as covariates, the baseline ADAS-Cog 13 
total score and the baseline ADCS-ADL total score  
  The imputation model will thus include treatment group, visit, and treatment-by-
visit interaction, the baseline score and the baseline score-by-visit interaction, 
and the randomization stratification factors, namely: disease stage, geographic 
region, the use of AD medication at baseline and the APOE ε4 status  
 
  the analysis model will not include, as covariates, the baseline ADAS-Cog 13 
total score and the baseline ADCS-ADL total score  
  The analysis model will thus include treatment, the baseline score and the 
randomization stratification factors, namely: disease stage, geographic region, 
the use of AD medication at baseline and the APOE ε4 status 
In the following, confirmatory secondary endpoints refer to endpoints included in the 
type I error control procedure.  Other important secondary endpoints not subject to the 
type I error control procedure are considered as supportive secondary endpoints.  For all 
secondary endpoints, the treatment effect over time will also be considered and the 
change from baseline to Weeks 24, 52, 76, and 104 will be provided as supplementary 
analyses.


 
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Table 5 
Secondary Endpoints 
Secondary Efficacy Endpoint 
Confirmatory 
Type 
Alzheimer’s Disease Assessment Scale, Cognitive 
subscale, 13-item (ADAS-Cog 13) 
yes 
Continuous 
Alzheimer’s Disease Cooperative Study, Activities of Daily 
Living scale (ADCS-ADL) total score 
yes 
Continuous 
Functional Activities Questionnaire (FAQ) 
yes 
Continuous 
Mini Mental State Examination (MMSE) 
no 
Continuous 
Alzheimer’s Disease Assessment Scale, Cognitive 
subscale, 11-item (ADAS-Cog 11) 
no 
Continuous 
Coding (Digit Symbol Substitution Test [DSST]) 
no 
Continuous 
Verbal Fluency Task 
no 
Continuous 
Alzheimer’s Disease Cooperative Study, Activities of Daily 
Living scale (ADCS-ADL) instrumental score 
no 
Continuous 
ADAS-Cog 13 Alzheimer’s Disease Assessment Scale, Cognitive subscale, 13-item; 
ADCS-ADL Alzheimer’s Disease Cooperative Study, Activities of Daily Living scale; 
ADAS-Cog 11  Alzheimer’s Disease Assessment Scale, Cognitive subscale; DSST Digit 
Symbol Substitution Test; FAQ Functional Activities Questionnaire; MMSE Mini Mental State 
Examination. 
  
5.4.1 
Confirmatory Secondary Endpoints 
The confirmatory secondary endpoints are provided to increase the confidence in the 
treatment effect observed on the primary endpoint.  For these confirmatory secondary 
endpoints, as already outlined in the beginning of Section 5.4, the same primary 
estimand’s strategy will be applied, with some changes to the corresponding estimator 
(see Section 5.4 for the details).  
For these confirmatory secondary endpoints, MMRM analyses will also be considered as 
supplementary analyses.  In this case, the change from baseline in the confirmatory 
secondary endpoints will be adjusted on the following covariates: treatment group, visit, 
treatment-by-visit interaction, the respective baseline score for each secondary endpoint, 
the baseline score-by-visit interaction and the randomization stratification factors as 
specified for the primary endpoint, see Section 5.3.4, paragraph on MMRM. 
The method for controlling the overall Type I error is described in section 5.1. 
5.4.1.1 
Alzheimer’s Disease Assessment Scale, Cognitive Subscale, 
11- item and 13-Item (ADAS-Cog 11/ ADAS-Cog 13) 
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. 


 
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2012).  More specifically, the ADAS-Cog is a participant-based assessment that 
measures learning and memory, language production, language comprehension, 
constructional praxis, ideational praxis, and orientation.  The modified version will be 
used; it has 13 items and includes the addition of delayed word recall and a number of 
cancellation subtests, as well as use of only one trial for word recognition (Mohs et al. 
1997).  Equivalent alternate forms of the word recall, word recognition, and number 
cancellation subtests will be used in successive test administrations.  The ADAS-Cog 11 
and 13 will be used in this study, with ADAS-Cog 13 considered as a confirmatory 
secondary endpoint.  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. 
5.4.1.2 
Alzheimer’s Disease Cooperative Study, Activities of Daily 
Living Scale (ADCS-ADL), Total Score 
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. 
5.4.1.3 
Functional Activities Questionnaire (FAQ) 
The FAQ (Pfeffer et al. 1982) is an informant-based measure of functional abilities. 
Informants provide performance ratings of the target person on ten complex higher-order 
activities.  The FAQ is a 30-point scale, the higher the score the worse the performance. 
5.4.2 
Supportive Secondary Endpoints 
For context, additional clinical endpoints collected longitudinally in the studies will be 
provided (see Table 5).  The Sponsor proposes not to rank these hierarchically as for 
confirmatory secondary endpoints. 
5.4.2.1 
Mini Mental State Examination (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.  The score ranges from 0-30, with lower values indicating 
a greater impairment. 
5.4.2.2 
Digit Symbol Substitution Test (DSST) 
Coding, also called Digit Symbol Substitution Test (or DSST), is a subtest from the 
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV; Wechsler 2008).  Coding is a 
participant-based assessment that measures speed of processing and associative 


 
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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. 
5.4.2.3 
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).  
5.4.2.4 
Alzheimer’s Disease Cooperative Study, Activities of Daily 
Living Scale (ADCS-ADL), Instrumental Score 
The ADCS-ADL instrumental score is a sub score of the ADCS-ADL scale, see 
Section 5.4.1.2.  The ADCS-ADL instrumental score used in this study is the sum of 
items 6a and 7 to 23. 
5.4.3 
COVID-19 Related Sensitivity Analyses for Secondary 
Endpoints 
During the COVID-19 pandemic, many countries took movements’ restriction policy.  
Among the clinical outcomes collected in the study, some questionnaires may be 
particularly impacted.  These questionnaires include items describing actions that are 
strongly constrained or prohibited by restriction policies.  
We define modified versions of the total score for these scales.  These modified scales 
scores may be used to perform sensitivity analysis aiming at understanding and 
mitigating the impact of the COVID-19 pandemic on study results and interpretation, in 
line with the primary clinical question of interest. 
5.4.3.1 
ADCS-ADL COVID-19 Modified Total Score 
The original ADCS-ADL is a 23 item scale with a total score range of 0-78.  The 
following items were identified as being particularly impacted by the pandemic related 
restrictions: 
 
Item 2:  Optimal walking performance, maximum 3 points 
 
Item 15:  Optimal performance getting around/travelling outside the home, maximum 
4 points 
 
Item 16a/b:  Shopping trips - selecting items and paying without supervision, 
maximum 4 points 
 
Item 18:  Left away from home, maximum 3 point 
A sensitivity analysis may be conducted, using a modified version of the ADCS-ADL total 
score after removing of these four items, resulting in a 19-item scale with a score range 
of 0-64.  This alternative version will be referred to as “ADCS-ADL COVID-19 modified 
total score”. 


