Clinical trial NCT01224106
Conditions: Alzheimer's Disease
Sponsor: Hoffmann-La Roche
Start date: 2010-11-30; Completion date: 2020-09-10
Enrollment: 799 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This multi-center, randomized, double-blind, placebo-controlled parallel-group study will evaluate the effect of gantenerumab (RO4909832) on cognition and functioning and the safety and pharmacokinetics in participants with prodromal Alzheimer's Disease. Participants will be randomized to receive subcutaneous (SC) injections of either gantenerumab or placebo. Participants who consent to be part of the sub study will undergo positron emission tomography (PET) scanning to assess brain amyloid. The anticipated time on study treatment is 104 weeks in Part 1, with an option for an additional up to 2 years of treatment in Part 2, followed by an open-label extension (Part 3) until July 2020.

The dosing for Parts 1 and 2 was stopped after a planned futility interim analysis showed a low probability of meeting the primary outcome measure with the doses studied. The study has converted to open-label to investigate higher gantenerumab doses.

Detailed description:

Arms: arm 1: Participants with Alzheimer's disease received Placebo by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2. arm 2: Participants with Alzheimer's disease received Gantenerumab 105 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2. arm 3: Participants with Alzheimer's disease received Gantenerumab 225 mg by SC injection every 4 weeks (Q4W) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1, for 2 additional years in Part 2. arm 4: Participants with Alzheimer's disease who had received Placebo by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years. arm 5: Participants with Alzheimer's disease who had received Gantenerumab by SC injection in Part 1 or Part 2, now received Gantenerumab at doses up to 1200 mg by SC injection every 4 weeks (Q4W) for up to 5 additional years.
Interventions: intervention 1: Gantenerumab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants received Gantenerumab at 105 mg , 225 mg, or at doses up to 1200 mg SC injection Q4W. intervention 2: Participants received Placebo SC injection Q4W.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel- 
Group Two Year Study to Evaluate the Effect of Subcutaneous 
RO4909832 on Cognition and Function in Prodromal Alzheimer's 
Disease With Option for up to an Additional Two Years of Treatment 
and an Open-Label Extension With Active Study Treatment 
NCT Number: NCT01224106 
Document Date: Protocol Version H: 09-July-2018 
 
 


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
Protocol WN25203, Version H
CLINICAL STUDY PROTOCOL
PROTOCOL NUMBER WN25203H
RO4909832
EUDRACT NO.: 2010-019895-66
IND 102,266
Multicenter, 
Randomized, 
Double-Blind, 
Placebo-Controlled, 
Parallel-Group Two Year Study to Evaluate the Effect of Subcutaneous 
RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease 
with Option for up to an Additional Two Years of Treatment and an 
Open-Label Extension with Active Study Treatment
PROTOCOL APPROVAL
Protocol Number/Version:
WN25203H
Date:  See last date in electronic signature manifestation below.
Protocol approved by:  See electronic signature manifestation below.
Confidentiality Statement
The information contained in this document, especially unpublished data, is the property 
of Roche (or under its control), and therefore provided to you in confidence as an 
investigator, potential investigator or consultant, for review by you, your staff and an 
applicable Independent Ethics Committee/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 those persons to 
whom the drug may be administered.
 
09-Jul-2018 21:03:07
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
2/Protocol WN25203, Version H
PROTOCOL AMENDMENT, VERSION H:
RATIONALE
Protocol WN25203 has been amended to allow patients to continue receiving open-label 
gantenerumab until July 2020, at which time anticipated results from other relevant 
monoclonal antibody treatments targeting amyloid-will be available.  Relevant sections 
updated include the following:

Section 1.2.4 (Rationale for Prolonging Open-label Extension [Part 3])

Section 3.1 (Overview of Study Design and Dosing Regimen)

Section 5 (Table 9, Schedule of Assessments – Open-Label Extension Years 4 and 5 
for Participants Continuing Part 3 until July 2020)

Section 5.1.6 (Part 3 – the Open-Label Extension) 

Section 5.2 (Assessments and Procedures)

Section 8.7 (Analysis Considerations for Data Collected during Part 3 – the 
Open-Label Extension)

Section 10.1.2 (Independent Data Monitoring Committee)
Additional changes to the protocol are as follows:

Gantenerumab information has been updated (Section 1.1.2, Gantenerumab)

An overview the of clinical safety, and pharmacodynamics PET amyloid results from 
the ongoing open-label Studies WN25203 and WN28745 have been added (Section 
1.1.2.4, WN28745; Section 1.1.2.5, WN25203 and WN28745 Open-Label 
Extension Studies; Section 1.3.2, Reduction in Brain Aβ by Gantenerumab)

MRI findings have been updated (Section 1.3.3, MRI Findings).

Section 2.5 (Objectives of Part 3 [Open-Label Extension]) has been updated to clarify 
which objectives for Part 3 will be evaluated during the initial 3 years of Part 3.

Observation period after dosing has been adjusted to correspond with Study File 
Note 14 (Section 5.1.6, Part 3 – the Open-Label Extension)

Storage parameters of solution at ambient temperature has been adjusted from 
6 to 4 hours to correspond with Study File Note 12 (Section 6.3.2, Preparation and 
Administration of IMP in Part 3)

Conditions for recording MRI observations has been adjusted to correspond with 
Study File Note 12 (Section 7.1.4, MRI Observations)

To further strengthen safety monitoring and reporting, Section 7 (Safety Instructions 
and Guidance) has been updated to provide clarification on reporting of findings that 
may result in an adverse event (laboratory abnormalities, vital signs, MRI 
observations [as indicated above], events associated with overdose or medication 
error), to provide clarification of deaths to specify events that require immediate 
reporting to the Sponsor (serious adverse events, adverse events of special interest, 
pregnancies and medical device complaints), and to provide more information on 
expedite reporting, on recording of adverse events in the eCRF, and on follow-up of 
adverse events.  The Safety Plan (Section 7.3) has been included to address risks,
replacing the warnings and precautions section.  The following sections have been 
clarified or added:
–
Section 7.1.1 (Clinical Adverse Events)


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
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–
Section 7.1.1.1 (Intensity)
–
Section 7.1.1.2 (Drug-Adverse Relationship [Assessment of Causality of Adverse 
Events])
–
Section 7.1.1.3 (Serious Adverse Events [Immediately Reportable to Sponsor])
–
Section 7.1.1.4 (Adverse Events of Special Interest ([Immediately Reportable to
Sponsor])
–
Section 7.1.2 (Laboratory Test Abnormalities)
–
Section 7.1.2.1 (Follow-up of Abnormal Laboratory Tests Values)
–
Section 7.1.3 (Abnormal Vital Sign Values)
–
Section 7.1.5 (Adverse Events Associated with an Overdose or Error in Drug 
Administration)
–
Section 7.1.6 (Deaths)
–
Section 7.2.2 (Reporting of Serious Adverse Events and Adverse Events of 
Special Interest [Immediately Reportable])
–
Section 7.2.3 (Reporting of Pregnancy)
–
Section 7.2.4 (Reporting Requirements for Medical Device Complaints)
–
Section 7.2.5 (Expedited reporting to Health Authorities, Investigators, 
Institutional Review Boards and Ethics Committee)
–
Section 7.2.6 (Recording Adverse Events on the eCRF)
–
Section 7.2.7 (Follow-up of Patients after Adverse Events)
–
Section 7.3 (Safety Plan)

Protocol deviation assessment and reporting have been clarified (Section 13, 
Conditions for Modifying the Protocol) 
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................................................................ 13
1.
BACKGROUND AND RATIONALE................................................................................. 24
1.1
Background (Additional Information May Be Found in the 
Investigator’s Brochure)............................................................................. 24
1.1.1
Alzheimer’s Disease................................................................................... 24
1.1.2
Gantenerumab............................................................................................. 25
1.1.2.1
NN19866: Clinical Multiple Ascending Dose Study 
(MAD) ........................................................................................................ 25
1.1.2.2
Clinical Pharmacokinetics following Subcutaneous Dosing...................... 27
1.1.2.3
WN25203.................................................................................................... 27
1.1.2.4
WN28745.................................................................................................... 29
1.1.2.5
WN25203 and WN28745 Open-Label Extension Studies.......................... 29
1.2
Rationale for the Study............................................................................... 29
1.2.1
Rationale for Part 1 of the Study ................................................................ 29
1.2.2
Rationale for Part 2 of the Study ................................................................ 31
1.2.3
Rationale for the Open-Label Extension (Part 3) ....................................... 31
1.2.4
Rationale for Prolonging Open-Label Extension (Part 3)........................... 35
1.3
Overall Benefit-Risk Assessment............................................................... 35
1.3.1
Selecting Prodromal AD Subjects for Study WN25203............................. 36
1.3.1.1
Adjustment of CSF Aβ1-42 Cutoff.............................................................. 38
1.3.2
Reduction in Brain Aβ by Gantenerumab .................................................. 39
1.3.3
MRI Findings.............................................................................................. 45
48
1.3.5
Risk to Subjects without AD Pathology ..................................................... 48
1.3.6
Part 2 (Optional Extension Phase).............................................................. 48
1.3.7
Part 3 (Open-Label Extension)................................................................... 49
1.3.8
Overall Benefit Risk Summation................................................................ 50
2.
OBJECTIVES OF PART 1 (THE FIRST 2 YEARS OF THE STUDY)............................. 50
2.1
Primary Objective....................................................................................... 50
2.2
Secondary Objectives ................................................................................. 50
2.2.1
Cognition .................................................................................................... 50
2.2.2
Global ......................................................................................................... 50
2.2.3
Functioning................................................................................................. 50
2.2.4
Neuropsychiatric Functioning .................................................................... 50


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2.2.5
Dementia Assessment................................................................................. 50
2.2.6
Safety and Tolerability ............................................................................... 51
2.2.7
Brain MRI................................................................................................... 51
2.2.8
Cerebrospinal Fluid Biomarkers................................................................. 51
2.2.9
Pharmacokinetics........................................................................................ 51
2.2.10
Anti-Drug Antibodies................................................................................. 51
2.3
Exploratory Objectives............................................................................... 51
2.3.1
Plasma Biomarkers..................................................................................... 51
2.3.2
Clinical Genotyping.................................................................................... 51
2.3.3
Roche Clinical Repository.......................................................................... 52
2.4
Objectives of Part 2 (Optional Extension).................................................. 52
2.4.1
Cognition .................................................................................................... 52
2.4.2
Global ......................................................................................................... 52
2.4.3
Functioning................................................................................................. 53
2.4.4
Neuropsychiatric Functioning .................................................................... 53
2.4.5
Dementia Assessment................................................................................. 53
2.4.6
Safety and Tolerability ............................................................................... 53
2.4.7
Brain MRI................................................................................................... 53
2.4.8
Cerebrospinal Fluid Biomarkers................................................................. 53
2.5
Objectives of Part 3 (Open-Label Extension)............................................. 53
2.5.1
Safety and Tolerability ............................................................................... 53
2.5.2
Brain MRI Volumetry................................................................................. 53
2.5.3
Brain Amyloid Load by PET Imaging........................................................ 54
2.5.4
Cognition .................................................................................................... 54
2.5.5
Global Measures of Cognition and Function.............................................. 54
2.5.6
Functioning................................................................................................. 54
2.5.7
Dementia Assessment................................................................................. 54
2.5.8
Pharmacokinetics........................................................................................ 54
2.5.9
Anti-Drug Antibodies................................................................................. 54
3.
STUDY DESIGN ................................................................................................................. 54
3.1
Overview of Study Design and Dosing Regimen....................................... 54
3.1.1
Use of Symptomatic Treatments for AD in Part 1...................................... 55
3.1.2
Use of Symptomatic Treatments for AD in Part 2...................................... 56
3.1.3
Use of Symptomatic Treatments for AD in Part 3...................................... 56
3.1.4
Rationale for Dose Selection Parts 1 and 2................................................. 56
3.1.4.1
Dosing in Subjects Who Are 04 and 14.................................................. 56


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3.1.4.2
Dosing in Subjects Who Are 24 ............................................................... 57
3.1.5
Rationale for Dose Selection for the Open-Label Extension 
(Part 3)........................................................................................................ 57
3.1.5.1
Dosing in APOE 4 carriers (14 and 24 genotypes) 
previously on placebo, 105 mg Gantenerumab, and 225 mg 
Gantenerumab meeting criteria for dose reduction due to 
ARIAs......................................................................................................... 58
3.1.5.2
Dosing in APOE 4 non-carriers (04 genotype) and in 
APOE 4 carriers receiving 225 mg Gantenerumab until the 
end of double-blind treatment (14 genotype)............................................ 58
3.2
End of Study............................................................................................... 58
3.3
Number of Subjects / Assignment to Treatment Groups in 
Part 1........................................................................................................... 58
3.4
Centers........................................................................................................ 59
4.
STUDY POPULATION....................................................................................................... 59
4.1
Overview .................................................................................................... 59
4.2
Inclusion Criteria ........................................................................................ 59
4.3
Exclusion Criteria....................................................................................... 60
4.4
Eligibility for the Open-Label Extension (Part 3) ...................................... 64
4.5
Concomitant Medication and Treatment .................................................... 64
4.6
Criteria for Premature Withdrawal ............................................................. 65
4.6.1
Withdrawal from Study Drug..................................................................... 65
4.6.2
Withdrawal of Subjects from the Roche Clinical 
Repository (RCR)....................................................................................... 66
4.7
Replacement Policy [Ensuring Adequate Numbers of 
Evaluable Subjects] .................................................................................... 66
4.7.1
For Subjects................................................................................................ 66
4.7.2
For Centers ................................................................................................. 66
5.
SCHEDULE OF ASSESSMENTS AND PROCEDURES .................................................. 67
5.1
General Instructions by Study Phase .......................................................... 79
5.1.1
Assessors for Clinical Scales and Order of Assessments ........................... 79
5.1.2
Screening Period......................................................................................... 79
5.1.3
Treatment Period during Part 1 of the Study (Including 
Day of First Dose) ...................................................................................... 80
5.1.3.1
Procedures for New MRI Findings in Part 1 of the Study.......................... 81
5.1.4
Part 2 - Extension Period for Continued Double-Blind 
Treatment.................................................................................................... 83


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5.1.4.1
Procedures to Follow for Subjects who reach the Week 104 
Visit prior to Approval of Amendment D................................................... 83
5.1.4.2
Procedures to Follow for Subjects who reach the Week 104 
or 112 Visit without having made a Decision to Continue 
in Part 2 of the Study .................................................................................. 84
5.1.4.3
Dosing during Part 2 of the Study .............................................................. 84
5.1.4.4
Procedures for new MRI findings in Part 2 of the Study............................ 84
5.1.5
Treatment-Free Follow-Up......................................................................... 84
5.1.6
Part 3 – the Open-Label Extension............................................................. 84
5.1.6.1
Procedures for new MRI findings in Part 3 of the Study............................ 86
5.2
Assessments and Procedures ...................................................................... 87
5.2.1
CDR............................................................................................................ 87
5.2.2
Functional Activities Questionnaire (FAQ)................................................ 87
5.2.3
MMSE ........................................................................................................ 87
5.2.4
Neuropsychiatric Inventory (NPI-Q).......................................................... 87
5.2.5
Alzheimer Disease Assessment Scale-Cognition 
(ADAS-Cog)............................................................................................... 88
5.2.6
Free and Cued Selective Reminding Test (FCSRT-IR).............................. 88
5.2.7
Cambridge Neuropsychological Test Automated Battery.......................... 88
5.2.8
Dementia Assessment................................................................................. 88
5.2.9
Modified Hachinski Ischemia Scale ........................................................... 88
5.2.10
MRI............................................................................................................. 89
5.2.10.1
Healthy Volunteer MRI Scans for Site Qualification................................. 89
5.2.11
Pharmacokinetic [PK] Sampling ................................................................ 90
5.2.11.1
Plasma Gantenerumab ................................................................................ 90
5.2.11.2
CSF Gantenerumab (Parts 1 and 2) ............................................................ 90
5.2.12
Anti-Drug Antibody Sampling ................................................................... 90
5.2.13
Clinical Genotyping.................................................................................... 91
5.2.14
CSF and Plasma Biomarker Sampling (Parts 1 and 2) ............................... 91
5.2.14.1
Plasma Biomarkers Sampling..................................................................... 91
5.2.14.2
CSF Sampling............................................................................................. 91
5.2.15
Roche Clinical Repository Specimen(s)..................................................... 92
5.2.15.1
Specimen Types [the following list is not exhaustive]............................... 93
5.2.16
Safety.......................................................................................................... 94
5.2.16.1
Physical Examination ................................................................................. 94
5.2.16.2
Neurological Examination.......................................................................... 94
5.2.16.3
GDS ............................................................................................................ 94


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5.2.16.4
Vital Signs .................................................................................................. 94
5.2.16.5
ECG ............................................................................................................ 94
5.2.16.6
Laboratory Assessments............................................................................. 95
5.2.16.7
Columbia-Suicide Severity Rating Scale (C-SSRS)................................... 95
6.
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................... 96
6.1
Formulation, Packaging and Labeling........................................................ 96
6.2
Dose and Schedule of IMP ......................................................................... 96
6.2.1
Dose Modifications, Interruptions, and Delays .......................................... 96
6.3
Preparation and Administration of the IMP................................................ 96
6.3.1
Preparation and Administration of the IMP in Parts 1 and 2...................... 96
6.3.2
Preparation and Administration of the IMP in Part 3................................. 97
6.4
Randomization, Blinding, and Unblinding................................................. 97
6.5
Accountability of IMP and Assessment of Compliance............................. 99
6.5.1
Accountability of IMP................................................................................ 99
6.5.2
Assessment of Compliance......................................................................... 99
6.6
Destruction of the IMP/Comparator ........................................................... 99
7.
SAFETY INSTRUCTIONS AND GUIDANCE................................................................ 100
7.1
Adverse Events (AEs)............................................................................... 100
7.1.1
Clinical Adverse Events ........................................................................... 100
7.1.1.1
Intensity .................................................................................................... 101
7.1.1.2
DrugAdverse Event Relationship (Assessment of 
Causality of Adverse Events) ................................................................... 101
7.1.1.3
Serious Adverse Events [Immediately Reportable to 
Sponsor].................................................................................................... 102
7.1.1.4
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ....................................................................... 103
7.1.2
Laboratory Test Abnormalities................................................................. 104
7.1.2.1
Follow-Up of Abnormal Laboratory Test Values .................................... 105
7.1.3
Abnormal Vital Sign Values..................................................................... 105
7.1.4
MRI Observations..................................................................................... 105
7.1.5
Adverse Events Associated with an Overdose or Error in 
Drug Administration................................................................................. 106
7.1.6
Deaths....................................................................................................... 106
7.2
Handling of Safety Parameters................................................................. 107
7.2.1
Reporting of Adverse Events.................................................................... 107
7.2.2
Reporting of Serious Adverse Events and Adverse Events 
of Special Interest [Immediately Reportable]........................................... 107


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7.2.3
Reporting of Pregnancy............................................................................ 108
7.2.4
Reporting Requirements for Medical Device Complaints........................ 108
7.2.5
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees .............................. 108
7.2.6
Recording Adverse Events on the eCRF .................................................. 109
7.2.7
Follow-Up of Patients after Adverse Events ............................................ 110
7.2.7.1
Investigator Follow-Up............................................................................. 110
7.2.7.2
Sponsor Follow-Up................................................................................... 111
7.3
Safety Plan................................................................................................ 111
8.
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN................................ 111
8.1
Primary and Secondary Study Endpoints ................................................. 111
8.1.1
Primary Efficacy Endpoint ....................................................................... 111
8.1.2
Secondary Efficacy Endpoints.................................................................. 112
8.1.2.1
Cognition – Change from Baseline at Week 104 in the 
following................................................................................................... 112
8.1.2.2
Global ....................................................................................................... 112
8.1.2.3
Functioning............................................................................................... 112
8.1.2.4
Neuropsychiatric Functioning .................................................................. 112
8.1.2.5
Dementia Assessment............................................................................... 112
8.1.2.6
MRI Volumetric Measures ....................................................................... 112
8.1.2.7
Cerebrospinal Fluid Biomarker Measures................................................ 112
8.1.3
Safety........................................................................................................ 113
8.1.4
Pharmacokinetics...................................................................................... 113
8.1.5
Exploratory Endpoints.............................................................................. 113
8.1.5.1
Plasma Biomarkers................................................................................... 113
8.1.5.2
Genotype................................................................................................... 113
8.2
Statistical and Analytical Methods........................................................... 113
8.2.1
Efficacy Data ............................................................................................ 114
8.2.1.1
Primary Efficacy Variable........................................................................ 114
8.2.1.2
Secondary Efficacy Variables................................................................... 115
8.2.2
Safety Data ............................................................................................... 115
8.2.3
Exploratory Analysis ................................................................................ 116
8.2.4
Subgroup Analyses................................................................................... 116
8.3
Sample Size .............................................................................................. 116
8.3.1
Analysis Populations ................................................................................ 117
8.3.1.1
Safety Population...................................................................................... 117