 
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5.4.3.2 
FAQ COVID-19 Modified Total Score 
The original FAQ is a 10-item scale with a score range of 0-30.  The following items 
were identified as being particularly impacted by the pandemic related restrictions: 
 
Item 3:  Shopping alone, maximum 3 points 
 
Item 10:  Travelling outside of the neighborhood, maximum 3 points 
A sensitivity analysis may be conducted, using a modified version of the FAQ total score 
after removing of these 2 items, resulting in an 8-item scale with a score range of 0-24.  
This alternative version will be referred to as “FAQ COVID-19 modified total score”. 
5.5 
EXPLORATORY ENDPOINT(S) ANALYSIS 
The same primary estimand’s analysis strategy (see Section 5.3.2) will be applied to 
continuous exploratory endpoints listed in Table 6, with the following exceptions for the 
corresponding estimator: 
 
.  the imputation model will not include, as covariates, the baseline ADAS-Cog 13 
total score and the baseline ADCS-ADL total score  
  The imputation model will thus include treatment group, visit, and treatment-by-
visit interaction, the baseline score and the baseline score-by-visit interaction, 
and the randomization stratification factors, namely: disease stage, geographic 
region, the use of AD medication at baseline and the APOE ε4 status  
 
  the analysis model will not include, as covariates, the baseline ADAS-Cog 13 
total score and the baseline ADCS-ADL total score  
The analysis model will thus include treatment, the baseline score and the 
randomization stratification factors, namely: disease stage, geographic region, 
the use of AD medication at baseline and the APOE ε4 status 
.  For all continuous exploratory endpoints, the ANCOVA analysis model will include the 
baseline score of the exploratory endpoint, the disease stage, geographic region, the 
use of AD medication at baseline and the APOE ε4 status as covariates. 
For ordinal endpoints, only descriptive analyses will be considered, summarizing the 
frequencies of the different categories, as well the proportion of participants with a 
certain shift in categories.  
The Resource Utilization in Dementia Scale–Lite (RUD-Lite) and the EuroQoL–5 
Dimensions (EQ-5D-5L) scales will be used in this study for informing 
pharmacoeconomic evaluations and will be reported separately. 


 
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Table 6 
Exploratory Endpoints 
Exploratory Efficacy Endpoint 
Type 
Clinical Dementia Rating-Global Score (CDR-GS) 
Ordinal  
CDR-Individual Components 
Continuous 
Dependency Level, as assessed by the Alzheimer disease cooperative 
study - activities of daily living (ADCS-ADL) score 
Ordinal 
Integrated AD Rating Scale (iADRS) 
Continuous 
Quality of Life–Alzheimer’s Disease (QoL-AD) 
Continuous 
Neuropsychiatric Inventory Questionnaire (NPI-Q) 
Continuous 
Zarit Caregiver Interview–Alzheimer’s Disease (ZCI-AD) 
Continuous 
ADCS-ADL  Alzheimer disease cooperative study-activities of daily living; ADCOMS  AD 
Composite Score; CDR-GS Clinical Dementia Rating-Global Score; EQ-5D EuroQoL–5 
Dimensions; iADRS  Integrated AD Rating Scale; NPI-Q Neuropsychiatric Inventory 
Questionnaire ; QoL-AD Quality of Life–Alzheimer’s Disease; ZCI-ADZarit Caregiver 
Interview–Alzheimer’s Disease. 
  
5.5.1 
Clinical Dementia Rating–Global Score (CDR-GS) and 
Individual Components of the CDR scale 
The Washington University CDR is a global assessment instrument that yields global 
scores (GS) and sum of boxes (SOB) scores.  The CDR is derived from a semi-
structured interview with the participant and an appropriate informant, and it rates 
impairment in six categories (Memory, Orientation, Judgment and Problem Solving, 
Community Affairs, Home and Hobbies, and Personal Care) on a 5-point scale for which 
0  no impairment, 0.5  questionable impairment, and 1, 2, and 3  mild, moderate, and 
severe impairment, respectively.  From the six individual category ratings, or box scores, 
the CDR-GS is established by clinical scoring rules, for which CDR 0  no dementia and 
CDR 0.5, 1, 2, or 3  questionable, mild, moderate, or severe dementia, respectively 
(Morris 1993). 
5.5.2 
Dependence Level Assessed by the ADCS-ADL Score 
To calculate dependence levels, scores on the ADCS-ADL can be transformed into 
discrete levels of disability via an algorithm developed initially by Kahle-Wrobleski 
(2015).  Items from the ADSC-ADL were mapped to 6 levels of dependence derived 
from the Dependence Scale (Zhu et al., 2009), ranging from Level 0: no impairment in 
instrumental or basic ADLs to Level 5:  complete incontinence or inability to transfer.  
Four subscales were used to aid the construction of dependence levels, including 
bADLs, domestic/household activities, communication/engagement and outside 


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activities.  The mapping of items to dependence levels was validated using additional 
clinical and economic measures.  
A revised algorithm, developed to a) remove ambiguity regarding the contribution of 
some items and b) add clarity on the handling of missing data, will be used to calculate 
the dependence levels.  Progression to greater levels of dependence is indicative of 
disease progression and is informative for a variety of care providers and 
stakeholders. This algorithm is provided in appendix, see Appendix 2. 
5.5.3 
Integrated AD Rating Scale (iADRS) 
The iADRS is a composite of cognition and function that combines scores from the 
ADAS-Cog-13 (cognition) and the instrumental component of the ADCS-ADL (function) 
(Wessels et al., 2018).  A sum score of the total scores of both components is calculated 
(ADAS-Cog is reversed) using the following formula:   
iADRS = [-(ADAS-Cog13) + 85] + ADCS-iADL. 
Total score range from 0 to 141.  The iADRS total score will be generated and results 
may be reported in the CSR. 
5.5.4 
AD Composite Score (ADCOMS) 
The ADCOMS was developed to assess cognition and function in early stages of AD.  It 
is a composite score that combines 12 items from existing AD measures, specifically the 
ADAS-Cog (Delayed word recall, Orientation, Word recognition, Word finding difficulty), 
MMSE (Orientation time and Constructional praxis) and all CDR-SB items (Wang et al., 
2016).  The ADCOMS score was built using a linear longitudinal model to characterize 
the relationship between disease progression and the individual items from existing AD 
clinical scales.  A PLS regression procedure was used to identify individual clinical scale 
items that represent AD-related clinical decline over time to calculate their respective 
weighting factors.  The resulting composite ADCOMS score is a weighted linear 
combination of the individual scale items selected in the fitted PLS model.  Items with 
small contribution to the PLS model were removed according to Wold's criterion (a 
Variable Importance of Projection below 0.8).  Total score range from 0 to 1.97, with 
lower scores indicating greater impairment.  The ADCOMS total score will be generated 
and results may be reported in the CSR.  
5.5.5 
Quality of Life–Alzheimer’s Disease (QoL-AD) 
The Quality of Life-Alzheimer’s Disease (QoL-AD) was developed to assess quality of 
life (QoL) in participants who have dementia (Logsdon et al. 1999, Logsdon et al 2002). 
The QoL-AD consists of 13 items covering aspects of participants’ relationships with 
friends and family, physical condition, mood, concerns about finances, and overall 
assessment of QoL.  The total score is the sum of the 13 items and ranges from 13 to 
52, with higher scores indicating better health-related QoL.  In this study, the QoL-AD 


 
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will be administered in a standardized, structured interview format to participants by 
investigative staff in order to gather participant responses about QoL.  The study partner 
will also complete the study partner version of the questionnaire to enable proxy 
responses from the study partner. 
5.5.6 
Neuropsychiatric Inventory Questionnaire  
The Neuropsychiatric Inventory-Questionnaire (NPI-Q) (Kaufer et al. 2000) was 
developed to assess a wide range of behaviors encountered in dementia participants, to 
provide a means of distinguishing severity of behavioral changes, and to facilitate rapid 
behavioral assessment through the use of screening questions.  It is an informant-based 
instrument in which 12 behavioral domains are evaluated.  The recall period is the past 
month, and severity scores range from 0 to 36, with higher scores indicating greater 
severity.  The study partner's distress portion of the scale was not used in this study. 
5.5.7 
Zarit Caregiver Interview–Alzheimer’s Disease (ZCI-AD) 
The Zarit Caregiver Interview-Alzheimer’s Disease (ZCI-AD) is a modified version of the 
Zarit Burden Interview 22-item version, which was originally designed to reflect the 
stresses experienced by caregivers for people with dementia (Zarit and Zarit 1990).  The 
modified version includes modifications in item and title wording (e.g., removal of “your 
relative “to refer directly to the participant, removal of “burden” from title), inclusion of 
additional items, the use of 11-point numerical rating scales for each item and a 4 week 
recall period.  The ZCI-AD measure consists of 27 items covering 13 domains (i.e., 
humanistic impact domain (14 items) including the domains physical (3 items), emotional 
(4 items), social (3 items), and daily life (4 items), and the additional domains exhaustion 
(2 items), dependence (2 items), worry (2 items), role perception (3 items), financial 
impact (1 items), difficulty with medication (1 item), overall difficulty of caregiving 
(1 item), and sadness (1 item)).  The ZCI-AD is completed by the study partner without 
involvement from the site staff.  The ZCI-AD is scored on a domain level with each 
domain score ranging from 0 to 100 with higher scores indicating higher level of impact.  
All item responses are re-coded on a 0 to 4 scale (response category 0  0; response 
category 1,2, and 3  1; response category 4,5,and 6  2; response category 7 and 8  3; 
response category 9 and 10  4)  and items of a domain are summed up and 
transformed to 0 to 100 score range.  Domain scores are only calculated if responses of 
at least 80% of items of the respective domain are available.  The ZCI-AD has been 
validated in prodromal, mild and moderate stages of AD (Bernaards, C et al.) 
5.6 
SAFETY ANALYSES 
Descriptive statistics will be used to analyze all safety data collected in the double-blind 
treatment period in the safety-evaluable analysis set, unless otherwise specified.  
Safety data collected from the day of the first dose of blinded study drug up to 14 weeks 
after the last dose of blinded study drug (but no later than the day before the first OLE 
dose for the participants who entered the OLE period) will be included in the 


 
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beyond the 14-week post last dose period and until the end of the study will be included 
in the follow-up period analyses. 
For participants who entered the OLE period, safety data collected from the day of the 
first OLE dose up to 14 weeks after the last OLE dose will be included in the OLE period 
analyses 
Safety analyses will be assessed through summaries of exposure to study treatment, 
adverse events, changes in laboratory test results (including shift tables), MRI findings, 
changes in vital signs and ECGs, and changes in C-SSRS scores.  
5.6.1 
Extent of Exposure 
Exposure to study drug information will be descriptively summarized by treatment as 
follows: 
 
Treatment duration (in weeks)  
 
Total number of administrations 
 
Total cumulative dose (mg) 
 
Number of dose-administrations at each dose level 
 
5.6.2 
Adverse Events 
All verbatim AEs terms will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version that is current at the time of the analysis (Version 25.0 or 
higher), and AE severity will be graded according to the scale defined in Table 5 in 
Section 5.3.3 of the study protocol (mild/moderate/severe).  For each treatment group, 
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 
safety-evaluable analysis set.  In summary tables, AEs will be sorted by body system (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 dose of study drug.  Non-treatment-
emergent AEs (with onset before the first dose) will be listed. 
The following safety information will be summarized by treatment group for the 
double-blind treatment period:   
 
AEs, AEs by intensity, AEs related to study drug 
 
Deaths 
 
SAEs, SAEs related to study drug 
 
AEs leading to discontinuation of study treatment  


 
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 
AEs leading to dose modifications (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 tick-boxes in the eCRF Adverse Events form: 
 - Action take with Gantenerumab due to AE/SAE: Dose Not Changed 
 - Was dose regimen modified from protocol schedule? Yes" 
 
Injection site reaction (ISR) signs and symptoms  
 
Systemic injection reactions (AEs with eCRF tickbox “systemic injection reaction” 
selected) 
 
‘Hypersensitivity reactions’ 
Protocol-specified adverse events of special interest (AESI) will be listed. 
 
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 blinded gantenerumab” 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 the summary table 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 
Magnetic Resonance Imaging Safety Findings 
ARIA-E and ARIA-H are identified risks associated with gantenerumab.  Sites were 
asked to capture all ARIAs as AEs in the eCRF that met any of the following criteria: 
 
Symptomatic ARIA-E (i.e., accompanied by CNS symptoms), and/or 


 
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 
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 
 
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, and 
severity (based on the Barkhof Grand Total Score [BGTS]) ARIA-E and the incidence of 
ARIA-H will be summarized by treatment group and within this also by APOE ε4 
genotype (by number of alleles) and by dose level.  Additionally, the timing of ARIA-E 
and the timing to meet the protocol-defined criteria for permanent discontinuation due to 
ARIA-H will be also summarized by descriptive statistics and eventually by Kaplan-Meier 
methods.  Recurrence of ARIA-E will be summarized by treatment group and within this 
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 
treatment group and within this also by APOE ε4 genotype.  Temporal co-occurrence of 
ARIA-E and ARIA-H will be summarized by treatment group and within this also by 
APOE ε4 genotype (by number of alleles).  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. 
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 


 
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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 (number of 
alleles). 
5.6.4 
Laboratory Data 
Laboratory data will be summarized by treatment group 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 by 
treatment group.  
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 
by treatment group 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 by treatment group.  
5.6.6 
ECGs 
ECG data will be summarized by treatment group 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 intervals (including QTcF) 
 
For QTcF, the summary will also include 2-sided 90% confidence interval at each 
time-point. 
In addition, ECG overall interpretations will be summarized by treatment group and 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. 