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8.3.1.2
Intent-to-Treat Population ........................................................................ 117
8.3.1.3
Per-Protocol Population............................................................................ 117
8.4
Interim Analysis ....................................................................................... 117
8.5
Other Analyses ......................................................................................... 117
8.5.1
Pharmacokinetic Analysis ........................................................................ 117
8.6
Analysis Considerations for Data Collected during Part 2, 
the Extension Period for Continued Double-Blind 
Treatment.................................................................................................. 118
8.7
Analysis Considerations for Data Collected during Part 3 –
the Open-Label Extension ........................................................................ 118
9.
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE ................... 118
9.1
Assignment of Preferred Terms and Original Terminology..................... 119
10.
REVIEW OF RESULTS DURING THE CONDUCT OF THE STUDY.......................... 119
10.1
Review of Safety Data.............................................................................. 119
10.1.1
MRI Review Committee........................................................................... 119
10.1.2
Independent Data Monitoring Committee................................................ 119
10.2
Interim Analysis ....................................................................................... 120
10.2.1
Administrative Interim Analysis............................................................... 120
10.2.2
Sample Size Adjustment........................................................................... 120
10.2.3
Futility Analysis ....................................................................................... 121
11.
REFERENCES ................................................................................................................... 122
12.
ETHICAL ASPECTS ......................................................................................................... 126
12.1
Local Regulations/Declaration of Helsinki............................................... 126
12.2
Informed Consent ..................................................................................... 126
12.2.1
Main Study Informed Consent.................................................................. 126
12.2.2
Written Informed Consent from the Study Partner................................... 126
12.2.3
RCR Informed Consent ............................................................................ 126
12.2.4
Death or Loss of Competence of Participant who Has 
Donated a Specimen(s) That is Stored in the RCR .................................. 127
12.3
Independent Ethics Committee(IEC)/Institutional Review 
Board(IRB) ............................................................................................... 127
12.4
Role of the Science and Ethics Advisory Group (SEAG) ........................ 128
13.
CONDITIONS FOR MODIFYING THE PROTOCOL..................................................... 128
14.
CONDITIONS FOR TERMINATING THE STUDY ....................................................... 128
15.
STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING................................ 129
15.1
Investigator's Files / Retention of Documents.......................................... 129


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15.2
Source Documents and Background Data ................................................ 129
15.3
Audits and Inspections.............................................................................. 129
15.4
Electronic Case Report Forms.................................................................. 130
15.5
Financial Disclosure ................................................................................. 130
16.
MONITORING THE STUDY............................................................................................ 130
17.
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS.......................................................................................................................... 131
18.
CLINICAL STUDY REPORT (CSR)................................................................................ 131
19.
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS...................... 131
LIST OF TABLES
Table 1
Schedule of Assessments – First Year .............................................67
Table 2
Schedule of Assessments – Second Year........................................68
Table 3
Schedule of Assessments – Extension Year 1 ................................70
Table 4
Schedule of Assessments – Extension Year 2 ................................71
Table 5
Schedule of Assessments – Open-Label Extension Year 1 -
for ApoE 4 carriers previously on:  1) Placebo, 2) 105 mg 
Gantenerumab and 3) 225 mg Gantenerumab meeting 
Criteria for Dose Reduction due to ARIAs ........................................72
Table 6
Schedule of Assessments – Open-Label Extension Year 1-
for:  1) ApoE 4 non-carriers and 2) ApoE 4 Carriers 
receiving 225 mg Gantenerumab until the End of Double-
blind Treatment .....................................................................................73
Table 7
Schedule of Assessments – Open-Label Extension Year 2 
for all Participants .................................................................................74
Table 8
Schedule of Assessments – Open-Label Extension Year 3 
for all Participants .................................................................................75
Table 9
Schedule of Assessments – Open-Label Extension Years 4 
and 5 for Participants Continuing Part 3 until July 2020............77
LIST OF FIGURES
Figure 1
Treatment Response in ADAS-Cog-13 by Gantenerumab Serum 
Concentration, 2-Year Completing Fast Progressors ..............................33
Figure 2
Mean Percent Changes from Baseline after 2 Years of Treatment in 
(A) CSF P-Tau and (B) T-Tau (ITT population).....................................34
Figure 3
CSF Biomarkers at baseline in MCI subjects (taken from [8])...............36
Figure 4
Kaplan-Meier Estimates of the Rate of Progression to Alzheimer's 
Disease in Patients with MCI who Have Either Normal CSF or 
Pathological CSF at Baseline ..................................................................37


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
12/Protocol WN25203, Version H
Figure 5
A. Cerebrospinal Fluid–derived A42 Mixture Model Applied to 
Individuals with Amnestic MCI from the ADNI Study..........................39
Figure 6
Median Amyloid PET Percent Change from Baseline:  Composite, 
6 Months (ITT Population)......................................................................40
Figure 7
Mean Percent Changes from Baseline in Composite Amyloid PET 
SUVR after 2 years of Treatment (ITT Population)................................41
Figure 8
Time Course PET SUVR during 2 Years of Treatment by 
Gantenerumab Serum Concentration Category.......................................42
Figure 9
Voxel-Wise Changes in PET SUVR After 1 Year of Treatment 
with Gantenerumab .................................................................................43
Figure 10
Reduction of Brain Amyloid PET SUVR in Patients Exposed 
to at Least 900 mg for 69 Months in Studies WN25203 
(SR) and WN28745 (MR) Open-Label Extension Studies ............45
Figure 11
ARIA Adverse Events by APOE ε4 Genotypes......................................46
LIST OF APPENDICES
Appendix 1
ICH Guidelines for Clinical Safety Data Management, Definitions 
and Standards for Expedited Reporting, Topic E2................................133
Appendix 2
CANTAB – Descriptions of tests used in this study .............................136
.139
 
140
154
158


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
13/Protocol WN25203, Version H
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP 
TWO YEAR STUDY TO EVALUATE THE EFFECT 
OF SUBCUTANEOUS RO4909832 ON COGNITION 
AND FUNCTION IN PRODROMAL ALZHEIMER'S 
DISEASE WITH OPTION FOR UP TO AN 
ADDITIONAL TWO YEARS OF TREATMENT AND 
AN OPEN-LABEL EXTENSION WITH ACTIVE 
STUDY TREATMENT
PROTOCOL NUMBER:
WN25203
VERSION NUMBER:
H
EUDRACT NUMBER:
2010-019895-66
IND NUMBER:
102,266
TEST PRODUCT:
Gantenerumab (RO4909832)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of the 
signed form as instructed by your local study monitor.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
14/Protocol WN25203, Version H
SYNOPSIS OF PROTOCOL NUMBER WN25203H
TITLE
Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Two Year Study to Evaluate the Effect of 
Subcutaneous RO4909832 on Cognition and Function in 
Prodromal Alzheimer's Disease with Option for up to an 
Additional Two Years of Treatment and an Open-Label 
Extension with Active Study Treatment
SPONSOR
Roche
Clinical Phase
3
INDICATION
Prodromal Alzheimer’s Disease
OBJECTIVES OF DOUBLE-
BLIND PART OF THE STUDY
Primary
Secondary
Cognition, global, and functioning
Safety
MRI volumetry
    
   
CSF Biomarkers
Pharmacokinetics/
Anti-Drug Antibodies
Exploratory
Plasma Biomarkers
To evaluate the effect of gantenerumab versus placebo on the 
change in the Clinical Dementia Rating scale Sum of Boxes 
(CDR-SOB), a global measure of cognition and functional 
ability.
To evaluate the effect of gantenerumab versus placebo on 
cognition (assessed with the Alzheimer Disease Assessment 
Scale-Cognition [ADAS-Cog], Mini Mental State Exam 
[MMSE], Cambridge Neuropsychological Test Automated 
Battery [CANTAB], and the Free and Cued Selective Reminding 
Test-Immediate Recall [FCSRT-IR]) on global measures (based 
on the CDR global score), and on functioning (assessed with the 
Functional Activities Questionnaire [FAQ]), on  
neuropsychiatric functioning (assessed with  the 
Neuropsychiatric Inventory Questionnaire [NPI-Q]) and on time 
to onset of dementia.
To assess the safety and tolerability of gantenerumab assessed 
by magnetic resonance imaging (MRI), physical and 
neurological examinations, vital signs, blood and urine safety 
tests, ECGs, Columbia-Suicide Severity Rating Scale (C-SSRS), 
Geriatric Depression Scale (GDS), and adverse event 
monitoring.
To evaluate the effect of gantenerumab versus placebo on 
hippocampal volume, whole brain volume, ventricular 
enlargement, and possibly other volumetric measures of the 
brain.
To evaluate the effect of gantenerumab versus placebo on levels 
of cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease 
(AD) pathology (i.e., total tau [T-tau], phospho-tau [p-tau], and 
amyloid-beta (A1-42]). 
To determine the relationship of plasma and CSF concentrations 
of gantenerumab on other responses. To assess incidence of
anti-gantenerumab antibodies, and if relevant, evaluate its effect
on the pharmacokinetic (PK), pharmacodynamic (PD), efficacy. 
and safety parameters. 
To evaluate the effect of treatment on peripheral biomarkers of 
amyloid deposition and/or clearance, neurodegeneration, 
inflammation, and other markers known to be involved in the 
pathogenesis of AD.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
15/Protocol WN25203, Version H
Clinical Genotyping
To evaluate the effect of gene encoding apoliprotein E 
(ApoE) 4 genotype and fragment crystalizable gamma receptor 
(FcR) genotype on PK/PD, efficacy, and safety parameters
OBJECTIVES OF THE 
OPEN-LABEL EXTENSION -
PART 3
Primary:
Safety:
Secondary:
Brain MRI Volumetry
Brain Amyloid Load by Positron
Emission Tomography (PET) 
Imaging
Pharmacokinetics
Anti-Drug Antibodies
Cognition, Global, Functioning, and 
Dementia Assessment
To assess short-term and long-term safety and tolerability of 
gantenerumab (RO4909832) given at doses up to 1200 mg 
subcutaneous (SC) every 4 weeks (Q4W) by MRI, physical and 
neurological examinations, vital signs, blood safety tests, ECGs, 
C-SSRS, and adverse event monitoring.
To evaluate the effect of gantenerumab over time on 
hippocampal volume, whole brain volume, ventricular 
enlargement, and possibly other volumetric measures of the brain 
compared to baseline and to the start of Part 3
To assess changes in amyloid load over time using 
Florbetapir 8F (AV-45; Amyvid) compared to screening 
(if applicable) and to the start of Part 3.  PET scans performed 
within 12 months prior to the first study drug administration in 
Part 3 will be used for the baseline of Part 3.  This objective will 
be evaluated in a subset of consenting subjects participating in 
the PET substudy.
To determine the relationship of plasma concentrations of 
gantenerumab on other responses
To assess the development of anti-gantenerumab antibodies and, 
if detected, explore their association with the PK, PD, efficacy, 
and safety parameters of gantenerumab. 
To evaluate the effect of gantenerumab over time as assessed 
with the CDR-SOB, the ADAS-Cog, the MMSE, the FCSRT-IR, 
the CDR global score, the FAQ compared to baseline and to the 
start of Part 3, and to determine the presence of and time to onset 
of dementia.
TRIAL DESIGN
Multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study, followed by open-label extension with 
active study drug treatment
NUMBER OF SUBJECTS
Approximately a total of 770 subjects; 514 on gantenerumab and 
256 on placebo.  The sample size was confirmed following a 
planned blinded evaluation of the variance in the change in the 
CDR-SOB at Week 76. The study enrolled 799 subjects, and 797 
subjects were dosed with double-blind treatment:  266 subjects in 
the placebo group, 271 subjects in the gantenerumab 105 mg 
group, and 260 subjects in the gantenerumab 225 mg group. 
The number of subjects enrolled in Part 3 is 154.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
16/Protocol WN25203, Version H
TARGET POPULATION
Subjects who meet memory and biomarker criteria which 
indicate a strong likelihood that they are in the prodromal phase 
of Alzheimer’s Disease
LENGTH OF STUDY 
Double-blind treatment period:
Part 1:  Approximately 2 years and 2 months which includes 
8 weeks for screening and 2 years (104 weeks) of treatment.
Part 2:  Up to additional 2 years of treatment.
Dosing was suspended on 19 December 2014. As a result 
duration of the double-blind treatment period varied depending 
on the number of study weeks that subjects completed.
Treatment-free follow-up period:  
Twelve weeks of follow up after completion of the double-blind 
treatment in Part 1 or Part 2, with an optional follow-up visit 
approximately 1 year (52 weeks) after the end of the double-
blind treatment.  
Approximate duration of the study for subjects completing both 
Part 1 and Part 2 with the maximum 52-week follow-up and not 
continuing in Part 3 will be 5 years and 2 months.  For the last 
subjects enrolled, approximate duration of the study will be 
2 years and 2 months (year 1 of Part 1 and 1 year of treatment-
free follow-up).
Open-label extension
Part 3:  Up to 3 years of active study drug treatment (with a 
4-week follow-up visit) after treatment-free follow-up period. 
For subjects continuing in Part 3, treatment-free follow-up period 
will last approximately between 12 and 18 months (depending on 
the approval of study protocol WN25203G by local Competent 
Authorities).  All subjects who complete 3 years of 
open-label treatment will be given the option of extending 
open-label treatment until July 2020 and may receive up 
to 21 additional administrations every 4 weeks during 
Years 4 and 5.  
END OF STUDY
The end of the study will be considered to be the date of the last 
visit (including the last scheduled follow-up visit according to 
study protocol) of the last subject in the study.
INVESTIGATIONAL MEDICAL 
PRODUCT(S)
DOSE/ROUTE/REGIMEN
Part 1 and Part 2:  Gantenerumab (105 or 225 mg for the 04 and 
14 ApoE genotypes or 105 mg for the 24 ApoE genotype 
subjects) by SC injection Q4W
Part 3 (open-label extension):  Gantenerumab will be 
administered SC Q4W to the subjects using up-titration regimens 
dependent on APOE ε4 genotype (and on the dose received 
during the double-blind treatment period) that will allow subjects 
to reach the target dose of 1200 mg gantenerumab within 10 and 
6 months for titration schedules below. 
Titration schedule 1: Dosing in APOE ε4 carriers (14 ApoE and 
24 ApoE genotypes who were in the placebo and 105 mg 
gantenerumab groups, and in the 225 mg gantenerumab group 
meeting criteria for dose reduction due to amyloid-related 
imaging abnormalities (ARIAs) during double-blind treatment 
period):

Doses 1, 2, and 3:  105 mg 

Doses 4, 5, and 6:  225 mg 

Doses 7 and 8:  450 mg 

Doses 9 and 10:  900 mg 

Dose 11 onwards:  1200 mg 


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
17/Protocol WN25203, Version H
Titration schedule 2: Dosing in subjects who are APOE ε4 
non-carriers (04 genotype) and in APOE 4 carriers receiving 
225 mg gantenerumab until the end of double-blind treatment 
(14 genotype):

Doses 1 and 2:  225 mg 

Doses 3 and 4:  450 mg 

Doses 5 and 6:  900 mg 

Dose 7 onwards:  1200 mg  
Gantenerumab doses of 105 and 225 mg will be administered SC 
 
 
The 1200-mg gantenerumab dose will 
be administered SC 
.
COMPARATOR 
DOSE/ROUTE/REGIMEN
Placebo, by SC injection, Q4W in Part 1 and Part 2.
PART 3 ASSESSMENTS OF:
- EFFICACY
CDR-SOB, ADAS-Cog, MMSE, FAQ, FCSRT-IR, CDR global, 
onset of dementia, during the initial 3 years of Part 3.  
After which only MMSE will be administered.
- SAFETY
MRI, physical and neurological examinations, vital signs, 
laboratory assessments (blood safety tests, urine pregnancy [for 
women of childbearing potential]), Columbia-Suicide Severity 
Rating Scale (C-SSRS), ECGs, and adverse event monitoring
- PHARMACOKINETICS
Gantenerumab levels in plasma
- BIOMARKERS
MRI and PET, to assess changes in brain volumetry and brain 
amyloid load over time during the initial 3 years of Part 3, 
respectively.
PROCEDURES (summary):
Screening and baseline:  After written informed consent is obtained, screening 
assessments, which include general health and cognitive testing, brain MRI, and lumbar 
puncture for cerebrospinal fluid (CSF) collection, and must be completed within 8 weeks 
followed by up to 1 week for baseline assessments. (See schedule of assessments in 
protocol)
Treatment (Part 1):  In this study, all subjects will receive 26 treatments (drug 
administrations) with a 4-week interval between each dose.  On each dosing day, 
gantenerumab or matching placebo will be administered as two SC injections in the 
abdominal area.  Safety and efficacy evaluations will be performed according to the 
schedule of assessments. 
Treatment Extension (Part 2):  Subjects who complete the entire 2 years of treatment and 
the Week 104 follow-up visit may continue to receive the same treatment that they were 
receiving at the Week 100 visit.  The double-blind treatment can resume at the Week 104 
visit after all assessments have been completed for that visit.  
Follow-up:  Subjects will be followed for 12 weeks, with an optional follow-up visit 
approximately 1 year (52 weeks) after the last dose of study treatment in Part 1 or Part 2 
(double-blind treatment phase). The Week 52 visit is not required for subjects entering 
Part 3.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
18/Protocol WN25203, Version H
Futility Analysis:  A futility interim analysis was performed when approximately 50% of 
the sample size completed the Week 104 visit.  As the study was declared futile, with a 
low likelihood of meeting the prespecified primary outcome measure with the doses 
studied (105 and 225 mg), dosing was suspended on 19 December 2014.  This analysis 
did not reveal any new safety signal.
Open-Label Extension (Part 3):  Additional analyses of efficacy and PD results (CSF 
biomarkers of neurodegeneration and amyloid PET standardized uptake value ratio 
[SUVR]) indicated that higher doses of gantenerumab may have clinically relevant effect 
on cognition and function.  Doses were modeled based on the results of the PET substudy 
(brain amyloid PET SUVR) and on the supportive results of the Phase 1b (PRIME) study, 
investigating the effects of aducanumab on a total of 165 patients with prodromal or mild 
AD.  Aducanumab is a monoclonal antibody with similar properties and mode of action 
as gantenerumab.  The results showed a dose- and time-dependent reduction of amyloid 
plaques in the brain that was associated with dose-dependent clinical effect, which 
reached statistical significant clinical effect with the highest aducanumab dose tested.  
Extrapolation of the data indicated that approximately 20% reduction in brain amyloid 
detected by PET may be needed to achieve clinical effect, compared to overall 
approximately 5% achieved with 225 mg gantenerumab over 2 years.
All subjects who were eligible for and enrolled into protocol WN25203 and had at least 
one follow-up/dropout visit after the double-blind treatment will be offered the 
opportunity to participate in Part 3.  Subjects who meet any of the following criteria will 
be exempted:

Prematurely discontinued from Part 1 and Part 2 for safety reasons (e.g., MRI 
findings meeting criteria for treatment discontinuation in Part 1 and Part 2)

 

Received another investigational medication after the end of double-blind treatment

Participation in Part 3 deemed inappropriate by investigator or Sponsor
During Part 3 study, subjects will receive gantenerumab Q4W that will be uptitrated 
starting from 105 or 225 mg based on the ApoE genotype to up to 1200 mg to reach the 
doses expected to give clinically meaningful effect in a less than 1 year.  The titration 
schemes were designed to optimally manage ARIA events in ApoE e4 carriers and 
non-carriers by a PK-PD model using PK and safety results from this study and from 
similarly acting anti-amyloid antibodies (aducanumab and bapineuzumab).  In addition, 
all subjects entering Part 3 at centers already involved in a WN25203 PET substudy of 
brain amyloid imaging during Part 1 and Part 2 will be offered to take part in the PET 
substudy, independent of their previous participation during the double-blind treatment.  
Subjects will be followed until the end of treatment phase (4 weeks after the last dose).