 
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Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent will 
be summarized by treatment group.  In addition, change from baseline to worst 
post-baseline assessment in suicidality categories will be summarized by treatment 
group. 
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 by 
treatment arm: 
 
Number of participants enrolled and randomized 
 
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 protocol deviations – overall and by four main categories (inclusion 
criteria, exclusion criteria, medication and procedural) 
 
Stratification factor reported in IxRS and used for randomization  
 
Number of participants with home nursing 
 
Number of participants initiating or changing symptomatic treatment of AD during 
the study 
Major protocol deviations and premature withdrawals will be listed. 
5.7.2 
Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, medical history, 
randomization stratification factors) will be summarized descriptively by treatment arm as 
assigned for the ITT analysis set using:  
 
means, SDs, medians, and ranges for continuous variables 
 
counts and proportions for categorical variables 
 
Exposure to AD concomitant medication (including post-baseline initiation or change in 
dose) will be summarized by treatment arm for the ITT analysis set.   
5.7.3 
Immunogenicity Analyses 
Immunogenicity analyses include the evaluation for antibodies against gantenerumab, 
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. 


 
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5.7.4 
Summaries of COVID-19 Impact on the Trials 
Studies GRADUATE I and GRADUATE II were 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 by treatment arm for 
the ITT analysis set (see Table 2), 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 
 
Missed doses due to COVID-19 
 
Study discontinuations due to COVID-19 as determined by the adjudication 
committee for ICEs 
 
Study drug administrations of 1020 mg Q4W  
 
Remote scale administrations 
 
Duration of study site closure 
 
5.7.5 
Amyloid PET Substudy 
The objective of the GRADUATE I and GRADUATE II longitudinal amyloid PET 
substudies is to assess changes in brain amyloid load over time using the change in 
florbetaben or flutemetamol from baseline to the last amyloid PET visit in the Standard 
Uptake Value Ratio (SUVR).  
Two amyloid PET ligands are allowed in the GRADUATE I and GRADUATE II 
longitudinal amyloid PET substudies to provide assessment of β-amyloid protein 
deposition according to country and site availability: radiopharmaceuticals florbetaben-
F18 and flutemetamol-F18.  However, the same ligand has to be used for the same 
participant throughout the study (e.g., if a participant has been enrolled in the main study 
with a positive florbetaben PET scan, only florbetaben will be allowed and used for the 
longitudinal follow-up scans for the participant).  
Centiloid mapping will be completed for SUVR data from the two amyloid PET ligands.  
The primary amyloid PET outcome measure is the change in amyloid PET Centiloid from 
baseline to Week 116.   
5.7.5.1 
General considerations on Amyloid PET statistical analyses 
With the Centiloid endpoint, data from both tracers will be pooled and analyzed together.  
Separate analysis by tracer with the Centiloid endpoint may also be conducted as 
appropriate.  When SUVR metrics is the endpoint, the analysis will be done separately 
and reported separately for each tracer, when possible.   
Missing values will not be imputed.  


 
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The amyloid PET analyses will be performed on the Amyloid-PET-mITT analysis set 
(see Table 2), unless otherwise specified, and participants will be analyzed according to 
the treatment assigned at randomization by IxRS. 
5.7.5.2 
Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, medical history, 
randomization stratification factors) will be summarized descriptively by treatment arm as 
assigned for both the Amyloid-PET-mITT analysis set and the Amyloid-PET-longitudinal 
analysis set (see Table 2) using:  
 
means, SDs, medians, and ranges for continuous variables 
 
counts and proportions for categorical variables 
 
5.7.5.3 
Visit Windowing 
For amyloid PET assessments, due to the long time between scheduled assessments, 
time windows based on study days, as defined in Table 7, will be used.  Study days are 
defined based on days on study since the date of the first dose, with the day of the first 
dose being study day 1. 
Table 7 
Time Windows for Amyloid PET Assessments 
Visit 
Target day 
Time window 
Baseline 
1 
Up to day 35 
Week 52 
365 
281, 449 
Week 116 
813 
645, 897 
  
For Week 116, the time window will cover the week 104 timepoint as well.  In case of 
more than one assessment within a time window, the assessment with the date closest 
to the target day is selected.  For the combined window of Week 104 and 116, the target 
day is the Week 116 assessment day. 
Because of visit windowing, data collected at an early termination visit will be 
summarized at the corresponding visit as defined by the time window.  For participants 
who have discontinued treatment early, if a PET scan is performed more than 56 days 
(early termination visit expected 14 days after last dose, followed by time window per 
protocol for early termination is ±42 days) after the date of last dose, the PET scan will 
not be used for the analysis. 
The end of a substudy is defined as the date when all participants enrolled in the 
substudy have: 
1. 
completed the last required amyloid PET scan (Week 116), or 
2. 
completed an early termination scan, or 
3. 
discontinued from the main study. 


 
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5.7.5.4 
Definition of the Estimand for Amyloid PET 
The scientific question of interest for the amyloid PET substudies is to assess the effect 
of the intended study treatment on the PD endpoint, change from baseline in amyloid 
load burden at Week 116, in the absence of a substantial impact of the COVID-19 
pandemic and as if treatment discontinuation would not have occurred. 
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 Sections 4.1.1 and 4.1.2 of the substudy protocols and Sections 4.1.1 
and 4.1.2 of the main study protocols 
 
Variable: 
Change from baseline to Week 116 in amyloid PET Centiloid 
 
Treatment: 
Prescribed study drug including up-titration to the target dose 
 
Population-level summary: 
Difference in variable means between treatment arms 
 
Intercurrent events 
 
Substantial reduction in drug exposure due to the COVID-19 pandemic (defined 
as   4 missed dose-months) 
 
Treatment discontinuation due to any reason 
Amyloid PET is listed in the protocol under “Pharmacodynamic Biomarker Objective”. 
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.  
Details for Definition of Variable 
The Centiloid variable will be used rather than the original SUVR, because it allows to 
combine data from different tracers, by mapping SUVR values to a standardized scale.  
The Centiloid variable is the current common standard in the scientific community. 
The primary SUVR measure of interest is computed using a weighted composite target 
region and whole cerebellum as reference region.  The weighted composite target region 
is composed of (both left and right side): 
 
frontal lobe, 
 
parietal lobe, 
 
temporal lobe lateral, 


 
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 
cingulum posterior and 
 
anterior cingulate gyrus 
Each region is weighted by its own volume.  The Centiloid conversion is a linear 
transformation of SUVR with tracer-specific parameters that are given below: 
Centiloid Equation: 
CL  SlopeCL  SUVR  InterceptCL 
CL  Centiloids; SlopeCL  slope; SUVR  standard uptake value ratio of the target region; 
InterceptCL  intercept. 
The pertinent values for the two tracers are: 
Table 8 
Primary Centiloid Equation Parameters 
Tracer 
Reference 
Slope 
Intercept 
Florbetaben-F18 
whole cerebellum 
175.6 
-174.2 
Flutemetamol-F18 
whole cerebellum 
143.5 
-141.1 
  
5.7.5.5 
Main Analytical Approach 
An MMRM will be used to estimate the mean change in Centiloid from baseline to 
Week 116 within each of the substudies.  The model will include the change from 
baseline in Centiloids as the dependent variable, while adjusting for treatment arm (as 
categorical), visit (as categorical), APOE ε4 status (as categorical; carrier vs non-
carrier), type of tracer (as categorical; Florbetaben vs Flutemetamol), baseline Centiloid, 
baseline Centiloid-by-visit and treatment-by-visit interaction.  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 estimand definition, data acquired after the ICE “Substantial reduction in 
drug exposure due to the COVID-19 pandemic” (as defined in Table 3) or more than 
56 days from treatment discontinuation 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 provides 
unbiased estimates and valid inference in the presence of missing data, under the MAR 
(missing at random) assumption.  
The difference in least squares means between active drug and placebo arms at 
Week 116 will be estimated and presented alongside p-value and the 95% confidence 
interval for treatment difference.  A p-value <0.0001 will be regarded as a statistically 
significant evidence, irrespective of the results of the other primary/secondary endpoints 


 
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(along the lines of the Haybittle–Peto rule, and thus maintaining the overall type-I error 
within the study). 
 
5.7.5.6 
Supplementary analyses 
Changes in weighted Composite Summary region SUVR (for each tracer) and Centiloids 
from baseline will be summarized using descriptive statistics.  
Based on the same model as specified in the Section 5.7.5.4, the change from baseline 
to Week 52 in Centiloids will also be reported as supplementary analysis. 
Additionally, the number and proportion of participants with values below or equal to the 
positivity threshold will be summarized for each assessment time point.  Centiloid zero is 
the mean amyloid burden for a typical population of young healthy controls, and 
100 Centiloid is the typical mean of a population with AD.  The Centiloid value of 24 is 
consistent with the diagnostic amyloid positivity threshold (Klunk et al. 2015; Navitsky et 
al. 2018) (see Section 5.7.5.3 for definition of CentiloidError! Reference source not 
found.).   
A chi-square test (or Fisher’s exact test, whichever is appropriate) will be used to 
compare the proportions of participants with values below or up to the positivity 
threshold between the active drug and placebo arm. 
In order to account for the potential impact of missing values, a completers analysis will 
be performed, i.e., restricting the analysis to participants who completed the visit with 
non-missing data.  
5.7.6 
Tau PET Substudy 
There is a single tau PET substudy enrolling subjects from both studies 
(WN29922/WN39658 Longitudinal Tau PET Substudy).  This substudy utilizes 
[18F]GTP1 (RO6880276) as tau PET radioligand.  
Statistical analyses will be conducted on tau PET Median Standardized Uptake Value 
Ratios (SUVR) in the following four target regions of interest.  In composite target 
regions, each region is weighted by its own volume. 
 
A temporal composite target region.  This region is composed of (both left and right): 
o anterior and posterior superior temporal gyrus, 
o posterior temporal lobe, 
o fusiform gyrus, 
o middle and inferior temporal gyrus; 


 
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 
A medial temporal composite region not including the hippocampus, composed of 
(both left and right): 
o Amygdala, 
o Parahippocampus, 
o Anterior medial and lateral temporal lobe; 
 
Frontal lobe (both left and right); 
 
Parietal lobe (both left and right); 
The inferior cerebellar grey matter will be used as reference region for the calculation of 
median SUVRs for all four target regions considered. 
All the statistical analyses will be based on the Tau-PET-mITT analysis set (see Table 2) 
unless otherwise specified. 
5.7.6.1 
Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, medical history, 
randomization stratification factors) will be summarized descriptively by treatment arm as 
assigned for both the Tau-PET-mITT analysis set and the Tau-PET-longitudinal analysis 
set (see Table 2) using:  
 
means, SDs, medians, and ranges for continuous variables 
 
counts and proportions for categorical variables 
 
5.7.6.2 
Definition of the Estimand 
The scientific question of interest for the Tau PET substudy is to assess the effect of the 
intended study treatment on the PD endpoint, change from baseline in tau PET median 
SUVR at Week 116, in the absence of a substantial impact of the COVID-19 pandemic 
and as if treatment discontinuation would not have occurred.  The same estimand will be 
considered for all four median SUVRs regions. 
The primary Tau 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 Sections 4.1.1 and 4.1.2 of the substudy protocols and Sections 4.1.1 
and 4.1.2 of the main study protocols 
 
Variable: 
Change from baseline to Week 116 in tau PET median SUVR 
 
Treatment: 
Prescribed study drug including up-titration to the target dose 
 
Population-level summary: 
Difference in variable means between treatment arms 
 
Intercurrent events 


 
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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 
Tau PET is listed in the protocol under “Pharmacodynamic Biomarker Objective”. 
Considering that tau PET aims at estimating the Pharmacodynamic effect of treatment, 
reporting treatment effect estimated "as if there were no treatment discontinuations and 
no substantial reduction in exposure due to COVID-19 pandemic" (thus using an 
hypothetical strategy) addresses the scientific question of interest. 
Since there are not individual Tau PET substudies for GRADUATE I and GRADUATE II, 
but rather a single Tau PET substudy across all patients from GRADUATE I and 
GRADUATE II, Tau PET will be analyzed at the pooled level of GRADUATE I and 
GRADUATE II. 
5.7.6.3 
Main Analytical Approach 
An MMRM analysis will be used to estimate the mean change from baseline to Week 
116 for each of the median SUVRs defined.  The model will include the change from 
baseline in median SUVR as the dependent variable, while adjusting for treatment arm 
(as categorical), visit (as categorical), APOE ε4 status (as categorical; carrier vs 
non-carrier), baseline median SUVR, baseline median SUVR-by-visit, study, 
study-by-visit and treatment-by-visit interaction.  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 estimand definition, data acquired after the ICE “Substantial reduction in 
drug exposure due to the COVID-19 pandemic” (as defined in Table 3) or more than 
56 days from 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 provides 
unbiased estimates and valid inference in the presence of missing data, under the MAR 
(missing at random) assumption.  A subgroup analysis by parent study may be also 
considered in order to derive a study-specific treatment effect.  
Based the same MMRM model already described in this section, the change from 
baseline to week 52 in tau PET will also be reported as supplementary analysis. 
5.7.6.4 
Visit Windowing 
For tau PET assessments, due to the long time between scheduled assessments, time 
windows based on study days, as defined in Table 9, will be used.  Study days are 


 
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defined based on days on study since the date of the first dose, with the day of the first 
dose being Study Day 1. 
Table 9 
Time Windows for tau PET Assessments 
Visit 
Target study day 
Time window 
Baseline 
1 
Up to day 35 
Week 52 
365 
281, 449 
Week 116 
813 
645, 897 
  
5.7.7 
Cerebrospinal Fluid (CSF) Analyses 
The main analysis for the CSF biomarkers will be based on the pooled dataset of 
GRADUATE I and GRADUATE II studies (due to the small number of CSF samples 
within each study).  Analyses at individual study level will be conducted as well.  
Analysis of CSF biomarkers will be based on the CSF-mITT analysis set unless 
otherwise specified. 
CSF biomarker data will be summarized by treatment group and visit (see schedule of 
assessment in the study protocol). 
For each CSF biomarker, two statistically equivalent ANCOVA models will be 
considered: 
1. using the change from baseline to Week 116 as dependent variable, with 
covariates: treatment arm (as categorical), APOE ε4 status (as categorical; 
carrier vs non-carrier) and baseline biomarker.   
2. using the value at Week 116 as the dependent variable, with covariates: 
treatment arm (as categorical), APOE ε4 status (as categorical; carrier vs non-
carrier) and baseline biomarker. 
Both models will use log (base 10) transformed biomarker data. The following 
summary statistics will be estimated after the appropriate back-transformation of the 
original model parameters: 
 
The geometric mean at Week 116 for each treatment arm, obtained as 10^LSM, 
where LSM is the least square mean for the corresponding treatment arm based 
on model 2. 
 