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
19/Protocol WN25203, Version H
STATISTICAL ANALYSES IN THE OPEN-LABEL EXTENSION:  
Statistical analyses will primarily focus on safety aspects during and after the uptitration 
phase in Part 3 of the trial.  In addition, it is planned that efficacy analyses will be 
conducted on cognitive and functional measures as well as biomarkers.  It is planned that 
efficacies will be calculated using both, the original, drug-naïve baseline as well as the 
baseline that gets available before start of Part 3.  Results of these analyses will be 
interpreted in an exploratory fashion.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
20/Protocol WN25203, Version H
GLOSSARY OF ABBREVIATIONS
A
Amyloid-beta
AChEI(s)
Acetylcholinesterase Inhibitor(s)
AD
Alzheimer’s disease
ADA
Anti-drug antibodies
ADAS-Cog
Alzheimer Disease Assessment Scale-Cognition
ADL
Activities of Daily Living
ADNI
Alzheimer’s Disease Neuroimaging Initiative
AE
adverse event
ApoE 
gene encoding Apolipoprotein E
ARIA
Amyloid Related Imaging Abnormality
ARIA-E
Amyloid Related Imaging Abnormality-Edema
ARIA-H
Amyloid Related Imaging Abnormality-Hemosiderin
AUC
area under the plasma concentration-time curve
AUC0-
area under the time-plasma concentration curve at steady 
state
AUCinf
area under the plasma concentration-time curve from time 
zero extrapolated to the infinite time
CA
Competent Authorities
CANTAB
Cambridge Neuropsychological Test Automated Battery
CDR
Clinical Dementia Rating Scale
CDR-SOB
Clinical Dementia Rating – Sum of Boxes
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CSF
cerebrospinal fluid
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctrough
trough concentrations
CV
coefficient of variation
DMS
Delayed match to sample
DO
dropout


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
21/Protocol WN25203, Version H
GLOSSARY OF ABBREVIATIONS
DSM
Diagnostic and Statistical Manual of Mental Disorders
EC
Ethics Committee
eCRF
Electronic Case Report Form
EDC
electronic data capture
EEA
European Economic Area
ELISA
Enzyme Linked Immunosorbent Assay
Ext
extension
FAQ
Functional Activities Questionnaire
FCSRT-IR
Free and Cued Selective Reminding Test – Immediate 
Recall
FcR
Fragment crystalizable gamma Receptor
FDA
U.S. Food and Drug Administration
FLAIR
Fluid-attenuated Inversion Recovery
FU
follow-up
GDS
Geriatric Depression Scale
HAHA
Human-antihuman antibodies
HbA1c
Hemoglobin A1c (glycosylated hemoglobin)
HCLF
high concentration liquid formulation
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
iDMC
Independent Data Monitoring Committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IgG
Immunoglobulin G
IMC
internal monitoring committee
IMP
Investigational Medicinal Product
IND
Investigational New Drug
INN
International Non-proprietary Name
ITT
intent to treat
IV
intravenous


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
22/Protocol WN25203, Version H
GLOSSARY OF ABBREVIATIONS
IVRS
Interactive Voice Recognition System
IxRS
Interactive Voice Recognition System or Interactive Web 
Recognition System
Kd
dissociation constant
LOCF
Last observation carried forward
LP
Lumbar puncture
MAD
Multiple Ascending Dose
MCI
Mild Cognitive Impairment
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MMRM
Mixed-effects model repeated measures
MMSE
Mini Mental State Exam
MOT
Motor screening test
MRI
Magnetic resonance imaging
MRI-C
MRI Review Committee
NINCDS-ADRDA
National Institute of Neurological and Communicative 
Disorders and Stroke and the Alzheimer's Disease and 
Related Disorders Association
NPI-Q
Neuropsychiatric Inventory Questionnaire
OLE
open-label extension
PAL
Paired associates learning
PD
Pharmacodynamic
PET
Positron Emission Tomography
PK
Pharmacokinetic
PP
per protocol
PRM
Pattern recognition memory
PT
Prothrombin time
P-tau
phospho-tau


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
23/Protocol WN25203, Version H
GLOSSARY OF ABBREVIATIONS
Q4W
every 4 weeks
QC
quality control
QTcF
QT corrected with Fridericia equation
RCR 
Roche Clinical Repository
RTI
Reaction time
RVP
Rapid visual information processing
SAD
Single ascending dose
SAE
serious adverse event
SC
subcutaneous
SD
Standard deviation
SEAG
Science and Ethics Advisory Group
SMT
Study Management Team
SNRI
Selective Norepinephrine Reuptake Inhibitor
SSNRI
Selective Serotonin/Norepinephrine Reuptake Inhibitor
SUVR
Standardized Uptake Value Ratio
SSRI
Selective Serotonin Reuptake Inhibitor
SUSAR
Suspected Unexpected Serious Adverse Reaction
SWM
Spatial working memory
T
Tesla
T4
thyroxine
Tmax
maximum plasma concentration
T-tau
total tau
ULN
upper limit of normal


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
24/Protocol WN25203, Version H
PART I:
STUDY DESIGN AND CONDUCT
1.
BACKGROUND AND RATIONALE
1.1
Background (Additional Information May Be Found in the 
Investigator’s Brochure)
1.1.1
Alzheimer’s Disease
According to the figures provided by Alzheimer’s Association in 2015, an estimated 
47 million people are living with dementia, with the number projected to increase to 
76 million cases in 2030.  Alzheimer’s disease (AD) is the most common cause of 
dementia, accounting for 60%–80% of cases.  In the United States it is the sixth leading 
cause of death, with the rate increased by 71% from 2000 to 2013. 
AD is clinically characterized by a progressive impairment in cognitive and executive 
abilities, which results in decreased function and gradual loss of independence [39].  
Although the course of illness will vary from patient to patient, in general, the clinical 
picture evolves from “predementia/prodromal AD” to mild, moderate, and ultimately, 
severe AD.  The progressive decline that starts in the predementia stage of AD initially 
presents as an impairment of memory, language, and visuospatial function, some of 
which can be explained by loss of cholinergic neurons in the basal forebrain.  This 
neuronal loss contributes to the symptom development of AD.  As AD advances, patients 
become progressively impaired and the burden on caregivers significantly increases.  
Because of its increasing prevalence, long duration, and high cost of care, AD is expected 
to continue to represent a major public health problem.
The main pharmacological approach to treatment is aimed at ameliorating the symptoms 
and improving functioning of AD patients for 6–18 months by increasing synaptic levels 
of acetylcholine through the use of acetylcholinesterase inhibitors (AChEIs).  Currently 
available AChEIs include donepezil (Aricept®), galantamine (Reminyl®/Razadyne®), 
rivastigmine (Exelon®), and tacrine (Cognex®) [40].  Overstimulation of the N-methyl-
D-aspartate (NMDA) receptor by glutamate is also implicated in neurodegenerative 
disorders [40].  Memantine, an NMDA antagonist, provides only modest improvement in 
global measures of functioning both with and without an AChEI.  Unfortunately, none of 
these medications have an effect on the progressing neuropathology nor significantly 
change the course of the disease [40].
Consequently, drug discovery and development in AD are focused on disease-modifying 
treatments that target, for example, amyloid-beta (Aβ) peptide or tau pathology.  Genetic 
and pathological evidence suggests that Aβ processing and deposition play a critical role 
in the cascade of biological events involved in the pathogenesis of AD.  Aβ accumulation 
in the brain begins well before the development of clinical dementia in AD, and studies 
have shown that while intermediate or high levels of Aβ may be present at a very early 
disease stage (previously referred to as amnestic Mild Cognitive Impairment [MCI]), near 
maximal amounts are generally reached by the time dementia is evident [1].  For these 
reasons, treatments which prevent, slow, or decrease the accumulation of brain Aare 
being tested as therapeutic agents in AD.  Accumulating evidence suggests that 
monoclonal anti-Aβ antibodies can bind to Aβ and promote its clearance [16,41,42], thus 


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
25/Protocol WN25203, Version H
potentially reducing deposition of Aβ aggregates, reducing neurodegeneration, and, 
ultimately, slowing progression of AD. 
1.1.2
Gantenerumab
Gantenerumab or RO4909832 is a fully human anti-Aβ peptide antibody developed by 
in vitro maturation within a complete human immunoglobulin , subclass-1 framework 
(IgG1).  Gantenerumab recognizes a conformational epitope of Aβ demonstrated for both 
major types of Aβ, i.e., Aβ1-40 and Aβ1-42.  In vitro, gantenerumab recognizes aggregated 
(fibrillar) Aβ with high affinity (Kd approximately 0.5 nM).  Based on further in vitro 
studies and studies in animal models, the pharmacologic profile suggests that in humans 
gantenerumab may prevent, inhibit, or reduce the accumulation of Athat is believed to 
play an important role in the pathogenesis of AD. 
Gantenerumab was investigated in 10 completed Phase 1 clinical trials:  three 
single-ascending-dose (SAD) studies (BN18726,
JP22474, and BP30042);
two 
multiple- ascending-dose (MAD) studies in patients with mild to moderate AD 
(NN19866 described in Section 1.1.2.1 and JP22431); and four bioavailability studies in 
healthy subjects, one comparing intravenous (IV) and subcutaneous (SC) formulations 
(WP22461), two comparing lyophilized and liquid SC formulations (WP27951 and 
BP29113), 
and 
a 
relative 
bioavailability 
study 
(WP40052) 
comparing 
gantenerumab SC formulation from the G3 manufacturing process (used in the 
ongoing WN25203 and WN28745 open label studies) to the new G4 
manufacturing process, to be used in upcoming studies.  In addition, a 
tolerability study (WP39322) investigating the association of pain with speed of 
SC administrations of gantenerumab has been completed.  A total of 543 subjects 
participated in these Phase 1 studies, of whom 406 healthy volunteers and 101 patients 
with AD received gantenerumab. 
Two Phase III studies designed to examine efficacy and safety of gantenerumab 
in patients with prodromal AD (the current protocol Study WN25203) and mild 
AD (Study WN28745) have been converted to open-label extension (OLE) 
studies.  The OLE studies examining the safety and tolerability of higher doses of 
gantenerumab in prodromal AD (Study WN25203) and in mild AD (Study 
WN28745) are ongoing.  Two additional Phase III studies (WN29922 and 
WN39658) investigating the effect of gantenerumab in early (prodromal to mild) 
AD were initiated in 2018.
In addition, a Phase II/III study, the Dominantly-Inherited Alzheimer’s Network 
Trials Unit (DIAN-TU-001), is ongoing. 
Information on the preclinical and clinical studies can be found in the Investigator’s 
Brochure (IB) for gantenerumab.  
1.1.2.1
NN19866: Clinical Multiple Ascending Dose Study (MAD)
This study was conducted in patients with mild to moderate AD and as mentioned above, 
a subset of patients had amyloid imaging via positron emission tomography (PET)
scanning.  Dosing was an IV infusion given once every 28 days for 7 administrations.  


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
26/Protocol WN25203, Version H
There were four dosing cohorts: the 6 mg and 20 mg cohorts each included 10 patients 
(8 active, 2 placebo), and the 60 mg and 200 mg cohorts each included 20 patients 
(16 active, 4 placebo).  Due to reports in the literature that other monoclonal antibodies 
increased cerebral microbleeds in transgenic AD model mice, patients with any 
microbleeds on the screening magnetic resonance imaging scan (MRI) were excluded. 
PET data available from the MAD substudy suggested an amyloid-removing effect of 
gantenerumab over the period of up to 6 months at doses of 60 and 200 mg IV whereby 
the effect at the higher dose appeared larger.
Pharmacokinetics showed a terminal half-life of approximately 24 days (similar to other 
IgG molecules).  There was minimal and predictable accumulation in the periphery and 
CSF concentrations were approximately 0.12%–0.27% of the plasma concentration 
across the treatment groups.
Monitoring for antidrug antibodies (ADAs) did not reveal an immunogenicity signal.
No changes were seen on measures of cognition or biological fluid markers (in this 
Phase 1 study with the small sample size and of short duration).
The main clinical safety observations reported were amyloid-related imaging 
abnormalities (ARIAs).  The ARIAs included edema/effusion (ARIA-E) and 
hemosiderosis (ARIA-H; [microbleeds and areas of leptomeningeal hemosiderosis]) and 
were also observed with other anti-Atherapies (see Section 1.3.3).  Standard safety 
measures (adverse events [AEs], laboratory tests, ECGs, and physical and neurological 
examinations) demonstrated that all doses were well tolerated. 
Six serious adverse events (SAEs) in 6 patients were reported during this study, two of 
which resulted in death (one case of coronary atherosclerosis in the placebo group and 
one in the gantenerumab 6 mg group).  There were two Suspected Unexpected Serious 
Adverse Reactions (SUSARs) (i.e., serious adverse events where an association with 
treatment cannot be excluded):  cerebral microbleed and left bundle branch block.  Both 
subjects had received 200 mg of gantenerumab.  No patient withdrew prematurely from 
the study due to an adverse event. 
Study NN19866 was prematurely terminated due to MRI findings consistent with 
ARIA-E (vasogenic oedema/inflammation) seen after two to four doses of gantenerumab 
200 mg.  Two of the 16 patients in this dose group were homozygous for ApoE4 (ε4/ε4), 
and each had distinct ARIA-E and ARIA-H; 1 patient also had associated symptoms that 
were reported as a serious adverse event (cerebral microhemorrhage) but no treatment 
was required.  Of the 11 patients who were heterozygous for ApoE4 (ε4/ε3), two had 
minor ARIA-E findings.  There were no such MRI findings in the 3 patients who were 
ApoE4 non-carriers. Concomitant ARIA-H (ie, concomitant microbleeds) findings were 
only seen in the two patients who were homozygous for ApoE4.  No patient required 
treatment, and the ARIA-E findings spontaneously resolved 1-4 months after 
discontinuation of gantenerumab.
Three patients had isolated microbleeds (without ARIA-E): one placebo patient (ε4/ε3) 
had two microbleeds, and single microbleeds were seen in 1 patient at 60 mg (ε4/ε4) and 


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1 patient at 200 mg (a non-ApoE4 carrier).  Overall, isolated microbleeds were 
uncommon and did not show a convincing relationship to treatment.
Because microbleeds are associated with increased cerebrovascular amyloid and this may 
increase the risk for an MRI finding, including further hemorrhages when treated with an 
anti-Aantibody, Study WN25203 restricts patient enrollment based on the number of 
microbleeds seen on the screening MRI.  In addition, the protocol includes an algorithm 
for adjusting treatment should ARIA-H or ARIA-E finding described above occur.  
Subjects will be monitored by regularly scheduled MRIs which will be centrally read and 
any relevant new findings will be brought to the attention of an independent MRI Review 
Committee (MRI-C) (see Section 5.1.3.1).
1.1.2.2
Clinical Pharmacokinetics following Subcutaneous Dosing
The pharmacokinetics of gantenerumab following a single SC dose 
 
 in healthy subjects were compared with IV administration (Study 
WP22461) and with SC administration of the high concentration liquid formulation 
(HCLF; Studies WP27951 and BP29113).
Absorption of gantenerumab is relatively slow after SC injection, with plasma 
concentrations reaching maximum levels generally 7 days after dosing, followed by a 
subsequent monophasic decline with a terminal half-life of approximately 24 days, and is 
similar to that recorded following IV administration.  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
SC administration of gantenerumab caused minimal local erythema and transient pain.  
In Study WP27951, the most common adverse event was injection site erythema, 
 
.  It is likely 
that the injection site reactions may be at least partly related to the injection volume.  See 
the IB for additional information. 
1.1.2.3
WN25203
The study enrolled 799 subjects and 797 subjects were dosed with double-blind 
treatment:  266 subjects in the placebo group, 271 subjects in the gantenerumab 105 mg 


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group and 260 subjects in the gantenerumab 225 mg group.  One hundred twelve subjects 
participated in the PET substudy. 
Randomization was based on the ApoE 4 carrier status (Section 1.3.3).  In the context of 
the clinical understanding of ARIAs at the time of study design, selection of 
gantenerumab doses (105 mg for 24 genotype and 225 mg for 04- and 14 genotype) 
was largely driven by reducing risk of MRI findings.  Baseline characteristics were well 
balanced between treatment arms in the study, as well as in the PET substudy.  Per 
protocol, subjects were to be treated for 2 years (104 weeks) with an option for additional 
2 years of double-blind treatment. 
Unblinded safety data were reviewed on an ongoing quarterly basis by the independent 
Data Monitoring Committee (iDMC).  A planned interim futility analysis was performed 
by the iDMC when approximately 50% of the sample completed 104 weeks of treatment 
(see Section 10.2.3).  Following the analysis that estimated a low probability for meeting 
the pre-specified primary outcome measure (with the predictive probability of success of 
6%), the study was declared futile.  As a result, dosing with originally selected doses 
(105 mg and 225 mg) was suspended on 19 December 2014. 
This analysis did not reveal any new safety signals.  Approximately 90% of the patients 
experienced at least one AE, with the incidence comparable between the treatment arms.  
Incidence of SAEs was 19.5%, 17.3%, and 16.9% in the placebo-, gantenerumab 105 mg-
and gantenerumab 225 mg groups, respectively.  ARIAs and injection-site reactions 
remain the main clinical safety findings for gantenerumab.  Comprehensive information 
on ARIA events in the study is provided in Section 1.3.3.  Regarding injection site 
reactions, overall incidence in the study in the safety population (797 subjects) was 
15.4% with majority of the events of mild intensity.  Incidence of injection site reactions 
by treatment arm was 4.5%, 18.8%, and 23.1% in the placebo-, gantenerumab 105 mg-
and gantenerumab 225 mg groups, respectively, leading to withdrawal in only 2 cases.  
Notably, there was no difference in overall withdrawal rate between the treatment arms.  
The number of subjects withdrawing because of adverse event (which includes 
withdrawals due to protocol-imposed measures mandating treatment discontinuation as 
part of management of MRI findings) was 14 (5.3%), 23 (8.5%) and 25 (9.6%) subjects 
in the placebo-, gantenerumab 105 mg- and gantenerumab 225 mg groups, respectively.  
Overall, gantenerumab doses studied in the double-blind phase of Study WN25203 were 
safe and well tolerated [49].
Additional analyses indicated that higher doses of gantenerumab may have clinically 
relevant effects on cognition and function, prompting the Sponsor to provide subjects the 
opportunity to be treated with higher doses of gantenerumab in an open-label extension 
(including those who were in the placebo group), as outlined in Sections 1.2.3 (Rationale 
for the Open-Label Extension) and 1.3.2 (Reduction in Brain Aβ by Gantenerumab), with 
dosing regimen designed to minimize the risk of ARIAs (Section 1.3.3).  
 