The geometric mean ratio (gantenerumab relative to placebo) at week 116, 
obtained as 10^LSM_GvsP, where LSM_GvsP is the least square means of the 
contrast of Gantenerumab against placebo based on model 2. 
 
The %-difference in geometric mean (relative to placebo) at week 116, obtained 
as [(10^LSM_GvsP) - 1]*100 based on model 2. 


 
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 
The %-change from Baseline to Week 116 in the Geometric Mean for each 
treatment arm, obtained as [10^LSM -1]*100, where LSM is the least square mean 
for the corresponding treatment arm at the corresponding visit based on model 1 
There will be no data imputation for missing data. 
The following CSF biomarkers will be analyzed: 
 
Total tau (tTau) 
 
Phosphorylated tau (pTau-181) 
 
Neurogranin 
 
Neurofilament light (NFL) 
 
Other exploratory CSF biomarker may be reported separately. 


 
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Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, medical history, 
randomization stratification factors) will be summarized descriptively by treatment arm as 
assigned for both the CSF-mITT analysis set and the CSF-longitudinal analysis set (see 
Table 2) using:  
 
means, SDs, medians, and ranges for continuous variables 
 
counts and proportions for categorical variables 
 
Visit Windowing 
For CSF assessments time windows based on study days, as defined in Table 10, will 
be used.  Study days are defined based on days on study since the date of the first 
dose, with the day of the first dose being Study Day 1. 
Table 10 Time Windows for CSF Assessments 
Visit 
Target study day 
Time window 
Baseline 
1 
Up to day 35 
Week 116 
813 
645, 897 
  
5.7.8 
Plasma Biomarker Analyses 
Plasma biomarkers will be analyzed separately for each study (GRADUATE I and 
GRADUATE II). 
Analysis of plasma biomarkers will be based on the ITT analysis set unless otherwise 
specified. 
The plasma biomarkers will be summarized by treatment group and visit (see schedule 
of assessment in the study protocol). 
For each plasma biomarker, two statistically equivalent MMRM models will be 
considered: 
1. using the change from baseline as dependent variable, with covariates: treatment 
arm (as categorical), visit (as categorical), treatment-by-visit interaction, APOE ε4 
status (as categorical; carrier vs non-carrier), baseline biomarker and baseline 
biomarker-by-visit. 
2. using the value at the post-baseline visit as the dependent variable, with 
covariates: treatment arm (as categorical), visit (as categorical), 
treatment-by-visit interaction, APOE ε4 status (as categorical; carrier vs non-
carrier), baseline biomarker and baseline biomarker-by-visit. 


 
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For both models, 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).   
Both models will use log (base 10) transformed biomarker data.  The following 
summary statistics will be estimated after the appropriate back-transformation of the 
original model parameters: 
 
The geometric mean at each visit for each treatment arm, obtained as 10^LSM, 
where LSM is the least square mean for the corresponding treatment arm at the 
corresponding visit based on model 2. 
 
The geometric mean ratio (gantenerumab relative to placebo) at each visit, 
obtained as 10^LSM_GvsP, where LSM_GvsP is the least square means of the 
contrast of Gantenerumab against placebo at the corresponding visit based on 
model 2. 
 
The %-difference in geometric mean (relative to placebo) at each visit, obtained as 
[(10^LSM_GvsP) - 1]*100, at the corresponding visit, based on model 2. 
 
The %-change from Baseline to each visit in the Geometric Mean, obtained as 
[10^LSM -1]*100, where LSM is the least square mean for the corresponding 
treatment arm at the corresponding visit based on model 1. 
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 plasma biomarkers will be analyzed: 
 
Amyloid beta (1-42) (Abeta-42) 
 
Phosphorylated tau (pTau-181) 
 
Other exploratory plasma biomarkers may be reported separately. 
Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, medical history, 
randomization stratification factors) will be summarized descriptively by treatment arm as 
assigned for both the ITT analysis set and the Plasma-longitudinal analysis set (see 
Table 2) using:  
 
means, SDs, medians, and ranges for continuous variables 
 
counts and proportions for categorical variables 
 
Visit Windowing 


 
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For Plasma assessments time windows based on study days, as defined in Table 11, 
will be used.  Study days are defined based on days on study since the date of the first 
dose, with the day of the first dose being Study Day 1. 
Table 11 Time windows for Plasma assessments 
Visit 
Target study day 
Time window 
Baseline 
1 
Up to Day 35 
Week 24 
169 
85, 253 
Week 52 
365 
281, 449 
Week 104 
729 
645, 770 
Week 116 
813 
771, 897 
  
5.7.9 
Volumetric MRI Analyses 
Structural MRI will be analyzed separately for each study (GRADUATE I and 
GRADUATE II). 
Analysis of structural MRI (volumetric MRI) will be based on the MRI-mITT analysis set 
unless otherwise specified. 
Volumetric MRI, for each brain region, will be summarized by treatment group and visit 
using descriptive statistics for the absolute volume at baseline and percent change from 
baseline at post-baseline visits. 
An MMRM analysis will be used to estimate the mean percent change from baseline to 
Week 116 (as well Week 48 and 104) 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 treatment arm (as categorical), visit (as categorical), 
treatment-by-visit interaction, 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 
 
Ventricles 


 
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 
Hippocampus right and left 
 
Cortical gray matter 
Other exploratory analyses based on other brain regions may be reported separately. 
Summaries of Treatment Group Comparability 
Demographics and baseline characteristics (including age, sex, medical history, 
randomization stratification factors) will be summarized descriptively by treatment arm as 
assigned for both the MRI-mITT analysis set and the MRI-longitudinal analysis set (see 
Table 2) using:  
 
means, SDs, medians, and ranges for continuous variables 
 
counts and proportions for categorical variables 
Visit Windowing 
For Volumetric MRI assessments time windows based on study days, as defined in 
Table 12, will be used.  Study days are defined based on days on study since the date of 
the first dose, with the day of the first dose being Study Day 1.