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1.1.2.4
WN28745
Study WN28745 was 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 
up-titrated independent of their APOE ε4 genotype, starting at 105 mg of SC 
gantenerumab every 4 weeks (Q4W) for the first 24 weeks, with a subsequent 
dose increase to 225 mg, based on acceptable MRI scan results.  The study 
enrolled 389 patients, and 387 patients were treated.  Following the futility 
analysis (see Section 1.1.2.3) in this study (WN25203), recruitment was stopped 
but double-blind dosing continued.  In a PET substudy of brain amyloid imaging 
(WN28745-PET), 108 patients were enrolled. The study was converted to an 
OLE study evaluating the safety and tolerability of gantenerumab doses up to 
1200 mg. 
1.1.2.5
WN25203 and WN28745 Open-Label Extension Studies
As of 13 February 2018, 384 patients had been enrolled in the OLE studies 
WN25203 (154 patients) and WN28745 (230 patients), with 365 patients 
exposed to gantenerumab doses higher than 225 mg (i.e., more than the highest 
repeat dose previously tested in the double-blind parts of these studies), and 
289 patients have reached the OLE target 1200-mg dose. Safety data and MRI 
findings are continuously monitored by an internal monitoring committee 
(IMC).
The iDMC was also reviewing relevant safety findings from both OLE 
studies on a regular basis until the majority of patients have reached the target 
dose and no new safety signal has been identified in these ongoing studies. The 
last meeting took place on 10 April 2017; the iDMC reviewed the data with the 
cutoff date of 13 February 2018 and recommended to continue both OLE studies 
without modification. 
All relevant new MRI findings are brought to the 
attention of the MRI-C, as described in Section 5.1.6.1.
The safety profile of 
gantenerumab when administered at doses up to and including 1200 mg remains 
comparable to the safety profile of gantenerumab at lower doses (investigated 
during double-blind Studies WN25203 and WN28745), with injection-site 
reactions and ARIAs remaining the only identified risks for gantenerumab.
From the open-label studies WN25203 and W28745, 81 patients continued in the 
respective 
amyloid-PET 
substudies 
of 
brain 
amyloid 
imaging 
using 
Florbetapir 18F (Amyvid).  As of 31 August 2017, 40 patients treated with 
9001200 mg gantenerumab for ≥6 months across both open-label studies had a 
scheduled PET scan at OLE Week 52 (see Section 1.3.2 for results). 
1.2
Rationale for the Study
1.2.1
Rationale for Part 1 of the Study
As described above, the accumulation of Agenerally begins well before the onset of 
AD dementia and probably even before any cognitive decline associated with AD.  It is 
therefore reasonable to think that the benefit of anti-amyloid therapy may be greater if 
initiated before prominent symptoms of AD manifest, such as dementia.  Consistent with 


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this concept, this study will enroll subjects who do not yet meet a diagnosis for 
Alzheimer's dementia but have findings that characterize the predementia or prodromal 
phase of AD [3].  The main selection criteria used here for prodromal AD are: a report of 
a recent gradual decline in memory function, impaired episodic memory on testing, a 
Clinical Dementia Rating scale (CDR) global score of 0.5, a CDR memory score of 0.5 or 
1 and a CSF A1-42 level of less than 600 pg/mL [as measured by Innogenetics Enzyme 
Linked Immunosorbent Assay (ELISA) assay at a central testing laboratory; the threshold 
is based on extensive literature derived from multicenter studies in the US and Europe, 
and data available at the central laboratory].  In addition the subject cannot meet criteria 
for dementia and there can be no other better explanation for the findings than 
prodromal AD.
Many of the selection criteria for this study are based on the selection criteria for 
amnestic MCI subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) 
protocol [4].  The ADNI study itself based its selection criteria on the Alzheimer's 
Disease Cooperative MCI Study of vitamin E and donepezil [5].  In both studies MCI 
subjects converted to Alzheimer's dementia at a rate of approximately 16% per year with 
few subjects reverting to normal cognition or developing a dementia that was not of the 
Alzheimer's type.  The main difference in the selection criteria for this study is the 
requirement for a low CSF A1-42 level.
Alzheimer’s disease is characterized by changes in CSF biomarkers which reflect the 
disease pathology.  The AD biomarker signature consists of reduced CSF Aβ1-42, a 
marker of amyloid deposition, and elevated total tau (T-tau) and phospho-tau (P-tau), 
which reflect neurodegeneration [6].  Studies, including several large multicenter ones, 
have consistently shown that these biomarkers have a high predictive value for 
identifying prodromal AD in patients with MCI; estimates for sensitivity and specificity 
vary in these studies due to different factors including the combination of biomarkers, 
patient follow up time, and inter-site assay variability [7, 8, 9].  Within ADNI, CSF 
Aβ1-42  was identified as the most sensitive marker for AD detection using an independent 
autopsy confirmed AD cohort (96.4% sensitivity, 95.2% negative predictive value, 78.6% 
specificity, and 81.8% positive predictive value) [9].  When a cutoff for this marker 
defined in the above autopsy cohort was applied to MCI patients, an incidence of an 
AD-like profile of 86.5% was reported for the relatively small number of MCI patients 
who converted to dementia of the AD type within a year of the study start; in contrast the 
incidence of this biomarker profile was 74% in all MCI patients [9].  Even though future 
work will be needed to further characterize the utility of the above CSF biomarkers, the 
accumulated body of evidence from multiple studies indicates that they can be used in 
clinical trials to enrich MCI populations with AD patients.  The fact that gantenerumab is 
an anti-amyloid agent is an additional reason to select patients based on low CSF Aβ1-42 
in this study.  As indicated above, selecting MCI subjects who have low CSF Aβ1-42 will 
increase the likelihood that they are actually in the early stages of Alzheimer's disease 
and therefore will likely show cognitive decline/progress clinically during the study.  Due 
to the rigorous screening procedures in this study including centralized MRI reading and 
CSF biomarkers assessment, and specifically selected cognitive testing, it is expected that 
relatively few cases of non-AD patients will be enrolled.  The amyloid based enrichment 
criterion allows the study objective to be answered with relatively fewer subjects and 


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increase the possibility to observe an effect from the therapy.  As anti-amyloid therapy is 
not expected to provide any acute symptomatic improvement, a 2year treatment period 
was selected.
In addition, in certain centers consenting subjects will participate in a substudy of PET 
brain amyloid imaging in an attempt to assess whether gantenerumab, at the doses 
selected, can remove fibrillar brain amyloid as determined by amyloid PET.  Details of 
this substudy are described in a separate protocol.
1.2.2
Rationale for Part 2 of the Study
Subjects who completed Part 1 of the study through the Week 104 visit could enter the 
optional extension part of the study and continue receiving the same treatment for up to 
2 additional years.  The rationale for Part 2 is to assess the long-term safety of 
gantenerumab as well as effects on biomarkers after an additional 2 years of treatment 
(e.g., PET, brain volumes, CSF markers). 
Continuing the placebo control is important for discerning effects due to gantenerumab 
from those due to advanced age, more advanced cognitive impairment, and concurrent 
illness.  Analyses of cognition and functioning assessed in Part 2 will be exploratory, due 
to the high rate of attrition expected in a study in this population and of this duration.  
During Part 2, approved symptomatic treatments for AD are permitted at the discretion of 
the Principal Investigator.  Dosing in Parts 1 and 2 of the study was terminated on 
19 December 2014 as a result of the planned futility analysis, and subjects continued with 
treatment-free safety follow-up as per protocol.
1.2.3
Rationale for the Open-Label Extension (Part 3)
The futility analysis revealed low likelihood for trial success with the original doses 
studied.  The decline in the primary endpoint, Clinical Dementia Rating – Sum of Boxes 
(CDR-SOB) scale observed across treatment groups over 2 years was approximately 1.06 
(lower than expected for this population, see below).  No significant differences were 
detected between treatment arms over 2 years in the secondary endpoints, Mini Mental 
State Exam (MMSE), Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)-13 
or Functional Activities Questionnaire (FAQ).  In addition, no significant differences 
were observed across groups on any cognitive or functional measure by pre-specified 
mixed model repeated measures analysis (MMRM; Section 8.2.1).  Furthermore, 
subgroup analysis, based on larger number of baseline characteristics (demographics, 
cognitive, CSF biomarkers, and disease severity) or ApoE 4 allele status, did not reveal 
any differences compared to the overall population. 
Additional analyses indicated that the rate of clinical decline was lower than predicted for 
this study population (with higher than expected proportion of “slow-progressors”) and 
strongly suggested that the doses studied in Study WN25203 (105 and 225 mg) were 
sub-therapeutic and that a higher gantenerumab dose should have clinically relevant 
effect [49]:
1. Study WN25203 was the first global study in prodromal AD to use amyloid screening 
to enrich the patient population and create a more homogenous prodromal AD 
population, which was predicted to decline by approximately 1.92 points in CDR-SOB 


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over the course of the 2-year study, compared with the observed decline of 1.06 
points.  Based on an independent ADNI-based model that identified “fast progressors” 
by baseline characteristics [43], only one-third of the studied population would be in 
this category, whereas the majority did not have anticipated clinical decline over the 
2-year period.  Among “slow progressors”, clinical decline was similar across 
treatment groups (3-point change in ADAS-Cog-13). In contrast, among “fast 
progressors”, there was a clear differentiation dependent on gantenerumab exposure, 
with a 6-point increase in the placebo group compared to a 3-point increase in the 
group with the highest gantenerumab concentration (Figure 1).  Similar drug 
concentration-dependent trends were observed for MMSE and Cambridge 
Neuropsychological Test Automated Battery (CANTAB) results, although no trend 
could be observed for CDR-SOB.
2. Significant treatment effect could be detected by posthoc multi-filter analysis in a 
subject subpopulation with a more pronounced pathology at baseline (CDR-SOB 2, 
FAQ 4, and hippocampal volume less than median), a p-value <0.05 on ADAS-
Cog-13, and a CANTAB with 225 mg gantenerumab dose.  The limitation of this 
analysis is a relatively small sample size with approximately one quarter of the 
enrolled prodromal study population.
3. Dose-dependent changes were observed after 2 years of treatment for the biomarkers 
of neurodegeneration assessed in the cerebrospinal fluid (CSF), P-tau and T-tau.  
Reduction of P-tau reached significance with 225 mg gantenerumab versus placebo 
(p<0.01).  Mean percent changes for P-tau were 2.62, −4.85, −7.52, for placebo, 
125 mg and 225 mg gantenerumab groups, respectively (Figure 2A), and for T-tau 
3.11, −1.45 and −2.94 (Figure 2B). 
4. Decrease in amyloid load was detected in PET substudy with 225 mg gantenerumab.  
After 2 years of treatment, mean percent change from baseline in amyloid PET 
Standardized Uptake Value Ratio (SUVR) using the cerebellum was −1.11, 0.19, and 
−5.37 in the placebo-, gantenerumab 105 mg and gantenerumab 225 mg group, 
respectively.  Details are provided in Section 1.3.2 (Reduction in Brain Aβ by 
Gantenerumab).


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Figure 1
Treatment Response in ADAS-Cog-13 by Gantenerumab Serum Concentration, 2-Year Completing Fast 
Progressors
Purple bold line   median; shaded 50% observations; red dotted line 5th and 95th percentile


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Figure 2
Mean Percent Changes from Baseline after 2 Years of Treatment in 
(A) CSF P-Tau and (B) T-Tau (ITT population)
A
B
Further supportive data came from the results of Phase 1b trial (PRIME; NCT01677572), 
which examined effects of an anti-Amonoclonal antibody, aducanumab (Biogen) 
versus placebo (1, 3, 6, and 10 mg/kg by IV infusion every 4 weeks [Q4W]), in 
165 prodromal and mild AD patients.  Aducanumab and gantenerumab display a number 
of similar biological, PK and pharmacodynamic (PD) features.  Both are fully human 
antibodies of IgG1 isotype that recognize a conformational epitope at the N-terminus of 
A, binding preferentially to the Aaggregates with a similar affinity, have a similar 
brain penetration and exert their action by microglia-mediated clearance of amyloid 


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plaques.  PRIME results showed a significant dose- and time-dependent reduction of 
brain Aβ plaques versus placebo by PET imaging that was associated with 
dose-dependent slowing of decline on MMSE and CDR-SOB observed at 1 year, which 
reached statistical significance with the highest aducanumab dose.  PET SUVR showed 
no changes or very minimal changes at Weeks 26 and 54 in the placebo and 1 mg/kg 
treatment arms, respectively; whereas, statistically significant reductions were observed 
in the higher doses.  Aducanumab had an acceptable safety profile at Week 54, the main 
findings being ARIA-Es that were dose- and APOE 4 status dependent. 
Considering the similar properties of gantenerumab and aducanumab, PK-PD models 
were developed based on PK, PD, efficacy, and safety results from WN25023 and 
PRIME studies, allowing prediction of clinically effective dose and dosing regimen to 
leverage safety.  All subjects who were eligible for and enrolled in Study WN25203 and 
had at least one follow-up/drop-out visit after double-blind treatment will be offered the 
opportunity to receive active treatment with higher gantenerumab doses (predicted to 
have relevant clinical effect) in an open-label extension, Part 3, initially for 3 years
(unless exempted for the reasons listed in Section 4.4).  In addition, all subjects entering 
Part 3 at centers already involved in a WN25203 PET substudy of brain amyloid imaging 
will be offered to take part in the PET substudy, independent of their previous 
participation during double-blind treatment.  To ensure the minimum number of 
participants in the PET substudy during Part 3, additional centers may be included. 
A PET scan previously done for the Study WN25203 within 12 months prior to first dose 
in Part 3 does not need to be repeated. 
During Part 3, approved symptomatic treatments for AD will be permitted at the 
discretion of the Principal Investigator.
1.2.4
Rationale for Prolonging Open-Label Extension (Part 3)
As of 13 February 2018, a total of 384 patients have been enrolled in the OLE 
studies (WN25203 and WN28745) with no new identified safety findings.  
Because AD is characterized by progressive decline, it will be important to 
further characterize the long-term safety of gantenerumab beyond the initial 
3 years.  Given that the safety profile of gantenerumab in the OLE studies 
remains similar compared with the double-blind studies, the duration of both 
OLE studies will be increased.  Treatment duration in Part 3 of this study 
(WN25203) will be extended until the end of July 2020, at which time 
anticipated results from other relevant monoclonal antibody treatments will be 
available.  The Sponsor will then evaluate the appropriateness of providing 
patients continued gantenerumab anti-amyloid treatment.
1.3
Overall Benefit-Risk Assessment
As described in Section 1.1.1, one of the leading explanations for the cause of AD is the 
accumulation of Aβ in the brain.  In addition it has been shown that by the time a 
diagnosis of AD can be made due to the development of dementia, brain Aβ has already 
reached maximal or near maximal amounts [10, 11, 12].  It has therefore been 
hypothesized that treatments directed at reducing Aβ may be more effective, or perhaps 
may only be effective, if begun early in the course of AD and specifically before the 


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onset of dementia.  As such, the purpose of this study is to determine whether 
gantenerumab, which has been shown to reduce brain Aβ in AD patients by PET scan, 
can benefit subjects when treatment is initiated in the pre-dementia or prodromal stage of 
AD. 
Section 1.3.1 describes how it is now possible to make a reliable diagnosis of prodromal 
AD by using the recent advances in knowledge and laboratory techniques regarding 
biomarkers in AD.
Section 1.3.2, describes the reduction in brain amyloid with gantenerumab, which 
hopefully will be the underlying basis for any benefit of gantenerumab.
Finally in Section 1.3.3 the various measures taken throughout the protocol to minimize 
risks of MRI events are discussed.
The benefit-risk for Part 2 (the optional extension) is in Section 1.3.6.
Section 1.3.7 depicts the benefit-risk for the open-label extension (Part 3).
1.3.1
Selecting Prodromal AD Subjects for Study WN25203
The selection criteria for Study WN25203 are designed to select subjects with prodromal 
or pre-dementia AD, which are MCI subjects who have a very high likelihood of having 
AD pathology.  The ability to accurately identify such subjects has been made possible 
by advances in AD biomarkers.  Consensus is developing in the field about how these 
individuals can be identified.  A group of internationally renowned experts proposed an 
updated diagnostic criteria for (a) AD dementia, (b) MCI due to AD, and (c) for 
preclinical AD [34].  The criteria for MCI due to AD contains a description of 
“prodromal Alzheimer’s Dementia” which requires the kind of cognitive decline 
specified in this study as well as a positive biomarker for the molecular neuropathology 
of AD such as low CSF Aβ1-42.  These criteria were based on studies such as the one by 
Hansson et al. [8] where individuals with MCI (and controls) were followed for 
46 years.  CSF biomarkers assessed at baseline (see Figure 3 below) show low CSF
Aβ1-42 in MCI subjects who convert to clinical AD dementia (MCI-AD) as opposed to 
MCI patients who progress to a different type of dementia (MCI-Other), or remain stable 
over the course of the observation (Stable MCI).
Figure 3
CSF Biomarkers at baseline in MCI subjects (taken from [8])
VaD = vascular dementia, DLB = Dementia with Lewy bodies, FTD = frontotemporal dementia, SD = 
semantic dementia, TBI = brain injury-induced dementia


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The study furthermore shows that individuals with pathological CSF at baseline (here 
defined as low CSF Aβ1-42 and high CSF T-tau) have a high likelihood to convert to 
dementia of the Alzheimer’s type (see Figure 4 below) during the follow-up period.
Figure 4
Kaplan-Meier Estimates of the Rate of Progression to Alzheimer's 
Disease in Patients with MCI Who Have Either Normal CSF or 
Pathological CSF at Baseline
Note: Numbers at risk are the number of patients with MCI at each time point who had not developed any 
type of dementia and for whom clinical follow-up was still ongoing.  Cutoff values for pathological CSF 
were >350 ng/L for T-tau and <530 ng/L for Aβ42 [note: exact cut-off values are assay dependent].
Low CSF Aβ1-42 is associated with high plaque load on amyloid PET [11], with a 
suggestion that the changes in the CSF marker preceding PET positivity [12].  Using the 
selection criteria requiring a low CSF Aβ1-42, an annual conversion rate to dementia of 
approximately 20% may be expected [14].  As indicated in Section 1.2, within the ADNI, 
CSF Aβ1-42 was identified as the most sensitive marker for AD detection using an 
independent autopsy confirmed AD cohort (96.4% sensitivity, 95.2% negative predictive 
value, 78.6% specificity, and 81.8% positive predictive value) [9].  With longer 
follow-up, the incidence of a correctly identified AD-like biomarker profile at baseline is 
expected to increase as more patients convert to dementia.  Moreover, as a follow-up of 
their original publication, Hansson and colleagues reported that at the study-defined 
cutoff, the sensitivity and specificity of Aβ42 to predict development of AD dementia 
within 10 years of clinical follow-up were 90% and 76%, respectively [36]. 
Based on the applied clinical and biomarker criteria [34], the population in this study 
consists with a high degree of certainty of individuals with AD in the prodromal phase 
who would inevitably progress to dementia in the years to come and for whom in the 


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prodromal phase there is no approved medication.  The screening MRI will furthermore 
help exclude other neurodegenerative diseases (exclusion criterion 1, e.g., frontotemporal 
dementia) as well as extensive cerebrovascular disease (exclusion criterion 8) that could 
explain cognitive decline.  However, since no criteria will provide absolute certainty of 
diagnosis, Section 4.6 states that “…the subject must be withdrawn from the study if it 
becomes clear that the subject's cognitive impairment is not due to AD.”  It is expected 
that this decision may be made at any time during the course of the study and that it will 
be based on the investigator’s clinical judgment.
If gantenerumab works as expected and if halting amyloid deposition and/or removal of 
amyloid plaque are processes relevant to slowing disease progression, individuals in the 
prodromal phase of the disease might possibly benefit more than patients who have 
developed AD dementia already, since the intervention occurs relatively earlier in the 
disease process when presumably less damage to neurons has occurred.
1.3.1.1
Adjustment of CSF Aβ1-42 Cutoff
Rationale for the original CSF Aβ42 cutoff
For Study WN25203, Roche chose to use low CSF Aβ42, an indicator of amyloid 
pathology, along with appropriate clinical and imaging criteria, to identify subjects for 
treatment with gantenerumab.  As the study population is very similar to that studied by 
the ADNI, WN25203  CSF Aβ42 inclusion criterion was based on the ADNI-defined 
cutoff (192 pg/mL measured by Luminex xMAP assay and based on pre-mortem CSF 
samples obtained from patients with autopsy-diagnosed AD and age-matched controls) 
[9].  Measurements of CSF Aβ42 levels for inclusion into Study WN25203 are performed 
at a central laboratory using a different validated assay (Innotest ELISA).  To bridge 
between the two assay platforms [35], Roche used a correlation between the Innotest 
ELISA and Luminex to derive the threshold level of 500 pg/mL included in the original 
study protocol.
Rationale for the new CSF Aβ42 cutoff
Using ADNI CSF data, De Meyer and colleagues [37] applied a mixture modeling 
approach to identify two distinct AD biomarker signatures, one related to AD (low CSF 
Aβ42) and the other to the non-AD group (high CSF Aβ42) (Figure 5, panel A below)
consistent with the current understanding that some of these individuals have MCI due to 
AD but others will remain stable, revert to normal, or develop dementias of other types.  
Remarkably, the cutoff of 188 pg/mL selected in the mixture model based on CSF Aβ42 
concentration only and in the absence of any clinical data was almost identical to the 
value of 192 pg/mL determined by Shaw et al. using autopsyconfirmed clinical 
diagnoses.  Such bimodal type distribution was also confirmed in a European study of 
MCI patients with up to 10 years clinical follow-up [36] where an unbiased “natural” 
cutoff was determined using the same mixture model classification (Figure 5, panel B).  
In this study, at this natural cutoff, CSF Aβ42 was able to predict future development of 
AD dementia with a sensitivity of 90% and 76% specificity.  
The above clustering method was applied to screening data from all subjects screened for 
Study WN25203 who had CSF Aβ42 measured (269 samples up to December 21, 2011).  


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A similar bimodal distribution as in ADNI and the European MCI cohort (Figure 5, 
panel C) was observed with a natural cutoff between the two populations of 599 pg/mL, 
instead of 500 pg/mL, currently specified in protocol WN25203.
Figure 5
A. Cerebrospinal Fluid–derived A42 Mixture Model Applied to 
Individuals with Amnestic MCI from the ADNI Study
Note:  Results are shown as histograms of observed biomarker levels overlaid with the 2 mixture 
distributions (adapted from [37]).  B. Model based clustering in European MCI study [36]. 
C. Model based clustering of CSF A42 in WN25203
The robustness of the cutoff estimate of 599 pg/mL was evaluated by performing the 
model-based clustering approach using distinct subsets of the data set of WN25203 CSF 
screening samples, and also using snapshots of this data set at several different time 
points.  Both analyses provided consistent estimates of the cutoff, which did not vary 
substantially from the cutoff value estimated based on the entire data set.  In addition to 
the above modeling approach, Roche has obtained from its central lab an independent 
dataset consisting of CSF Aβ42 levels from patients diagnosed with AD (n=43) and 
cognitively normal age-matched controls (n=43).  The patients with AD met the 
Diagnostic and Statistical Manual of Mental Disorders (DSM), vIII-revised criteria of 
dementia (1987) and the criteria of probable AD defined by NINCDS-ADRDA [15], and 
were also followed clinically in order to increase the clinical diagnostic accuracy [38].  
At the originally defined cutoff of 500 pg/mL sensitivity and specificity were 91% and 
81%, compared to 100% and 75% at the adjusted cutoff of 600 pg/ml.  As the estimated 
assay performance at the adjusted cutoff is in line with the autopsy (gold standard) ADNI 
dataset (96% sensitivity and 77% specificity) [9], it appears that the proposed adjustment 
of the WN25203 CSF inclusion criterion will not change the population that was planned 
to be enrolled in Study WN25203.  Thus a “natural” cutoff identified in the Study 
WN25203 screened population (600 pg/ml) will be used to select patients for treatment 
with gantenerumab. 
1.3.2
Reduction in Brain Aβ by Gantenerumab
The potential benefit of gantenerumab can be anticipated from its mechanism of action 
which is to reduce brain amyloid.  This was shown in the NN19866 MAD study in AD 
MCI n=137
aMCI n=267
A.
B.
C.
aMCI n=196


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patients where amyloid PET imaging was performed.  Figure 6 below shows the mean 
change in PET tracer activity (11C-Pittsburgh Compound B [11C-PIB] which indicates 
the amount of brain amyloid) for a composite cortical brain region of interest (including 
bilateral frontal, sensorimotor, lateral temporal, parietal, anterior cingulate, and posterior 
cingulate cortex).
Figure 6
Median Amyloid PET Percent Change from Baseline:  Composite, 
6 Months (ITT Population)
Since prodromal AD is considered part of the continuum of AD the amyloid removing 
effect of gantenerumab in patients with mild to moderate AD is expected to be relevant to 
the prodromal AD population in this new study.  This type of positive biomarker data is 
probably among the strongest that could be expected in a short-term trial of a 
diseasemodifying drug candidate and it is hoped that amyloid removal will provide 
benefit to individuals with prodromal AD.
The WN25203 PET substudy, which enrolled 114 participants, confirmed the findings 
from NN19866 MAD study (the reduction of brain amyloid by gantenerumab) using 
Florbetapir 18F (or AV-45), a novel 18F-labeled PET ligand for imaging fibrillar Aβ.  
A time-dependent reduction was observed with 225 mg gantenerumab in PET composite 
cortical SUVR with all the reference regions used.  With the mean cerebellar grey cortex 
as the reference, after 2 years of treatment mean percent change from baseline in PET 
SUVR was −1.11, 0.19 and −5.37 in the placebo-, gantenerumab 105 mg- and 
gantenerumab 225 mg-groups, respectively (Figure 7).  Following 3 years (156 weeks) of 
treatment, the difference was more pronounced with a 9.1% decrease in the 
gantenerumab 225 mg group.
pet_bar_med_comp_6m_i Amyloid PET Percent Change from BL: Composite, 6 months
18SEP2008 20:22
Output : $PROD/cdp11751/i19866f/reports/pet_bar_med_comp_6m_i.cgm
Program : $PROD/cdp11751/pet_bar_med_comp.sas
Treatment Group
PLACEBO
RO4909832 200 mg
RO4909832 60 mg
Median
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
Test Name
COMPCTX


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PK 
analyses 
corroborated 
that 
the 
reduction 
in 
PET 
SUVR 
was 
drug 
concentration-dependent (i.e., subjects with higher plasma gantenerumab concentration 
had higher reduction in PET SUVR).  Figure 8 shows PET SUVR percent changes from 
baseline after 2 years of treatment based on the drug exposure category with cerebellar 
grey cortex as the reference.  No significant changes were present in the placebo- and the 
low concentration (1.9–5 µg/mL) gantenerumab groups; in contrast, higher gantenerumab 
concentration groups (5–10 µg/mL and 10–20.72 µg/mL) displayed PET SUVR 
reductions of up to 5% and 10%, respectively.
 
 This apparent inconsistency may 
be due to a difference between target population (moderate AD population in 
Study NN19866 and prodromal AD population enriched with “slow progressors” in 
Study WN25203) and to differences in the ligands used in study amyloid load in the brain 
(11C-PIB and Florbetapir 18F).  An additional voxel-wise exploratory analysis was also 
performed looking at region specific treatment effects after 1 year of study treatment, 
using cerebellar grey matter as a reference region.  An extensive anatomical network 
covering precuneus, ventral striatum, anterior, middle and posterior cingulate, insular, 
medial, and lateral prefrontal regions showed significant treatment-related SUVR 
reductions as compared with placebo, in both 105 and 225 mg gantenerumab treatment 
groups (Figure 9).  At the peak voxel in precuneus, the most significant region in the 
voxel-wise analyses, an SUVR reduction of 15% from baseline and of 18% relative to 
placebo was observed in the 225 mg group.  In the 105 mg gantenerumab group an 8% 
and an 11% reduction relative to baseline and placebo, respectively, were detected.
Figure 7
Mean Percent Changes from Baseline in Composite Amyloid PET 
SUVR after 2 years of Treatment (ITT Population)


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Figure 8
Time Course PET SUVR during 2 Years of Treatment by 
Gantenerumab Serum Concentration Category
Purple bold line median; shaded 50% observations; red dotted line 5th and 95th percentile


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Figure 9
Voxel-Wise Changes in PET SUVR After 1 Year of Treatment with 
Gantenerumab
Results from the PRIME study showed dose-dependent PET composite SUVR reduction 
with aducanumab [42].  PK analysis demonstrated linear exposure across the 
aducanumab doses tested (1, 3, 6, and 10 mg/kg by IV infusion) after 26 weeks of 
treatment.  Based on PK-PD assessment, significant covariates for amyloid removal were 
aducanumab exposures and baseline PET SUVR [44].  PET SUVR showed no changes or 
very minimal changes at Weeks 26 and 54 in the placebo and 1 mg/kg treatment arms, 
respectively; whereas, dose-dependent, statistically significant reductions were observed 
with 3 mg/kg (mean absolute change from baseline of -0.087, p<0.01), 6 mg/kg (-0.143, 
p<0.001) and 10 mg/kg (-0.205, p<0.001) treatment arms at 26 weeks as well as in the 
3 mg/kg (-0.139, p<0.001) and 10 mg/kg (-0.266, p<0.001) treatment arms at 54 weeks.  
These reductions were also associated with clinical effects on both the MMSE and 
CDR-SOB with overall slowing of cognitive decline compared to placebo reaching 
statistical significance with the highest dose after 1 year.  The difference from placebo in 
CDR-SOB after 1 year of treatment was -0.33, -0.71, and -1.44 (p<0.05) with 1, 3, and 
10 mg/kg respectively.


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Overall, reduction in PET SUVR corresponding to the observed clinical effect after 
1 year of treatment with 10 mg/kg aducanumab, was approximately 20%.  Compared to a 
mean PET amyloid reduction of approximately 5% achieved by 225 mg gantenerumab 
over 2 years, higher doses of gantenerumab will be needed to achieve the plasma 
concentration associated with clinically effective ~20% PET SUVR reduction. 
A gantenerumab PK-PET model of amyloid reduction (details provided in 
) has been confirmed by PET data from the open-label Studies 
WN25203 and WN28745.  As of 31 August 2017, 40 patients treated with 
9001200 mg gantenerumab for ≥6 months had an OLE Week 52 PET-amyloid 
scan.  Patients were divided into three groups for analyses purposes, on the basis 
of the study and on the double-blind treatment prior to switching to open-label 
gantenerumab and dose increase:  patients in Study WN28745 treated with 
placebo during double-blind part (non-pre-treated), patients in Study WN28745 
pre-treated (active arm during double-blind part, received gantenerumab 
225 mg), and patients in Study WN25203 (off treatment for an approximate 
median of 78 weeks).  Across the three groups, there was a 7%16% reduction in 
PET SUVR from baseline, which was two to threefold greater than the reduction 
observed in the Study WN25203 double-blind PET substudy with 225 mg 
gantenerumab after 2 years of treatment (see
Figure 7
and
Figure 10). 
In addition, approximately one third of patients had results
below the 
quantitative amyloid positivity threshold after 1 year
of treatment with 
open-label gantenerumab, including a titration period and 69 months at higher 
doses (900 mg).
Taken together, these results strongly confirm the 
gantenerumab mechanism of action and support selection of a target dose in 
alignment with the PK-PET efficacy model (see 
). 


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Figure 10
Reduction of Brain Amyloid PET SUVR in Patients 
Exposed to at Least 900 mg for 69 Months in Studies 
WN25203 (SR) and WN28745 (MR) Open-Label Extension 
Studies
MR-NP Marguerite RoAD (Study WN28745) non-pretreated, N 14; 
MR-P Marguerite RoAD (Study WN28745) pretreated, N 17; PET positron 
emission tomography; SD standard deviation.
1.3.3
MRI Findings
As described in Section 1.1.2.1, MRI findings, ARIE-E, and microbleeds were seen at 
200 mg IV Q4W in the NN19866 MAD study, which was conducted in mild/moderate 
AD patients.  The risk of ARIA-E appeared to be ApoE4 carrier status dependent.  
None of the patients required any treatment for the MRI findings.  All ARIA-E resolved 
spontaneously when treatment was discontinued.
Based on the results of the NN19866 MAD study and on knowledge about ARIAs 
available at the time of WN25203 study design, selection of the doses was focused on 
safety.  As the ApoE 4 carrier status appears to be a risk factor for the development of 
MRI findings, the low dose of 105 mg SC was evaluated in individuals homozygous for 
ApoE 4.  On the basis of total exposure (plasma AUC), this dose is comparable to the 
MAD dose of 60 mg IV, which was not associated with MRI findings.  For individuals 
who are heterozygous for ApoE 4 or non-carriers for ApoE 4, doses of 105 and 225 mg 
SC were evaluated.  The high dose of 225 mg SC is (based on plasma concentrations) 
equivalent to approximately 137 mg IV, well below the 200-mg IV dose where promptly 
reversible ARIA-E events were detected in the heterozygous ApoE 4 population.  
 
 Also, additional protocol measures were put in place to mitigate any 


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risk due to ARIAs, including monitoring by regularly scheduled, centrally read MRIs;
intensified MRI monitoring in the case of ARIA events; and, as applicable, dose 
modifications, temporary interruption, or permanent treatment discontinuation.  All 
relevant new MRI findings were brought to the attention of the MRI-C (during Part 1 
those were all new cases of ARIA-E, ARIA-H meeting criteria for dose modification or 
discontinuation, non-ARIA findings requested to be reviewed by the central reading
center or sponsor, and MRI findings with associated symptoms).
In Study WN25203, out of 797 subjects who received blinded study treatment, 52 (6.5%) 
subjects had ARIA-E events, 2 (0.8%) subjects in the placebo group, 18 (6.6%) subjects 
in gantenerumab 105 mg group, and 32 (12.3%) subjects in gantenerumab 225 mg group.  
Over two-thirds (approximately 71%) of the ARIA-E cases occurred during the first 
6 months of treatment (corresponding to 5 gantenerumab administrations):  1 (0.4%), 
13 (4.8%) and 23 (8.8%), in the placebo-, gantenerumab 105 mg- and gantenerumab 
225 mg groups, respectively.  Approximately 75% of ARIA-E cases occurred in 
APOE 4 carriers.  Most of the events were asymptomatic (~90%), non-serious, resolved 
without consequences, and of mild severity by MRI Barkhof scoring that uses a scale 
from 0 (no edema) to 60 (whole brain edema) [45]. In Study WN25203, the median 
ARIA-E score was 3 (rated as low); only 10% of ARIA-E events were scored as >10.  
ARIA-E did not commonly recur in subjects who restarted treatment at half of the 
original dose.  The findings confirmed that the risk factors for developing ARIA-E are a 
higher gantenerumab dose and the presence of ApoE 4 allele (Figure 11).
One hundred fifteen (14.4%) subjects had ARIA-H findings during double-blinded 
treatment phase, 29 (10.9%) subjects in the placebo group, 52 (19.2%) subjects in 
gantenerumab 105 mg group, and 34 (13.1%) subjects in gantenerumab 225 mg group.  
Most of ARIA-H findings were without associated symptoms and non-serious.  The time 
dynamic of ARIA-H followed the pattern of ARIA-E. 
Figure 11
ARIA Adverse Events by APOE ε4 Genotypes
04
14
24
Placebo
(N=79)
105 mg
(N=57)
225 mg
(N=100)
Placebo
(N=134)
105 mg
(N=111)
225 mg
(N=160)
Placebo
(N=53)
105 mg
(N=103)
ARIA-E
2
(2.5%)
1
(1.8%)
10
(10.0%)
0
6
(5.4%)
22
(13.8%)
0
11
(10.7%)
ARIA-H
5
(6.3%)
8
(14.0%)
9
(9.0%)
15
(11.2%)
19
(17.1%)
25
15.6%)
9
(17%)
25
(24.3%)
Bapineuzumab is also a monoclonal antibody with an affinity for amyloid.  Similar MRI 
findings have been reported in a Phase 2 and Phase 3 studies [16, 46].  The majority of 
ARIA-E cases (69%) occurred after the first or second infusion (13 weeks apart) and 
were transient.  An increased risk to develop ARIA-E findings was also found to be 
dependent on the dose and on the number of ApoE ε4 alleles [2].  The increased risk for 
ARIA-H were found to be associated with APOE ε4 allele frequency, pre-existing 
ARIA-H, treatment with bapineuzumab, and use of antithrombotic agents [47].  
Homozygosity for APOE ε4 exhibited the greatest risk.


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In the PRIME study, incidence of ARIA-E with aducanumab was also dose- and ApoE 
ε4-status–dependent.  It was 5%, 5%, 43%, and 55% for 1, 3, 6, and 10 mg/kg 
aducanumab, respectively, versus 0% for placebo for ApoE ε4 carriers, and 0%, 9%, 
11%, and 17% versus 0% among ApoE ε4 non-carriers.  Most ARIA-E events (92%) 
were observed within the first 5 doses.  MRI findings resolved typically between 4 and 
12 weeks.
The exact mechanisms giving rise to ARIA remain to be fully elucidated; the frequent 
co-occurrence of ARIA-E and ARIA-H as observed with bapineuzumab suggests a 
common pathophysiological mechanism that may be related to transient increases in 
vascular permeability [2, 33].  Over the course of AD, vascular amyloid deposition may 
disrupt vascular integrity and impair perivascular pathways, leading to development of 
cerebral amyloid angiopathy, with age and APOE ε4 genotype being main contributors to 
these changes.  After initiation of an anti-Atherapy, vessels with pre-existing amyloid 
vascular pathology may be transiently more susceptible to vascular extravasation events 
as beta amyloid is removed from the vessel wall.  Also, excess amyloid accumulating in 
blood vessels as it is removed from amyloid plaques could also give rise to a transit 
increase in vascular beta amyloid, contributing to extravasation [17, 18].  Depending on 
the location of the vessel (intraparenchymal or meningeal), leakage of proteinaceous fluid 
could give rise to an increased signal detected on FLAIR images as ARIA-E in the brain 
parenchyma (vasogenic edema) and leptomeningeal spaces (sulcal effusions); leakage of 
red cells would result in ARIA-H [33].  An anti-Atherapy that maintains effectively 
vascular beta amyloid clearance would allow recovery of vascular structural integrity, 
and with time, the risk of such extravasation events is expected to decrease [2].
In summary, ARIA-E events in Study WN25203 were manageable, reversible, and 
mostly mild with the majority occurring early in treatment (with the highest frequency 
between 3 and 6 months).  To date, substantial information is available about MRI 
findings and their relationship of exposure to anti-aggregated Aantibodies; a PK-PD 
model could be developed allowing a more accurate prediction of ARIA-E incidence 
expected with higher dose gantenerumab treatment, taking into account drug 
concentrations, time of ARIA-E occurrence since the first dose, and APOE 4 genotype.  
The model was originally developed for bapineuzumab showing time-dependence of 
ARIA-E [48].  Please see 
for additional information on 
modeling of safety outcomes.
To date, data from the OLE studies indicate that the safety profile of 
gantenerumab when administered in doses up to 1200 mg is comparable to the 
safety profile of gantenerumab in earlier studies.  As of 13 February 2018, 
incidence of ARIA-E findings has been as expected (26% and 30.1% in Studies 
WN25203 and WN28745, respectively), with the majority of events being 
non-symptomatic and well controlled by protocol defined management rules.  
In a few cases, patients developed symptoms, sometimes of mild intensity 
(e.g., headache) and sometimes serious (e.g., confusion or seizures/epilepsy).  
Overall, epilepsy did not occur more frequently than expected in the AD 
population; however, it cannot be excluded that the presence of the ARIA-E 


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contributed to or triggered the onset of the symptoms.  Refer to the 
Gantenerumab IB for additional information about ARIAs. 
1.3.5
Risk to Subjects without AD Pathology
As an engineered monoclonal antibody, gantenerumab has an extremely high selectivity 
and specificity for aggregated amyloid-and therefore gantenerumab is not expected to 
have any biological effect in subjects who do not have aggregated amyloid-.  However 
as subjects must have a low level of CSF amyloid-at entry and this accurately selects 
for subjects with elevated aggregated brain amyloid, it is likely that very few subjects 
would be enrolled who do not have cerebral amyloid pathology and those who do not 
have amyloid pathology should not be at risk for MRI findings.  Nevertheless and as 
outlined above, the study protocol applies a safety monitoring scheme that is considered 
to sufficiently protect all study participants as if they were at similar risk for MRI 
findings like AD patients.
1.3.6
Part 2 (Optional Extension Phase)
The hypothesized mechanism of action of gantenerumab is the removal of and prevention 
of accumulation of brain amyloid.  Because this process is believed to continue 
throughout the course of AD, if gantenerumab has a beneficial effect on the course of 
prodromal AD, it is reasonable to expect that continuing therapy beyond 2 years may 
provide additional benefit.  Regarding the time course of known adverse effects with 
gantenerumab, based on experience with bapineuzumab, it is likely that the risk of ARIA 


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decreases substantially after approximately 6 months of treatment.  The other known risk 
factor is injection site reactions.  These, however, have generally been mild and have not 
led to treatment discontinuation.
In Part 2, symptomatic treatments for AD will be allowed.  These medications (such as 
donepezil and memantine) are unlikely to alter the safety profile of gantenerumab and 
vice versa because the adverse event characteristics are not overlapping and the 
pharmacological targets are different.  Dosing in Part 2 of the study was terminated on 
19 December 2014.
1.3.7
Part 3 (Open-Label Extension)
Since clinical efficacy may be related to both the degree of PET SUVR reduction and the 
timeframe over which it occurs, it is considered important to allow subjects to safely 
access the target dose of 1200 mg gantenerumab SC Q4W as quickly as possible, taking 
into account APOE 4 status.  
 
 
with ARIA-E findings seen after 
two to four doses as described in Section 1.1.2.1.  With the implementation of the dosing 
regimen with gradual up-titration, subjects should be able to reach the target dose of 
1200 mg safely within 10 months for APOE 4 carriers who were on placebo or on 
105 mg gantenerumab during double-blind treatment, and within 6 months for APOE 4 
carriers previously receiving 225 mg and for subjects who are non-carriers (see Sections 
3.1.5.1 and 3.1.5.2).  With such a titration schedule, the incidence of ARIA-E is expected 
to be <25%, compared to the predicted incidence of 61% in APOE 4 carrier subjects 
over 2 years in the case that the target dose would be administered from the start without 
the up-titration regimen.  The implemented protocol measures (which include dose 
adjustment and temporary interruption) aim to minimize the risk of MRI findings, 
allowing the subjects to reach the target dose in a flexible and safe manner. 
The PK-PD model predicts that PET SUVR (i.e., brain amyloid load) reduction will be 
~15% after 1 year of treatment with the implemented gradual up-titration schedule and 
~20% after 2 years.  Thus, the proposed dosing regimen attempts an optimal balance 
between safety and efficacy.
All subjects enrolled in Part 3 will receive active treatment and will be allowed to take 
symptomatic therapy.
Part 3 will only include patients who had participated in the study, either Part 1 or Part 2 
prior to the futility analysis, and had at least 1 follow-up/drop-out visit after double-blind 
treatment (placebo or 105 or 225 mg gantenerumab SC Q4W).