 
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Table 12 Time windows for Volumetric MRI assessments 
Visit 
Target study day 
Time window 
Baseline 
1 
Up to Day 35 
Week 48 
337 
253, 421 
Week 104 
729 
645, 770 
Week 116 
813 
771, 897 
  
5.8 
INTERIM ANALYSES  
Details of interim analysis plans are described in a separate interim analysis SAP 
(iSAP), providing information about a futility interim analysis based on the primary 
efficacy endpoint CDR-SB. 
Other than the futility analysis, there is no plan for an efficacy interim analysis based on 
the primary endpoint.  The primary analysis of the clinical efficacy endpoints will be 
performed only once, after completion of the efficacy data collection at the end of the 
double blind part of the study (as described in this SAP) and it will be the only 
opportunity to formally reject the primary null hypothesis of the trial.  


 
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6. 
SUPPORTING DOCUMENTATION 
This document is part of a broader Data Analysis Plan that has several documents, 
including:  
 
Graduates studies interim analysis SAP 
 
Graduates studies Data Analysis Plan Module 2  
 
Graduates studies Data Analysis Plan Module 3 


 
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Appendix 1 Type I Error Control Considerations for Reference-
Based Conditional Mean Imputation Combined with the 
Jackknife for Inference  
Introduction 
In the GRADUATE trials, hypothetical and treatment policy strategies are applied to Non 
Study Drug or Condition Related (NSDCR) intercurrent events (ICEs) and Study Drug or 
Condition Related (SDCR) ICEs, respectively That is, the clinical interest is in a scenario 
where SDCR ICEs but not NSDCR ICEs do occur.  For estimating the treatment effect, 
data after NSDCR are assumed to missing at random (MAR) whereas missing data after 
SDCR are imputed based on the placebo group in both treatment groups using the 
copy-increments-in-reference (CIR) imputation method, a specific type of 
reference-based imputation.  We refer to Section 5.3.3 for further details. 
The primary analysis of the GRADUATE trials is implemented using conditional mean 
imputation of missing data combined with the jackknife for inference.  This methodology 
has been described and justified in Wolbers et al. (2022).  In this appendix, we provide 
further details regarding type I error control of the method including additional 
simulations targeted to the setting of the GRADUATE trials.  
Theoretical and published simulation evidence for type I error control  
As demonstrated in Section 2.5 of Wolbers et al. (2022), the proposed conditional mean 
imputation methodology corresponds to a computationally efficient implementation of 
maximum likelihood multiple imputation.  Estimators based on maximum likelihood 
imputation are asymptotically normal and unbiased if the imputation model and the 
associated missing data assumptions are correctly specified (Wang and Robins (1998), 
Robins and Wang [2000]).  Moreover, standard error estimates based on resampling 
methods such as the jackknife or the bootstrap are consistent (Bartlett and Hughes 
(2020), von Hippel and Bartlett (2021), Wolbers et al. (2022). 
Therefore, large-sample (asymptotic) type I error control is guaranteed if the imputation 
model and the associated missing data assumptions are correctly specified.  This is the 
case if the following conditions hold: 
 
All ICEs are correctly identified and classified as NSDCR or SDCR. 
 
Observed outcome data prior to an ICEs follow a multivariate normal mixed model 
for repeated measures (MMRM) with an unstructured covariance matrix. 
 
Missing outcome data prior to an ICE are missing at random (MAR). 
 
Missing outcome data after NSDCR ICEs compatible with a hypothetical strategy is 
also MAR. 
 
Missing outcome data after SDCR ICEs are compatible with the copy-increments-in-
reference (CIR) assumption. 
 


 
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In contrast, the commonly used MMRM model requires that all missing data are MAR 
(Mallinckrodt et al. [2008]). In many settings, a reference-based missing data 
assumption for SDCR ICEs such as CIR is arguably more plausible and conservative 
than the MAR assumption of the classical MMRM model. 
In order to study type I error control for finite sample sizes, simulation studies are 
required.  A simulation study reported in Wolbers et al. (2022) assessed type I error via 
simulation (based on 100,000 simulations) for a setting with a relatively low sample size 
(100 subjects per group), a large proportion of ICEs (34% and 24% in the active and 
placebo groups, respectively), and a large probability of study drop-out after the 
occurrence of the ICE of 75%.  For standard MAR and all reference-based imputation 
methods, inference based on conditional mean imputation and jackknifing strictly 
protected type I error.  Simulation results reported in Liu and Pang (2016) for a similar 
method also found no evidence of type I error inflation for reference-based methods or 
the MMRM model if the missing date mechanism was correctly specified.  These 
simulation results are also consistent with simulation studies which report that the 
MMRM model (or an asymptotically equivalent multiple imputation model) provides 
adequate type I error control if all missing data are MAR (Siddiqui [2011], Lu and 
Mehrotra [2010]). 
In contrast, statistical methods cannot be expected to strictly control type I error if the 
missing data assumptions are not correctly specified.  For example, simulations reported 
in Liu and Pang (2016) demonstrate type I error inflation for both reference-based 
methods and the MMRM model if missing data are simulated under certain missing not 
at random (MNAR) scenarios.  Similarly, Mallinckrodt et al. (2004) demonstrated type I 
inflation of the MMRM model under MNAR scenarios but type I error control of the 
MMRM model was much closer to nominal values compared to naive approaches to 
missing data such as the last observation carried forward (LOCF) approach.  Whether or 
not the missing data assumptions is correctly specified is by nature something that 
cannot be verified 
In conclusion, reference-based imputation methods based on conditional mean 
imputation and jackknifing control type I error if the imputation model and the associated 
missing data assumptions are correctly specified.  Neither reference-based imputation 
methods nor the MMRM model can guarantee strict type I error control if the missing 
data assumptions are not correctly specified.  Therefore, sensitivity analyses such as 
tipping point analyses should always be performed to assess the robustness of the 
results to deviations from the missing data assumptions. 




 
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 
Two types of intercurrent events were simulated: Study Drug or Condition Related 
ICEs (SDCR) and Non-Study Drug or Condition Related ICEs (NSDCR).  
 
Simulation of SDCR ICEs: 
– 
The probability of an SDCR ICE after each visit was calculated according to a 
logistic model, which also depended on the observed outcome at that visit. 
– 
The visit-wise probability of an SDCR ICE for a subject with an observed 
outcome at that visit of 3.65 was varied across 4 different scenarios as reported 
in Table 2. 
– 
The odds of an SDCR ICE further increased by 45% for each 1 point increase 
in the observed outcome. 
– 
In the placebo group, an SDCR ICE had no effect on the mean trajectory. In the 
active group, subjects who experienced an SDCR ICE followed the slope of the 
mean trajectory from the placebo group from that time point onward (CIR). 
– 
Study drop-out after the SDCR ICE visit occurred with a probability of 80% 
leading to missing outcome data from that time point onward. 
 
Simulation of NSDCR ICEs: 
– 
The probability of an NSDCR ICEs after each visit was assumed to be 
independent of the visit and the observed outcome.  The specification of these 
probabilities for each of the 4 scenarios is presented in Table 2.  
– 
NSDCR ICEs always led to missing outcome data from that time point onward. 
 