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1.3.8
Overall Benefit Risk Summation
The following items support the Sponsor’s assessment that the overall risk-benefit for 
both the double-blind treatment phase (Parts 1 and 2) and the open-label extension 
(Part 3) of this study is favorable:
(i)
Recent progress in understanding the continuum from prodromal AD to AD 
dementia providing the strong rationale to investigate Aβ directed therapies at the 
very early stage of the disease 
(ii)
The proven effect of gantenerumab on amyloid plaques and, thus, the potential 
benefit for gantenerumab to slow the onset or progression of AD with doses 
higher than those studied during double-blind treatment phase 
(iii)
The various measures taken to reduce the risk of MRI findings (including gradual 
up-titration in Part 3) and, if these MRI findings should develop, to rapidly 
identify and effectively manage them 
(iv)
The likelihood that ARIAs are substantially less common after approximately 
6 months of treatment.  During this time period, subjects are exposed to lower 
doses and gradually exposed to higher gantenerumab concentrations (see also 
).
(v)
The lack of overlap of safety characteristics between gantenerumab and 
symptomatic AD treatments (allowed in Part 2 and Part 3 of this study)
2.
OBJECTIVES OF PART 1 (THE FIRST 2 YEARS OF THE STUDY)
2.1
Primary Objective
To evaluate the effect of 2 doses of gantenerumab versus placebo given as SC injections 
on the change in the CDR-SOB, a global measure of cognition and functional ability.
2.2
Secondary Objectives
To evaluate efficacy, safety, and tolerability of gantenerumab versus placebo given as SC 
injections using the following: 
2.2.1
Cognition
Assessed with the 1) ADAS-Cog 2) MMSE, 3) the CANTAB and 4) the FCSRT-IR.
2.2.2
Global
Assessed with the CDR global score.
2.2.3
Functioning
Assessed with the FAQ.
2.2.4
Neuropsychiatric Functioning
Assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q).
2.2.5
Dementia Assessment
To determine the onset of dementia.  This will be done at each of the visits when all the 
cognitive and functional scales are done (screening and Weeks 24, 52, 76, and 104).


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2.2.6
Safety and Tolerability
Assessed by MRI, physical and neurological examinations, vital signs, blood and urine 
safety tests, ECGs, geriatric depression scale (GDS), Columbia-Suicide Severity Rating 
Scale (C-SSRS), and adverse event monitoring.
2.2.7
Brain MRI
Hippocampal volume, whole brain volume, ventricular enlargement, and possibly other 
volumetric measures will be assessed in an effort to detect and quantify drug effects on 
disease progression.  Further exploratory analyses may be conducted as methods become 
available, in an effort to detect and quantify drug effects on disease progression.
2.2.8
Cerebrospinal Fluid Biomarkers
The effect of gantenerumab on CSF biomarkers A1-42, T-tau, and P-tau will be 
assessed to detect and quantify drug effects on underlying disease pathology. 
2.2.9
Pharmacokinetics 
Plasma and CSF concentrations of gantenerumab will be quantified to explore the 
relationships between pharmacokinetics and other responses. 
2.2.10
Anti-Drug Antibodies 
The development of anti-gantenerumab antibodies (also referred to as anti-drug 
antibodies, ADAs, or human antihuman antibodies, HAHAs) will be assessed, and if 
detected, explored for their association with the PK, PD, efficacy, and safety parameters 
of gantenerumab.
2.3
Exploratory Objectives 
2.3.1
Plasma Biomarkers
To evaluate the effect of study treatment on peripheral biomarkers of amyloid deposition 
and/or clearance, markers of neurodegeneration, inflammation, and other markers thought 
to be involved in the pathogenesis of AD. 
2.3.2
Clinical Genotyping
The effect of ApoE genotype and fragmented crystalizable gamma receptor (FcR) 
genotype on PK/PD/efficacy/safety parameters of gantenerumab will be assessed. 
Given the association of ApoE 4 allele and the occurrence of MRI findings seen with 
gantenerumab in the MAD study as well as reported for bapineuzumab, ApoE 4 status 
will be used for randomizing into study treatment groups (see Section 3.1.4) and also for 
assignment to the titration schemes in Part 3 (see Section 3.1.5).
The Fcreceptor will also be genotyped as it may play a role in response to IgG 
treatments.


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2.3.3
Roche Clinical Repository
Exploratory biomarkers will be assessed in consenting subjects.
The Roche Clinical Repository (RCR) is a centrally administered facility for the 
long-term storage of human biological specimens.  Specimens stored in the RCR will be 
used to:

Study the association of biomarkers with efficacy and/ or adverse events 
associated with medicinal products; and/or

Increase our knowledge and understanding of disease biology; and/or

Develop biomarker or diagnostic assays; establish the performance characteristics 
of these assays. 
The following sample types will be assessed in consenting subjects:
RCR DNA: may be used to explore the associations of variants of genes implicated in 
susceptibility and pathogenesis of AD, such as Clusterin and PICALM, and therapy 
response.
RCR RNA: RNA samples may be tested using techniques such as high-density 
microarray profiling and/or quantitative RT-PCR to study the expression profile of genes 
known to be involved in AD, and any other differentially expressed genes relative to 
treatment or dose response. 
RCR plasma: may be used for exploratory biomarker analysis, including but not limited 
to markers of oxidative stress, neurodegeneration, inflammation or other processes 
involved in AD pathology.  
RCR CSF: samples remaining from the mandatory analysis will be stored as RCR 
samples for future exploratory analysis and to support the development of biomarker and 
diagnostic assays.
2.4
Objectives of Part 2 (Optional Extension) 
The main objectives of the study extension are to assess the long-term safety of 
gantenerumab as well as effects on biomarkers beyond 2 years of treatment.  In addition, 
cognition and related measures will be assessed in Part 2; however, due to the anticipated 
high rate of attrition over the several years of the study, these will be exploratory 
outcome measures.
The following outcome measures will be assessed at select visits during Part 2, as shown 
in Table 3 and Table 4.
2.4.1
Cognition
Assessed with the 1) ADAS-Cog, 2) MMSE, and 3) the FCSRT-IR.
2.4.2
Global
Assessed with the 1) CDR global score 


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2.4.3
Functioning
Assessed with the FAQ.
2.4.4
Neuropsychiatric Functioning
Assessed with the NPI-Q.
2.4.5
Dementia Assessment
To determine the onset of dementia.  This will be done at visits when all the cognitive 
and functional scales are done (Weeks 128, 156, 180, and 208).
2.4.6
Safety and Tolerability
Assessed by MRI, physical and neurological examinations, vital signs, blood and urine 
safety tests, ECGs, GDS, C-SSRS and adverse event monitoring.
2.4.7
Brain MRI
Hippocampal volume, whole brain volume, ventricular enlargement, and possibly other 
volumetric measures (Weeks 152, 208, and 256 [the final visit]). 
2.4.8
Cerebrospinal Fluid Biomarkers
The effect of gantenerumab on CSF biomarkers A1-42, T-tau, and P-tau will be 
assessed to detect and quantify drug effects on underlying disease pathology.
2.5
Objectives of Part 3 (Open-Label Extension)
The main objective of the open-label extension is to assess the short-term and long-term 
safety and tolerability of gantenerumab (RO4909832) given at doses up to 1200 mg SC 
Q4W (see Section 2.5.1). 
The secondary objectives include the following:  
1. To evaluate the effect of 1200 mg gantenerumab SC Q4W over time on imaging 
biomarkers (PD)
2.
To evaluate the effect of 1200 mg gantenerumab SC Q4W over time on clinical 
outcomes (cognition and function) compared to baseline and to start of Part 3 and 
3. To explore pharmacokinetics and ADAs with higher gantenerumab doses in target 
patient population.
2.5.1
Safety and Tolerability

To evaluate the safety and tolerability of gantenerumab as assessed by MRI, physical 
and neurological examinations, vital signs, blood safety tests, ECGs, Columbia-
Suicide Severity Rating Scale (C-SSRS), and adverse event monitoring
2.5.2
Brain MRI Volumetry

To evaluate the effect of gantenerumab over time on hippocampal volume, whole 
brain volume, ventricular enlargement, and possibly other volumetric measures of the 
brain compared to baseline and to the start of Part 3.  This objective will be 
assessed during the initial 3 years of Part 3.


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2.5.3
Brain Amyloid Load by PET Imaging

To assess changes in amyloid load over time using Florbetapir 18F (AV-45; 
Amyvid) compared to screening (if available), and to the start of Part 3.  PET scans 
performed within 12 months prior to the first study drug administration in Part 3 will 
be used for the baseline of Part 3.  This objective will be evaluated during the 
initial 3 years of Part 3 in a subset of consenting patients participating in the PET 
substudy. 
2.5.4
Cognition

To evaluate the effect of gantenerumab over time compared with baseline and 
with the start of Part 3 as assessed by the ADAS-Cog and the FCSRT-IR during 
the initial 3 years of Part 3, and by MMSE until the end of Part 3
2.5.5
Global Measures of Cognition and Function

To evaluate the effect of gantenerumab over time as assessed by the CDR-SOB and 
CDR global score, compared to baseline and to the start of Part 3.  This objective 
will be evaluated during the initial 3 years of Part 3.
2.5.6
Functioning

To evaluate the effect of gantenerumab over time as assessed by the FAQ, compared 
to baseline and to the start of Part 3.  This objective will be evaluated during the 
initial 3 years of Part 3.
2.5.7
Dementia Assessment

To determine the presence of and time to the onset of dementia, according to the 
investigator’s judgment.  This objective will be evaluated during the initial 
3 years of Part 3.
2.5.8
Pharmacokinetics

Plasma concentrations of gantenerumab will be quantified to explore the relationships 
between pharmacokinetics and responses. 
2.5.9
Anti-Drug Antibodies

The development of anti-gantenerumab ADAs will be assessed and, if detected, 
explored for their association with the PK, PD, efficacy, and safety parameters of 
gantenerumab.
3.
STUDY DESIGN
3.1
Overview of Study Design and Dosing Regimen
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study, followed by open-label extension with active study drug treatment.  


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In Part 1 subjects will be selected who meet criteria of memory impairment and have 
reduced CSF A1-42 levels.  These requirements will select subjects with a high likelihood 
of prodromal AD who are in the pre-dementia phase of Alzheimer's disease.  SC study 
treatment will be given Q4W for 26 administrations so the total treatment duration is 
104 weeks or approximately 2 years.  
Subjects who complete Part 1 of the study through the Week 104 visit may continue in to 
the optional Part 2 where they will continue to receive blinded treatment Q4W for up to 
2 additional years. 
Subjects who complete the double-blind treatment period (Part 1 or both Parts 1 and 2), 
as well as subjects who prematurely discontinue double-blind treatment at any time 
during the study, will be asked to return for the follow up visits 4 and 12 weeks after the 
last dose of double-blind study treatment, and for an optional visit 1 year (52 weeks) after 
the last dose of double-blind study treatment.
All subjects who were eligible for and enrolled into Study WN25203 and had at least 
1 follow-up/drop-out visit after double-blind treatment (placebo or 105 or 225 mg 
gantenerumab SC Q4W) will be offered participation in an open-label extension (Part 3) 
during which they will be treated with higher gantenerumab doses (up to 1200mg 
gantenerumab SC) Q4W initially for an additional 3 years, unless exempted for the 
criteria listed in Section 4.4. All subjects who complete 3 years of open-label 
treatment will be given the option to continue receiving gantenerumab until July 
2020 (up to 19 additional months).
Subjects will undergo brain MRI exams for monitoring safety and response to study
treatment.  Subjects will also undergo common tests of safety as well as tests of cognition 
and other clinical scales commonly used when monitoring subjects likely to develop 
dementia.
3.1.1
Use of Symptomatic Treatments for AD in Part 1
Approved agents for the symptomatic treatment of AD are AChEIs and memantine.  
These agents are not to be taken for 2 months prior to signing of the Informed Consent 
Form (ICF) and are not permitted at entry to or during Part 1 of the study through the 
Week 104 or Drop-Out 1 visit.  This is the case even for subjects who develop dementia 
of the Alzheimer's type during Part 1 of the study.  These agents are not approved for 
prodromal/pre-dementia AD (clinically MCI) and several studies of multi-year durations 
have failed to show they delay the onset of dementia, which tends to suggest their effects,
once dementia is first diagnosed, are likely to be minimal [19].
Though it has been well established that there is a cholinergic deficiency in the brains of 
patients with advanced AD, it is controversial whether there is significant cholinergic 
deficiency in MCI or early AD.  Two recent imaging studies with different tracers have 
not shown a reduction in nicotinic receptors in MCI (MMSE 26.8 SD 2.3) or early AD 
(MMSE 22.5 SD 2.5).  These articles discuss and reference other studies that suggest that 
cholinergic deficits are not a prominent feature of MCI or early Alzheimer's disease 
[20, 21].  In addition, a recent postmortem study showed no decrease in cholinergic 
projections to the cortex in MCI subjects (MMSE range 2228).  However, there was a 


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decrease in the mild-to-moderate AD group (MMSE range 1425), which correlated with 
impairment on the MMSE, Global Cognitive Score, and frontal lobe functioning [22]. 
Though AChEIs are, for most subjects, likely to provide little or no benefit during the 
period of this study, an additional reason for not allowing them to be added on prior to 
completion of the first follow-up visit is that this will interfere with evaluating whether 
gantenerumab has an effect on disease progression.  As an example of this, if 
gantenerumab does slow the progression of prodromal AD, a disproportionately greater 
number of placebo subjects are likely to receive an AChEI and even though the agent 
may have little or no effect on cognition in MCI or early AD many of these subjects are 
likely to improve mainly due to a "placebo response" which will diminish any treatment 
difference between placebo and gantenerumab.  Such biased estimates of treatment 
difference cannot properly be addressed by any statistical analysis methods.  A recent 
publication of a 48-week study of one of these agents (donepezil) in MCI (MMSE of 
2428) showed a prominent placebo effect but did not show benefit of donepezil based 
on the primary endpoint [23].  The study reported a small but significant benefit of less 
than 1 point on the ADAS-Cog in the last observation carried forward (LOCF) analysis.  
However, as pointed out in a subsequent letter to the editor, this may be an artifact of 
significantly more donepezil subjects stopping treatment early, and the LOCF scores used 
in the analysis are likely to be better than the scores would have been had they stayed in 
the study for 48 weeks [24].  Overall about 42% of the donepezil group discontinued 
treatment early compared to 29% for placebo and of these, discontinuations due to 
adverse events were 18% for donepezil and 8% for placebo.  As commented in the 
article, MCI subjects may be less tolerant of these agents than patients with AD.  This 
would be an additional rationale for excluding these agents at trial entry or as added on 
during the trial as they would likely increase the incidence of adverse events and dropouts 
and may require adjustment of the symptomatic treatment which will further complicate 
the evaluation of effects of the study treatment on disease progression.
3.1.2
Use of Symptomatic Treatments for AD in Part 2
Subjects who continue into Part 2 of the study may start approved symptomatic AD 
treatments after the Week 104 assessments have been completed at the discretion of the 
Principal Investigator. 
3.1.3
Use of Symptomatic Treatments for AD in Part 3
Use of any approved symptomatic treatments for AD is allowed in Part 3 at the discretion 
of the Principal Investigator.
3.1.4
Rationale for Dose Selection Parts 1 and 2
Based on the results of the MAD study, the doses to be evaluated will depend on the 
ApoE genotype of the subject in order to minimize the possibility of MRI findings.
3.1.4.1
Dosing in Subjects Who Are 04 and 14
At 200 mg IV in the MAD study, of the 3 patients who were 04, the only MRI finding 
was 1 microbleed (first seen at treatment follow-up and not seen at subsequent MRI) and 
of the 11 who were 14, 3 had MRI findings of which 1 was probably a small ischemic 


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area and 2 were MRI findings suggesting “inflammation or vasogenic edema” (which in 
these cases were asymptomatic and resolved rapidly after treatment was suspended).
Given (i) the asymptomatic nature of these MRI findings together with the prompt 
reversibility of the FLAIR findings and the fact that the single microbleed was seen 
during the follow-up period (off treatment and within expected background incidence of 
microbleeds in this population), plus (ii) the absence of MRI findings in the 60 mg MAD 
dose cohort which included six 04 and six 14, plus (iii) the MRI monitoring schedule 
implemented in this study, SC doses equivalent to approximately 130 mg IV and 60 mg 
IV (based on plasma gantenerumab AUC) will be administered every 28 days to subjects 
with genotypes 04 and 14.
 
, the doses of 105 mg and 225 mg have been selected.  Results from the 
SC bioavailability study (Section 1.1.2.2) demonstrated that based on AUC comparison, 
these SC doses of 105 mg and 225 mg would translate into 
, 
respectively.  Therefore, subjects who are 04 or 14 will receive placebo, 105 mg 
(
) or 225 mg (
).  
3.1.4.2
Dosing in Subjects Who Are 24
Subjects who are 24 will receive either placebo or 105 mg.  In the MAD, no MRI effects 
were seen in the 3 subjects who were 24 at 60 mg IV.  However because both subjects 
who were 24 at 200 mg had prominent findings it has been decided to be more cautious 
with this group and to apply only the lower dose of 105 mg SC.
Also supporting dose selection for this study are the PET data available from the MAD 
study as mentioned in Section 1.1.2.1, suggesting an amyloid-removing effect of 
gantenerumab over the period of up to 6 months at doses of 60 and 200 mg IV with the 
effect at the higher dose appearing larger.  It is uncertain whether brain amyloid removal 
will result in clinical efficacy; however, the MAD data, together with the known 
preclinical profile of gantenerumab, suggest that the doses used in this Phase 3 study may 
lead to the desired amyloid-removing effect.
3.1.5
Rationale for Dose Selection for the Open-Label Extension 
(Part 3)
As described earlier in Sections 1.2.3, 1.3.3, and 1.3.7, PK-PD (PK-PET) models for 
anti-aggregated Ahave been developed to extrapolate clinically effective gantenerumab 
doses and to predict dosing regimens with up-titration to reduce the incidence of MRI 
findings.  Based on the results of the PRIME study, statistically significant clinical effects 
of aducanumab were present at 10 mg/kg IV Q4W, associated with ~20% reduction in 
composite amyloid PET SUVR after 2 years.  The equivalent gantenerumab dose to 
achieve this SUVR reduction was predicted as 1200 mg SC Q4W.  Additional 
information on population PK-PET response analysis of gantenerumab and aducanumab 
can be found in 
.
Safety outcomes at doses higher than the 225-mg dose (the highest gantenerumab dose 
tested in Phase 3) were projected from the results of the double-blind treatment period of 
Study WN25203 and from the PRIME study, using a bapineuzumab-based model [48], 


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taking into consideration known risk factors for ARIA-E: drug concentrations, time since 
the first dose, and APOE 4 allele status.  Gradual exposure to gantenerumab is predicted 
to be linked with an acceptable incidence of ARIA-E, mostly occurring during the first 
months of treatment.  The starting dose of gantenerumab and the titration schedule will 
be adapted to the presence of APOE 4 allele and to the dose of gantenerumab received 
during Parts 1 and 2 (Table 5 and Table 6).  
3.1.5.1
Dosing in APOE 4 carriers (14 and 24 genotypes) previously 
on placebo, 105 mg gantenerumab, and 225 mg gantenerumab 
meeting criteria for dose reduction due to ARIAs:

Doses 1, 2, and 3:  105 mg SC

Doses 4, 5, and 6:  225 mg SC

Doses 7 and 8:  450 mg SC

Doses 9 and 10:  900 mg SC

Dose 11 onwards:  1200 mg SC
The above titration schedule will allow subjects to reach the target dose of 1200 mg 
gantenerumab within 10 months and is predicted to result in an ARIA-E incidence close 
to 25% in subjects carrying APOE 4 allele, compared to 61% expecting to occur without 
up-titration by starting with 1200 mg gantenerumab.
3.1.5.2
Dosing in APOE 4 non- carriers (04 genotype) and in APOE 
4 carriers receiving 225 mg gantenerumab until the end of 
double-blind treatment (14 genotype):

Doses 1 and 2:  225 mg SC

Doses 3 and 4:  450 mg SC

Doses 5 and 6:  900 mg SC 

Dose 7 onwards:  1200 mg SC
The above titration schedule will allow the subject to reach the target dose of 1200 mg 
gantenerumab within 6 months. 
3.2
End of Study
The end of the study will be considered to be the date of the last visit (including the last 
scheduled follow-up visit according to the study protocol) of the last subject in the study.
3.3
Number of Subjects / Assignment to Treatment Groups in 
Part 1
The planned total number of subjects is approximately 770, 256 on placebo and 257 on 
each of the two gantenerumab doses.  Based on the ADNI data the approximate genotype 
distribution is expected to be 33% 04, 50% 14, and 17% 24 (with respective N’s of: 
257, 385, and 128).  Subjects with ApoE genotypes 04 or 14 will be randomized to 
gantenerumab 105 mg, 225 mg, or placebo.  Subjects with ApoE genotype 24 will be 
assigned to gantenerumab 105 mg or placebo.  Within each of the three ApoE genotype 
groups (04, 14, or 24) subjects will be assigned to either gantenerumab or placebo in 
2:1 ratio.  Additional information is given in Section 6.4.