If both SDCR and NSDCR ICEs were simulated to occur for a subject, then it was 
assumed that only the earlier of them counted.  In case both ICEs were simulated to 
occur at the same time, the event was considered a SDCR ICE.  This means that a 
single subject could experience either a SDCR or a NSDCR ICE, but not both of 
them. 
 
Additional missing data unassociated with an ICE was simulated by assuming that a 
subject missed any visit with a probability of 5%. 
 








 
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Clarification and details on the theoretical argument were provided and additional 
simulations were conducted.  These simulations explored plausible scenarios calibrated 
to the GRADUATE studies. They also assessed the impact of ICE misclassification. 
Based on this body of evidence, the proposed method for primary analysis (using 
conditional mean imputation of missing data combined with the jackknife for inference) 
adequately controls type I error. 


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Appendix  ADCS-ADL Dependence Scale Algorithm 
Version 2.1 
Item Domains Used in the Algorithm 

bADL - basic Activities of Daily Living: Questions 1-5, 6B

iADL – instrumental Activities of Daily Living
–
Household Activities: Questions 6A, 7, 10-14, 23
–
Communication and Engagement: Questions 17, 21, 22
–
Outside Activities: Questions 15, 16A, 16B, 18
Note that 4 items included in the original communication and engagement algorithm are 
not included in the updated algorithm.  Specifically concentrating on a television 
programme (Q8), participating in small talk (Q9), talking about current events (Q19), 
recalling information recently read in book/magazine (Q20) were excluded.  Whilst these 
concepts are clearly important to quality of life, they do not require supervision and are 
therefore not considered fundamental to independence.  
The algorithm starts by checking the requirements for Level 5 which is the highest level 
of impairment and continues to check each lower level until the patient meets the 
requirements of a level and is assigned to that level.  If a patient does not meet the 
requirements for any of Levels 1-5, then the patient is assigned Level 0. 

Level 0: is the dependence level assigned when a patient has no recorded
impairment

Level 1: Item score  2 on one or more items from only one of the following clusters:
Household Activities, Communication and Engagement, Outside Activities.  There
should be no bADL impairment.

Level 2: Item Score  2 on one or more items from two or more of the following
clusters: Household Activities, Communication and Engagement, Outside Activities,
OR Item Score   1 on one or more items from any of the following clusters:
Household Activities, Communication and Engagement. (There should be no bADL
impairment).

Level 3: Item Score    2 for all items from the following clusters: Household
Activities, Communication and Engagement, Outside Activities, OR Item Score    1
on one or more items from Outside Activities, OR Item Score  2 for Bathing (Q4),
Score  2 for toileting (Q3), Score  3 for dressing, score  1 or 2 for eating OR Item
score  2 for walking

Level 4: Any one of the following: Item Score    2 for Grooming (Q5), Item score   1
for Bathing (Q4) item score  1 for toileting (Q3) or Item score   2 for dressing, OR
item score  0 for Eating (Q1) or Item score  1 for walking

Level 5: Item Score  0 for either Walking (Q2) or Toileting (Q3)


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Item recoding in preparation for application of the algorithm 
Item 16B with a binary response (0/1) was recoded to 0/3 so that the “no impairment” 
level was consistent across items. 
Item 21 was recoded such that a score of 2 (ability to write short notes or messages that 
others understood) would not be considered “impaired” for the purposes of the 
dependence scale and was collapsed with response option 3 (letters or long notes that 
others understood).  This was achieved by recoding 2 to 3. 
Missing data was not imputed.  “Don’t know” responses were also treated as missing 
and not imputed.  The dependence scale score was not scored if there were more than 
2 missing items and/or any of the bADL items were missing.  


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Appendix 3 Charter for Adjudication Committee for Intercurrent 
Events  


CHARTER FOR ADJUDICATION COMMITTEE FOR 
INTERCURRENT EVENTS 
TITLE:  
TWO PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP,  EFFICACY, AND SAFETY 
STUDIES OF GANTENERUMAB IN  PATIENTS WITH 
EARLY (PRODROMAL TO MILD)  ALZHEIMER'S 
DISEASE  
PROTOCOLS:        
WN29922, WN39658 
AUTHOR: 
 
IND NUMBERS:  
102,266  
EUDRACT NUMBERS: 
2017-001364-38 (Study WN29922) 
2017-001365-24 (Study WN39658) 
SPONSOR:  
F. Hoffmann-La Roche Ltd
DATE FINAL: 
01 September 2021
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Gantenerumab—F. Hoffmann-La Roche Ltd ACI Charter GRADUATE studies WN29922 and 
WN39658, Version 1 
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1.
VERSION HISTORY
Version 
Date 
Details 
Version 1 
01September2021 
Creation 
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5.
COMMITTEE MEETINGS
5.1 
 ORGANIZATIONAL MEETING
A first introduction meeting will formally establish the ACI and acquaint the ACI with the process 
that will be followed. In advance of the  organizational meeting the committee will have received 
the study protocols, the IBs, the blank eCRF and the SAP (the latest draft if not yet final). 
5.2 
SCHEDULED MEETINGS 
The number of meetings will depend on the amount of data to be reviewed by the ACI. The Study 
Team and the ACI will agree on the number of meetings to be held during the organizational 
meeting.  
The Study Team will prepare reports including data to be reviewed. These reports will be provided 
to the ACI at least  three business days prior to each meeting (Appendix 1). The content of these 
reports is limited to eCRF data extracted from: 
●
“Study Drug Completion/Early Discontinuation” form including :
o
“Completion/discontinuation reason” item
o
Free text field " If primary reason is protocol deviation, withdrawal by subject,
physician decision or other, specify”
The data will be extracted from the eCRF and provided in a tabular format to the committee. ACI 
meetings will not be attended by the GRADUATE Study Team. 
For ACI meetings to take place all three members should be attending. The decisions should be 
made in a unanimous way. However if this is not possible in some cases, the Chair has the casting 
vote.  
6.
COMMUNICATION AND DATA FLOW
6.1 
COMMUNICATION
The GRADUATE study team  will communicate to the ACI the meeting dates and the SPA 
responsible will extract data to be reviewed. The ACI will communicate the adjudicated ICEs to 
the GRADUATE Study Team and the SPA responsible (see section 5.2). 
ACI members are to treat all communications regarding these clinical studies, including reports, 
data, review meeting discussions, teleconferences, and meeting minutes, as confidential material. 
All communications relative to these meetings will be archived in the eTMF. 
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6.2 
ICEs CATEGORIZATION REPORT 
After each scheduled meeting, ACI will provide input on ICEs categorization during the meetings 
to the GRADUATE Study Team within seven business days. The format of ICEs Categorization 
Report will be in a tabular format. An example is presented in Appendix 2. 
The GRADUATE Study Team will collect the outcome of ACI meetings, integrate them in an 
analysis dataset, and archive the documents in the eTMF.  
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Signature Page for Final SAP WN29922/WN39658 (Graduate) v3
System identifier: RIM-CLIN-453772
Approval Task
Company Signatory
05-Oct-2022 07:46:31 GMT+0000