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3.4
Centers
Approximately 150200 centers will participate in the study.
4.
STUDY POPULATION
Under no circumstances were subjects enrolled in this study (in Parts 1 and 2) permitted 
to be re-randomized to this study and enrolled for a second course of double-blind 
treatment.  Subjects who were eligible for and enrolled into Study WN25203 and had at 
least 1 follow-up/drop-out visit after double-blind treatment (placebo or 105 or 225 mg 
gantenerumab SC Q4W) will be offered participation in an open-label extension (Part 3).
4.1
Overview 
The population will consist of subjects with prodromal AD who were not receiving 
memantine or cholinesterase inhibitors and have not been treated with these agents for at 
least 2 months prior to signing the ICF for Part 1.
4.2
Inclusion Criteria 
A subject may be included if the answer to all of the following statements is “yes.”
1.
Written consent signed by the subject (co-signed by the subject’s next of kin or 
study partner, if required by the local regulations/guidelines/Ethics Committee 
[EC]/Institutional Review Board [IRB])
2.
Age: 5085 at the time of signing the ICF
3.
Males and females. Females must be either:

Of non-childbearing potential (more than 2 years after the cessation of 
menses or surgically sterile by means of hysterectomy, bilateral 
oophorectomy, or tubal ligation).  Additional blood tests will be done if 
required by 
the local regulations/guidelines/EC/IRB for further 
confirmation of non-childbearing potential or –

If she is of childbearing potential, she must:

Have a negative urine pregnancy test at screening and a negative urine 
pregnancy test at baseline.

Agree to use two methods of contraception from the screening visit until 
16 weeks after study drug discontinuation.  Of the two contraceptive 
methods, one must be from Group 1, and one must be from Group 2, 
defined as follows:  Group 1:  Oral, implantable, trans-dermal or injectable 
hormonal contraceptives, intrauterine devices, or partner’s sterilization 
(vasectomy).  If a hormonal contraceptive will be chosen from this group, 
it must have been taken for at least 1 month prior to randomization.  
Group 2:  Condoms, diaphragm or cervical cap, all in combination with 
spermicide.  Abstention and rhythm methods are not acceptable methods 
of contraception.
4.
Has a study partner, who in the investigator's judgment has frequent and sufficient 
contact with the subject so as to be able to provide accurate information as to the 
subject's cognitive and functional abilities, who agrees to provide information at 
clinic visits which require partner input for scale completion, and who signs the 
necessary consent form if applicable.


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5.
Fluent in the language of the tests used at the study site
6.
Mental retardation has been excluded by the investigator.  This may be based on, 
for example, sufficient education or work experience
7.
Willing to complete all aspects of the study (including MRI, lumbar puncture 
[LP], and genotyping) and capable of doing so either alone or with the help of the 
study partner
8.
Have not received within the past 2 months and are not currently being treated 
with approved marketed medications for AD and the study physician does not 
anticipate any treatment with one during the study 
9.
If not already aware, willing to have their ApoE genotype status withheld until the 
study is unblinded unless required by the relevant health authority or EC/IRB.  
If informing the subject of their ApoE status is required, the informed consent 
may be reviewed and re-signed before treatment begins.
10.
Visual and auditory acuity sufficient to perform the cognitive tests (eye glasses 
and hearing aids are permitted.)
11.
Agree not to donate blood or blood products for transfusion for the duration of the 
study and for 1 year after final dose
Cognition-related and test-based inclusion criteria indicating the subject has 
prodromal AD
12.
Study partner has noticed a recent gradual decrease in the subject's memory 
(e.g., over the prior 12 months), which the subject may or may not be aware of.
13.
Abnormal memory function at screening or 1 month prior to screening based on 
the FCSRT-IR of 
o
free recall <17, or 
o
total recall <40, or 
o
[free recall <20 and total recall <42]. 
14.
Screening MMSE score of 24 or above.
15.
Screening global CDR of 0.5 with a memory box score of 0.5 or 1.
16.
Aside from memory impairment, general cognition and functional performance 
are largely preserved such that a diagnosis of AD with dementia cannot currently 
be made.
17.
Modified Hachinski Ischemia Scale score of 4
18.
CSF A1-42 level 600 ng/L as measured by the central laboratory.  Individuals 
who do not meet this criterion may not be re-screened for this study.
4.3
Exclusion Criteria
A subject will be excluded if the answer to any of the following statements is “yes.” 
CNS Disorders
1.
Other prior or current neurologic or medical disorder which may currently or 
during the course of the study impair cognition or psychiatric functioning 
including but not limited to: head trauma, seizure disorder, neurodegenerative 
disease, hydrocephalus, cerebral / spinal hematoma, inflammatory disease, CNS 
infection (e.g., encephalitis or meningitis), neoplasm, toxic exposure, metabolic 


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disorder (including hypoxic or hypoglycemic episodes), or endocrine disorder.  If 
one of these disorders is suggested by the central reading of the baseline MRI, the 
subject may be included after consensus agreement between the investigator and 
the study director that the subject is still considered to have prodromal AD.
2.
A history of stroke
3.
A documented history of transient ischemic attack within the last 12 months
4.
History of schizophrenia, schizoaffective disorder, or bipolar disorder
5.
Currently meets criteria for major depression 
6.
Any other psychiatric condition/disorder which could significantly interfere with 
the subject’s cooperative participation (e.g., prominent anxiety, agitation, or 
behavioral problems)
7.
Current evidence or history of substance abuse disorder (DSM-IV) within 2 years, 
except, nicotine use is allowed. 
Imaging-Related Criteria
8.
As assessed by the central reader, MRI evidence of a) more than one lacunar 
infarct, b) territorial infarct or macroscopic hemorrhage, or c) any deep white 
matter lesion corresponding to an overall Fazekas score of 3 which requires at 
least 1 confluent hyperintense lesion on the FLAIR sequence which is 20 mm or 
greater in any dimension
9.
The combined number of ARIA-H (microbleeds and areas of leptomeningeal 
hemosiderosis) on MRI is more than 2 on a 1.5T machine or more than 3 on a 3T 
machine based on the review done by the central reader.
10.
Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, 
foreign metal objects in the eyes, skin or body or any other circumstance which 
would contraindicate an MRI scan or significantly impair MRI image quality 
based on review by the central reader.
Cardiovascular Disorders
11.
History of atrial fibrillation except if only one episode which resolved more than 
three years ago and for which treatment is no longer indicated
12.
Within the last 2 years, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction, angina pectoris, New York Heart Association Class II 
or more cardiac failure)
13.
Average QT interval corrected with Fridericia’s equation (QTcF) above 470 msec 
based on a set of three good quality ECGs, or clinically relevant abnormalities on 
screening ECG based on centralized reading (e.g., multifascicular block; left 
bundle branch block, AV block II) 
14.
Uncontrolled hypertension (i.e., blood pressure generally >160 systolic or 
>95 mmHg diastolic)
Hepatic/Renal Disorders
15.
Screening AST or ALT 2 or total bilirubin 1.5 times the upper limit of normal 
(ULN) which is still above these limits if retested due to a slightly elevated initial 
result


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16.
Screening creatinine clearance <30 mL/min as calculated by the central lab using 
the Cockcroft-Gault formula, which remains <30 mL/min if retested 
Infections/Immune Disorders
17.
History of HIV infection, history of Hepatitis B infection within the past year, 
history of Hepatitis C infection which has not been adequately treated or history 
of spirochete infection of the CNS, (e.g., syphilis, lyme, or borreliosis)
18.
Autoimmune disease which is debilitating or potentially debilitating (e.g., Lupus, 
multiple sclerosis).  Rheumatoid arthritis may be allowed if, in the opinion of the 
investigator, it will not put the subject at increased risk or interfere with the 
interpretation of the study. 
19.
Immunocompromised systemically due to continuing effects of immune 
suppressing medication
Metabolic/Endocrine Disorders
20.
Screening thyroid function tests are abnormal such that a new treatment or an 
adjustment of current treatment is required.  The subject may be rescreened if 
there is no improvement in cognition after 3 months of adequate treatment.
21.
Folic acid or B12 levels (current or within the past 6 months) that are sufficiently 
low such that deficiency may be contributing to cognitive impairment.  In such 
cases the subject may be rescreened if there is no improvement in cognition after 
6 months of appropriate treatment.
22.
Screening hemoglobin A1C (HbA1C) >8% (retesting is permitted if slightly 
elevated) 
or 
poorly 
controlled 
insulin-dependent 
diabetes 
(including 
hypoglycemic episodes).  The subject may be rescreened after 3 months to allow 
optimization of diabetic control.  
23.
Body mass index 36
Other
24.
Deformity of the lumbosacral spine which would contraindicate a lumbar 
puncture
25.
Screening prothrombin time (PT) is abnormal and remains abnormal when 
retested.
26.
History of cancer except if considered likely to be cured or in the case of prostate 
cancer there has been no significant progression over the last 2 years.
27.
Any other medical condition not previously mentioned that could be expected to 
progress, recur, or change to such an extent that it could bias the assessment of the 
clinical or mental status of the subject to a significant degree or put the subject at 
special risk or any pre-planned surgery, other than minor procedures.
28.
Clinically significantly abnormal screening blood, urine, or CSF which remain 
abnormal on retest
29.
Currently or within the last 1 month participated in a non-pharmacological trial 
with a key objective of improving cognition
30.
Residence in a skilled nursing facility such as a convalescent home or long-term 
care facility 


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
63/Protocol WN25203, Version H
Medications
31.
Ever participated in a study of gantenerumab
32.
Ever participated in a study of a vaccine or other long-acting biological agent 
which was being evaluated to prevent or postpone cognitive decline
33.
Received any other investigational treatment within 3 months of screening or 
5 half-lives, whichever is longer.
34.
Received within 2 months of screening a cholinesterase inhibitor,  memantine, or 
Souvenaid
35.
Within 1 month of screening:
a)
Started taking ginkgo biloba, lecithin, vitamin B12, or any other agent or 
supplement intended to improve cognition or reduce cognitive decline
b)
Received 
medication 
for 
systemic 
immunosuppression 
including 
corticosteroids
c)
Received medication used to treat Parkinsonian symptoms or any other 
neurodegenerative 
disorder 
even 
if 
it 
is 
being 
taken 
for 
a 
non-neurodegenerative disorder such as restless legs disorder
d)
Received medication that may currently be contributing to cognitive 
impairment (e.g., clonidine, alphamethyldopa)
e)
Received an antipsychotic or a neuroleptic medication except as brief 
treatment for a non-psychiatric indication (e.g., emesis)
f)
Received medication used to treat a mood or anxiety disorders except if it 
is a selective serotonin reuptake inhibitor (SSRI), selective norepinephrine 
reuptake inhibitor (SNRI), selective serotonin/norepinephrine reuptake 
inhibitor (SSNRI), bupropion, buspirone, mirtazapine, or trazadone and is 
given as maintenance treatment 
g)
Received anti-hemostasis medication (e.g., warfarin) except low-dose 
aspirin (dose depends on local practice but preferably 100 mg or less)
h)
Received medication with anticholinergic activity that may impair 
cognition or attention (e.g., centrally 
acting antihistamines or 
anti-spasmodics) except if used only intermittently (generally no more 
than twice per week) and there has been no use within the 4 days before 
the screening cognitive testing
i)
Received anticonvulsant medication except if for an approved pain 
indication
j)
Received narcotic analgesics except if typically on 4 or fewer days per 
month for a self-limited pain indication (e.g., migraine) or if used for 
cough or diarrhea (e.g., codeine) and there has been no use within the 
4 days before the screening cognitive testing  
k)
Received sedative, hypnotic, or benzodiazepine medication except if used 
only intermittently (generally no more than twice per week).  For example, 
use of a short-acting benzodiazepine-like medication (e.g., zolpidem) or 
trazadone for sleep and lorazepam for occasional mild anxiety are 
allowed.  These medications may not have been taken within the 4 days 
before the screening cognitive testing    


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd 
64/Protocol WN25203, Version H 
36. 
For the medication exceptions listed just above, any change in the prescribed 
regimen within the last month. 
 
4.4 
Eligibility for the Open-Label Extension (Part 3) 
Subjects who received double-blind treatment during either Part 1 or Part 2 prior to the 
futility analysis, and had at least one follow-up/drop-out visit will be eligible to enter 
Part 3.  For reasons related to subject safety, subjects who meet any of the following 
criteria will not be eligible for Part 3:  
 Prematurely discontinued from Parts 1 and 2 for safety reasons affecting participation 
in the study (e.g., MRI findings meeting criteria for treatment discontinuation in 
Parts 1 and 2) 
 
 
 
 Received another investigational medication after the end of double-blind treatment 
 Participation in Part 3 deemed inappropriate by investigator or Sponsor (eg, any 
serious medical condition or abnormality in clinical laboratory tests that precludes the 
patient’s safe participation in the open-label extension). 
 
4.5 
Concomitant Medication and Treatment 
Adding a new medication or changing the dose of a medication after signing the informed 
consent form should only occur for the treatment of an adverse event.  Exceptions to this 
include:  1) preventive medication such as prophylactic use of an anti-infective or 
vaccination 2) medication for a pre-existing condition which has not worsened, or 
3) temporary use or withholding of medication to help carry out certain study procedures 
(e.g., LP, MRI or PET scan). 
Adding a new vitamin regimen or dietary supplement during double-blind treatment 
(Parts 1 and 2) is discouraged.  Any medications that are used intermittently that may 
affect cognition such as a narcotic analgesics, hypnotics, or anxiolytics should be avoided 
as much as possible prior to the scheduled assessments of cognition.  If such a medication 
is required, sufficient time must have passed (preferably 4 or more days) so that the effect 
of the medication will not interfere with the assessment.  Anxiolytics may be given prior 
to an MRI, PET scan, or LP; however, cognition testing should not be done until 
sufficient time has passed for the effects to have diminished. 
If the subject requires treatment with a medication listed in the exclusion criteria, a 
medication listed as an exception above should be used if possible and appropriate 
(i.e., for depression an SSRI and not a tricyclic).  If the subject requires treatment that is 
not listed as an exception, the subject may need to be withdrawn from the trial 
(e.g., warfarin as an anticoagulant, anti-Parkinson medication, antipsychotic medication 
or continuous treatment with narcotics).  In these cases, the investigator should inform 
and consult with the Sponsor. 
Of special note, if a subject is to be started on a cholinesterase inhibitor, memantine, or 
Souvenaid during Part 1 of the study prior to completion of the visit at Week 104, the 
subject will need to be withdrawn from the study.  These medications should be withheld 
until after the Week 104 or first drop-out (DO1) is completed.  However, for subjects 


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd 
65/Protocol WN25203, Version H 
entering Part 2 of the study, these medications may be started after the Week 104 
assessments have been completed if judged appropriate by the Principal Investigator.  
These medications will be permitted at any time in Part 3. 
4.6 
Criteria for Premature Withdrawal 
In addition to withdrawals described above for concomitant medication, the subject must 
be withdrawn from the study if it becomes clear that the subject's cognitive impairment is 
not due to AD.  Subjects do not have to be withdrawn from the study if they develop 
dementia.  However, they do need to be withdrawn if prohibited AD medications will 
then be started prior to completion of the Week 104 or first drop-out (DO1) visit. 
Subjects have the right to withdraw from the study at any time for any reason.  
In the case that the subject decides to prematurely discontinue study treatment [“refuses 
treatment”], he/she should be asked if he/she can still be contacted for further information 
concerning their reasons for discontinuing and will be asked to return at 4 weeks, 
12 weeks, and, optionally, 1 year (52 weeks) from the time of their last dose of study 
drug in Parts 1 and 2 (see Table 2, Table 3, and Table 4), and 4 weeks after the end of 
treatment in Part 3 (see Table 8 and Table 9).  The outcome of that discussion should be 
documented in the medical records.  If lost to follow-up, the investigator should contact 
the subject or a responsible relative by telephone followed by registered mail or through a 
personal visit to establish as completely as possible the reason for the withdrawal.  
A complete final evaluation at the time of the subject’s withdrawal should be made with 
an explanation of why the subject is withdrawing from the study. 
Subjects should be informed of circumstances under which their participation may be 
terminated by the investigator without the subject’s consent.  The investigator may 
withdraw subjects from the study in the event of intercurrent illness, adverse events, lack 
of compliance with the study and/or study procedures (e.g., dosing instructions; missing 
more than three consecutive doses, or more than six study visits in a calendar year for no 
other reason than compliance), or any reason where it is felt by the investigator that it is 
in the best interest of the subject to be terminated from the study.  Any administrative or 
other reasons for withdrawal must be explained to the subject. 
If the reason for removal of a subject from the study is an Adverse Event, the principal 
specific event will be recorded on the AE eCRF.  The subject should be followed until 
the Adverse Event has resolved, if possible. 
An excessive rate of withdrawals can render the study non-interpretable; therefore, 
unnecessary withdrawal of subjects should be avoided.  Should a subject decide to 
withdraw, all efforts will be made to complete and report the observations prior to 
withdrawal as thoroughly as possible. 
4.6.1 
Withdrawal from Study Drug 
Study treatment must be discontinued for protocol-specific rules implemented for subject 
safety.  The pre-specified criteria for withdrawal from the study drug include the 
following: 
 Pregnancy (see Section 7.2.3) 


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd 
66/Protocol WN25203, Version H 
 MRI findings (see Section 5.1.6.1 for Part 3) 
 
In addition, study treatment may be also modified or discontinued based on MRI-C 
recommendations and/or iDMC recommendations (during double-bind treatment period), 
as deemed necessary (Section 10.1) 
4.6.2 
Withdrawal of Subjects from the Roche Clinical Repository 
(RCR)  
Subjects who gave consent to provide RCR specimens have the right to withdraw their 
specimen from the RCR at any time for any reason.  If a subject wishes to withdraw 
his/her consent to the testing of his/her specimen(s), the investigator must inform the 
Roche monitor in writing of the subject’s wishes using the RCR Subject Withdrawal 
Form.  A subject’s withdrawal from the main trial does not, by itself, constitute 
withdrawal of the specimen from the RCR.  Likewise, a subject’s withdrawal from the 
RCR does not constitute a withdrawal from the main trial. 
4.7 
Replacement Policy [Ensuring Adequate Numbers of 
Evaluable Subjects] 
4.7.1 
For Subjects 
Subjects prematurely discontinued from the study will not be replaced.  
4.7.2 
For Centers 
A center may be replaced for the following administrative reasons: 
 
Excessively slow recruitment. 
 
Poor protocol adherence. 
 
Non-GCP compliance or any significant audit findings 


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
67/Protocol WN25203, Version H
5.
SCHEDULE OF ASSESSMENTS AND PROCEDURES
Table 1
Schedule of Assessments – First Year
Visit by week #
Screen
Baseline
1
4
8
12
16
20
24
28
32
36
40
44
48
52
53
Dose Number
(8 wks)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Demographics12
X
Medical/surgical history
X
Physical Exam
X
X
Neurological Exam
X
X
Modified Hachinski
X
Clinical Genotyping
X
RCR Plasma and RNA
X6
X
RCR DNA
X6
Vital Signs
X
P
X
P
P
P
P
P
P
P
P
P
P
P
P
P
X
ECG (triple if underlined)
X
P
X
P
P
P
P
X
Blood and Urine Labs
X10
P
X
X
X
X
X
X10
Urine Pregnancy Test5
X
P
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
X
P
P
P
X
ADA samples
P
X
P
P
P
Plasma Biomarkers
P
P
P
CDR
X
P-1 wk
P
P
FAQ, NPI-Q, GDS
X
P-1 wk
P
P
MMSE
X
P-1 wk
P
P
P
P
Dementia Assessment
X
P
P
ADAS-Cog
X
P-1 wk
P
P
P
P
FCSRT-IR
X4
P-1 wk
P
P
CANTAB
X
P-1 wk
P
P
C-SSRS
P-1wk
X
X
X
X
X
X
X
X
X
X
X
X
X
LP/CSF, plasma PK and 
matching serum  sample3
X2
10/20d2
RCR CSF
X
10/20d2
MRI
X2
10/20d
*
10/20d
*
10/20d
*
10/20d
*
10/20d
*


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
68/Protocol WN25203, Version H
Table 2
Schedule of Assessments – Second Year
Visit by week #
56
60
64
68
72
76
80
84
88
92
96
100 101
FU1/1047
FU2/112
FU3/152
Unsch.1
FU1/DO1
FU2/DO2
FU3/DO312
Dose Number
15
16
17
18
19
20
21
22
23
24
25
26
Physical Exam
X
X
X
X
X
Neurological Exam
X
X
X
X
X
RCR Plasma and RNA
X6
X6
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
X
X
X
X
X
X
X
X
ECG (triple if underlined)
P
P
P
X
X
X
X
Blood and Urine Labs
X
X
X
X10
X
X
X
X10
X
X
Urine Pregnancy Test5
P
P
P
P
P
P
P
P
P
P
P
P
X
X
X
PK  plasma
P
P
X
X
X
X
ADA samples
P
P
X
X
X
Plasma Biomarkers
P
P
X
X
X
CDR
P
P
P
X
X
X
X
X
FAQ, NPI-Q, GDS
P
X
X11
X
X
X11
MMSE
P
P
P
X
X
X
Dementia Assessment
P
X
X
X
ADAS-Cog
P
P
P
X
X
X
FCSRT-IR
P
P
X
X
X
CANTAB
P
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LP/CSF,  plasma PK and 
matching serum sample3
10/20d2
X
10/20d2
RCR CSF
10/20d2
10/20d2
MRI
10/20d
*
10/20d
*
10/20d2
X8
X
10/20d2
X8
P indicates Prior to Injections: P-1 wk is within 1 week prior the 1st dose; P is prior to the injections on the day of dosing.
ECG readings underlined above to be done in triplicate for subjects enrolled prior to protocol amendment D.  Subjects enrolled after approval of amendment D will have triplicate 
ECG done only at Screen.  All ECGs are sent for central reading.
DO1, DO2 and DO3 are drop-out visits; FU1, FU2, and FU3 are 4, 12, and 52 weeks after last dose of study treatment.
LP/CSF and MRI: the times are days after the visit (e.g., 10/20d is 10-20 days.  Attempt to schedule MRI closer to 10 days than 20 days as the result must be received prior to the 
next dose).
RCR CSF:  after aliquoting the required samples, any remaining CSF fluid from consenting subjects will be saved for RCR sample.
Visit window:  +/- 7 days for dosing days; +/- 3 days for visits that are 1 week post-dose (see Section 5.1.2).
* The MRI result as determined by the central reader must be known before a subsequent dose can be given.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
69/Protocol WN25203, Version H
Table 2
Schedule of Assessments – Second Year (Cont.)
1.
Any procedure or assessment marked may be done at an unscheduled visit as required.
2.
LP performed in the morning (8 am12 pm); MRI should not be done during the 3 days following an LP.  The LPs at screening and Week 104 (FU1/104, 
FU1/DO 1 or 104 Ext) are mandatory.  The LPs at 1 year and during the extension part of the study are optional.  The final LP in the extension (FU1/208 or 
ext208/DO1) is highly encouraged. 
3.
LP/CSF for biomarkers and PK assays, plasma PK and matching serum samples: at screen, Wk 52 Wk FU1/104 (or FU1/DO 1 or Wk 104 Ext), Wk 156 and 
Wk FU1/208 (or ExtFU1/DO 1).  See Section 5.2.14.2.
4.
FCSRT-IR performed up to 1 month prior to screening can be used to satisfy inclusion criteria.
5.
Women who are of childbearing potential must have a urine pregnancy test done at the site prior to each dose.
6.
RCR plasma and RNA samples should be taken at the same time as the blood samples taken during the LP visit.
7.
Subjects continuing directly into the Extension, should follow Week 104 Ext schedule in Table 3.  FU2/112 and FU3/152 visit in Table 2 will not be 
performed.
8.
The final MRI should be done approximately 4 weeks before the final follow-up visit to allow review before the final visit.
9.
At screening, demographic data collected will include years of education.
10.
During the screening period, Week 53, the Week 101 or DO1 and, Week 204, or Ext DO1 only, HbA1C, folic acid and, B12, T4, free T4, and thyroid 
stimulating hormone levels will also be assessed.
11.
At FU, DO3, Ext FU3 or Ext DO3, only FAQ will be administered.
12.
Optional follow-up/drop-out visit.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
70/Protocol WN25203, Version H
Table 3
Schedule of Assessments – Extension Year 1
Visit by week #
104 Ext
108
112
116
120
124
128
132
136
140
144
148
152
Dose Number
27
28
29
30
31
32
33
34
35
36
37
38
39
Physical Exam
P
Neurological Exam
P
RCR Plasma and RNA
X6
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
ECG 
P
P
Blood and Urine Labs
X
X
Urine Pregnancy Test5
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
P
ADA samples
P
P
Plasma Biomarkers
CDR
P
P
P
P
FAQ, NPI-Q, GDS
P
P
MMSE
P
P
P
P
Dementia Assessment
P
P
ADAS-Cog
P
P
P
P
FCSRT-IR
P
P
P
CANTAB
P
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
LP/CSF, plasma PK and 
matching serum sample3
10/20d2
RCR CSF
10/20d2
MRI
10/20d
*
10/20d
*
10/20d
Also refer to footnotes Table 2.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
71/Protocol WN25203, Version H
Table 4
Schedule of Assessments – Extension Year 2 
Visit by week #
156
160 164 168 172
176
180 184 188 192 196 200 204
FU1/
208
FU2/
216
FU3/
256
Unsch.1 ExtFU1/
DO1
ExtFU2/ 
DO2
ExtFU3/ 
DO312
Dose Number
40
41
42
43
44
45
46
47
48
49
50
51
52
Physical Exam
P
P
X
X
X
X
X
Neurological Exam
P
P
X
X
X
X
X
RCR Plasma and RNA
X6
X6
X6
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
X
X
X
X
X
X
X
ECG 
P
P
P
X
X
X
Blood and Urine Labs
X
X
X10
X
X
X
X10
X
X
Urine Pregnancy Test5
P
P
P
P
P
P
P
P
P
P
P
P
P
X
X
X
PK  plasma
P
P
P
X
X
X
ADA samples
P
P
P
X
X
X
Plasma Biomarkers
X
X
X
CDR
P
P
P
P
X
X
X
X
X
FAQ, NPI-Q, GDS
P
P
X
X11
X
X
X11
MMSE
P
P
P
P
X
X
X
Dementia Assessment
P
P
X
X
X
ADAS-Cog
P
P
P
P
X
X
X
FCSRT-IR
P
P
X
X
X
C-SSRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LP/CSF, plasma PK and 
matching serum sample3
10/20d2
10/20d2
X
10/20d2
RCR CSF
10/20d2
10/20d2
10/20d2
MRI
*
10/20d
*
10/20d2
X8
X
10/20d2
X8
Also refer to footnotes in Table 2.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
72/Protocol WN25203, Version H
Table 5
Schedule of Assessments – Open-Label Extension Year 1 - for ApoE 4 carriers previously on:  1) Placebo, 
2) 105 mg Gantenerumab and 3) 225 mg Gantenerumab meeting Criteria for Dose Reduction due to ARIAs
Visit by week #
OLE Pre-baseline 
(8 weeks)
Day 1 (OLE 
Baseline)
4
8
12
16
20
24
28
32
33
36
40
44
48
52
Dose Number
1 
2
3
4
5
6
7
8
9
10
11
12
13
14
Dose (mg)
105
105
105
225
225
225
450
450
900
900
1200
1200
1200
1200
Physical Exam
P
P
P
Neurological Exam
P
P
P
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
P
ECG 
P
P
Blood Labs
P
X
Urine Pregnancy Test4
P
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
P
X
P
P
ADA samples
P
P
P
CDR
P-1wk
P
P
FAQ
P-1wk
P
P
MMSE
P-1wk
P
P
Dementia Assessment
P-1wk
P
P
ADAS-Cog
P-1wk
P
P
FCSRT-IR
P-1wk
P
P
C-SSRS
P-1wk
X
X
MRI
X
X2
*
X2
*
X2
*
X2
*
X2
*
Refer to Table 8 footnotes.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
73/Protocol WN25203, Version H
Table 6
Schedule of Assessments – Open-Label Extension Year 1- for:  1) ApoE 4 non-carriers and 2) ApoE 4 
Carriers receiving 225 mg Gantenerumab until the End of Double-blind Treatment
Visit by week #
OLE Pre-
baseline (8 
weeks)
Day 1 
(OLE 
Baseline) 
4
8
12
16
17
20
24
28
32
36
40
44
48
52
Dose Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Dose (mg)
225
225
450
450
900
900
1200
1200
1200
1200
1200
1200
1200
1200
Physical Exam
P
P
P
Neurological Exam
P
P
P
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
P
ECG 
P
P
Blood Labs
P
X
Urine Pregnancy Test4
P
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
P
X
P
P
ADA samples
P
P
P
CDR
P-1wk
P
P
FAQ
P-1wk
P
P
MMSE
P-1wk
P
P
Dementia Assessment
P-1wk
P
P
ADAS-Cog
P-1wk
P
P
FCSRT-IR
P-1wk
P
P
C-SSRS
P-1wk
X
X
MRI
X
X2
*
X2
*
X2
*
X2
*
X2
*
Refer to Table 8 footnotes.


Gantenerumab (RO4909832)—F. Hoffmann-La Roche Ltd
74/Protocol WN25203, Version H
Table 7
Schedule of Assessments – Open-Label Extension Year 2 for all Participants
Visit by week #
56
60
64
68
72
76
80
84
88
92
96
100
101
104
Dose Number
15
16
17
18
19
20
21
22
23
24
25
26
27
Physical Exam
P
Neurological Exam
P
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
ECG 
P
Blood  Labs
X
Urine Pregnancy Test4
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
P
X
P
ADA samples
P
P
CDR
P
P
FAQ
P
P
MMSE
P
P
Dementia Assessment
P
P
ADAS-Cog
P
P
FCSRT-IR
P
P
C-SSRS
X
X
MRI
X2
*
X2
*
Refer to Table 8 footnotes.


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Table 8
Schedule of Assessments – Open-Label Extension Year 3 for all Participants
Visit by week #
108
112
116
120
124
128
132
136
140
144
148
152
OLE156/
FU/DO 5
Unsch.1
Dose Number
28
29
30
31
32
33
34
35
36
37
38
39
Physical Exam
X
X
Neurological Exam
X
X
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
X
X
ECG
X
X
Blood  Labs
X
X
Urine Pregnancy Test4
P
P
P
P
P
P
P
P
P
P
P
P
X
X
PK  plasma
P
X
X
ADA samples
P
X
X
CDR
P
X
X
FAQ
P
X
X
MMSE
P
X
X
Dementia Assessment
P
X
X
ADAS-Cog
P
X
X
FCSRT-IR
P
X
X
C-SSRS
X
X
X
MRI
X2
*
X2,3
*
X


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Table 8
Schedule of Assessments – Open-Label Extension Year 3 for all Participants (Cont.)
Note: Visit window:   +/- 7 days for dosing days; +/- 3 days for visits that are 1 week post-dose.
OLE Open-Label Extension; P prior to study drug administration: P-1 wk is within 1 week prior the first dose.
Eligibility for Part 3 should be confirmed during OLE pre-baseline, and MRI should be performed within 8 weeks and the results available before 
the first dosing visit in the OLE.  Additional assessments can be performed as per the investigator’s judgment.
MRI scans must be performed within a maximum of 20 days (ideally 1020 days) after dose administration and results made available and reviewed before the 
next scheduled dose. 
* The MRI result as determined by the central reader must be known before a subsequent dose can be given.
1 Any procedure or assessment may be performed at an unscheduled visit as required. 
2 Subjects will be asked if they experience CNS adverse events up to 1 week before each MRI is performed.
3 The results of the final MRI should be available before the final follow-up visit to allow review before the final visit (after the last dose for patients not 
continuing in Part 3 extension after 3 years).
4 Women who are of childbearing potential must have a urine pregnancy test done at the site prior to each dose.
5 Follow-up/drop-out visit to be performed 4 weeks after the last dose during the initial 152 weeks of treatment.


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Table 9
Schedule of Assessments – Open-Label Extension Years 4 and 5 for Participants Continuing 
Part 3 until July 2020
Visit by week #
156
160176
180
184204
208
212Onwards 
(Up to 236)
OLE/FU/DO 
5
Unsch. 1
Dose Number
40
4145
46
4752
53
54Onwards 
(Up to 60)
Physical Exam
P
P
X
X
Neurological Exam
P
P
X
X
Vital Signs
P
P
P
P
P
P
X
X
ECG
P
P
X
X
Blood  Labs
P
P
X
X
Urine Pregnancy Test4
P
P
P
P
P
P
X
X
PK  plasma
P
P
X
X
ADA samples
P
P
X
X
CDR
P
FAQ
P
MMSE
P
P
P
X
X
Dementia Assessment
P
ADAS-Cog
P
FCSRT-IR
P
C-SSRS
P
P
P
X
X
MRI
*
L2, 3
*
L2, 3
*
L2, 3
*
X


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Table 9
Schedule of Assessments – Open-Label Extension Years 4 and 5 for Participants Continuing Part 3 
until July 2020 (Cont.)
Note: Visit window:   +/- 7 days for dosing days.
L an MRI after the Last dose within the indicated interval;  OLEOpen-Label Extension; P prior to study drug administration and prior to 
the injections on the day of dosing.
The schedule of assessment outlines the maximum number of week visits and doses until July 2020 and serves as guidance.  The duration of 
Part 3 extension will vary for each subject dependent on when the subject begins the OLE.
MRI scans are scheduled at approximately 6-month intervals and is mandatory after the last study drug administration.  The time between the 
previous scan and the final study scan should not exceed 8 months.
An MRI must be performed within 20 days (ideally 1020 days) after dose administration and results made available and reviewed before the 
next scheduled dose.
* The MRI result as determined by the central reader must be known before a subsequent dosing visit and should be available before the OLE 
follow-up/drop-out visit to allow review before the final visit.
1 Any procedure or assessment may be performed at an unscheduled visit as required. 
2 Subjects will be asked if they experience CNS adverse events up to 1 week before each MRI is performed.
3 The results of the final MRI (after the last dose) should be available before the final follow-up visit to allow review before the final visit.
4.Women who are of childbearing potential must have a urine pregnancy test done at the site prior to each dose.
5 OLE follow-up/drop-out visit to be performed 4 weeks after the last dose in Years 4or 5 of Part 3.


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5.1
General Instructions by Study Phase
All subjects must sign and date the most current IRB/IEC-approved written informed 
consent before any study specific assessments or procedures are performed.  Recording 
of adverse events begins after the informed consent form is signed.   
In general, results of study assessments should be shared with the subject only if the 
result may require that some action related to safety be taken.  For example an abnormal 
MRI which means an unscheduled MRI will be done.  This is to minimize any 
expectation bias.
See also Section 4.5 on concomitant medication use during the study.
5.1.1
Assessors for Clinical Scales and Order of Assessments
As much as feasible, the CDR should be administered for a single subject by the same 
assessor throughout the study and that assessor should not perform the MMSE or 
ADAS-Cog.  However, if in exceptional circumstances only this assessor is available to 
perform these other scales, then the CDR must be performed first.  The CDR assessor 
must be involved in the dementia assessment (Section 5.2.8). 
The remaining assessments may be done by other site staff as long as they have been 
qualified, trained, and where necessary certified to perform the scale.  As much as 
possible for any one scale, the same assessor should be used throughout the study.
When done at the same visit, other than screening (see below) the order of the following 
cognitive assessments should be:  CDR first (the entire scale in full), FCSRT before the 
ADAS-cog, ADAS-cog before the MMSE, and then CANTAB.  The order should be 
FCSRT, ADAS-Cog, and then MMSE at visits where these are the only assessments.  
As they are informant based and not subject-based questionnaires, there is no restriction 
on the order of the FAQ and NPI-Q.  As a general rule, the test sequence should remain 
the same for a given subject as at baseline and testing should occur around the same time 
of day at each visit.
5.1.2
Screening Period
The screening period is up to 8 weeks.  The screening assessments are shown in the 
Schedule of Assessments in Table 1.  
It is recommended that the first screening tests done are the CDR, FCSRT-IR, and 
MMSE in any order.  If the subject doesn't qualify on the basis of these tests the subject 
may be re-screened again after at least 3 months have passed if recruitment for the study 
is still on-going (see inclusion criteria 13, 14, and 15).
As noted in exclusion criteria 20, 21, and 22, subjects may be re-screened after 
appropriate treatment if they were originally excluded for abnormal thyroid, B12, or 
HbA1C results.
Subjects can be re-screened if the protocol is amended such that they would satisfy the 
amended criteria and if recruitment for the study is still on-going.  In this case, all 
screening assessments must be repeated other than the LP/CSF testing if done previously 
for this study. 


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Subjects can be re-screened if there is a substantial change in the subject’s condition 
(e.g., a disallowed medication was stopped) and if recruitment for the study is still 
ongoing.
Other laboratory tests which would exclude the subject may be repeated once 
(as unscheduled labs) if it is suspected that the abnormal result is transient and likely to 
be normal at repeat.   
The remaining screening tests except the lumbar puncture and MRI (and PET scan if a 
PET substudy subject) should be done within 12 weeks of signing the informed consent 
(to allow adequate time for the remaining tests).  As soon as all these results are available 
and none exclude the subject from the trial, the CSF collection and MRI scan should be 
done.  If the subject has had a brain MRI within the last 6 months as part of the 
evaluation of cognitive impairment, and if the scan did not have any obvious findings that 
would exclude the subject from the study, the CSF results can be obtained before the 
screening MRI is done and the screening MRI should then be done only after it is known 
that the CSF results satisfy the selection criteria.  If no recent scan is available, then the 
MRI should be done first and the lumbar puncture done after it is known the MRI 
satisfies the selection criteria unless, in the opinion of the Investigator there is sufficient 
reason that the LP should be done prior to the MRI.
It may take several days to receive the results of the MRI or CSF, and 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.
For subjects in the PET substudy, all other screening results including those on MRI and 
CSF will need to be available before the PET.  In these cases the MRI appointment and 
LP should be scheduled to occur no more than 3 weeks after the beginning of the 
screening period.  This is to allow sufficient time for the PET scan to be done and 
evaluated before the end of the screening period.  In rare cases where an MRI needs to be 
repeated or any other unexpected delay due to logistical or technical reasons, this may 
necessitate extending the screening period by a few days.  Extending the screening period 
beyond 8 weeks should be in exceptional circumstances only and careful scheduling 
should remain a priority.
A Subject Eligibility Checklist documenting the investigator’s assessment of each 
screened subject with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the investigator.
A screen failure log must be maintained by the investigator.
5.1.3
Treatment Period during Part 1 of the Study (Including Day of 
First Dose)
See Section 6.4 regarding treatment assignment.
All baseline assessments must be done before the first dose of study medication is given.  


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Subjects will receive up to 26 SC drug administrations over the course of 2 years in 
Part 1 of the study with a 4-week interval between each dose.  On each dosing day, after 
all assessments indicated in the schedule of assessments to be done prior to dosing are 
completed, the gantenerumab or matching placebo will be administered SC at room 
temperature.  For the first 4 doses, subjects should be observed for a minimum of 2 hours 
after dosing.  For doses 5 and beyond, the subject may leave the study center soon after 
the injections if the subject appears to be tolerating the injections.  Rescue 
medications/equipment to treat anaphylactic/anaphylactoid reactions must be available at 
the site.  Subjects and study partners will be alerted to watch for signs of 
anaphylactic/anaphylactoid reactions and to contact the study center as soon as possible if 
any such signs are noted.
The schedule (Table 1, Table 2) shows visits after baseline by the number of weeks since 
the first dose.  It also shows when assessments should be done relative to the time of the 
injections.  Visits at which the subject receives study medication may take place within 
7 days of the exact date.  Visits that occur one week after a dose may take place 
3 days of the exact date.  However all visits should be scheduled as close as possible to 
the exact day.  It is preferred that all assessments for a visit be done on the same day, but 
if necessary, assessments may be done over more than one day.  Preferably, all clinical 
scales and CANTAB should be performed on the same day.
The investigator may choose to repeat the informed consent process if the subject has had 
appreciable cognitive decline during the study.
5.1.3.1
Procedures for New MRI Findings in Part 1 of the Study
In addition to any local reading as per local procedures and requirements, all MRIs 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 patient eligibility as well as for analysis, results from the 
central expert read 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.  For 
relevant new MRI findings (as defined in the MRI-C Charter), the Sponsor will rapidly 
notify the MRI-C, who will then be actively involved in the review and can furthermore 
make recommendations that can deviate from the protocol guidelines, as deemed 
necessary. The iDMC will also be informed about relevant new MRI findings (see 
Section 10).
As described below, MRI findings will be classified into one of three types:  
ARIA-Edema (ARIA-E), ARIA-Hemosiderin (ARIA-H), and non-ARIA.  If an MRI scan 
shows any new finding, the following action should be taken: 
1. The site will contact the subject and study partner as soon as possible to determine if 
there are any symptoms that may be related to the MRI finding.  If the subject has 
developed or develops symptoms, the subject should be seen before the next 
scheduled visit, and the symptoms should be reported in the electronic case report 
form (eCRF) (see Section 7.1.4, MRI Observations).
2. A 4-week follow-up MRI will be done. 


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Prior to the follow-up MRI,  the site should immediately inform the Sponsor if there are 
any new or worsening symptoms that may be related to the MRI findings.  
5.1.3.1.1
New ARIA-E Findings in Part 1 of the Study
If the MRI shows new ARIA-E findings, the investigator will take action as described 
above.  Treatment will be withheld and the subject will continue to attend the scheduled 
visits and will have a follow-up MRI approximately 4 weeks after the prior MRI.  MRIs 
will then be done approximately every 48 weeks (done as “unscheduled” if not 
associated with the current visit schedule) until the ARIA-E finding has resolved or has 
clearly decreased and stabilized (as per the central read) at which point treatment may be 
restarted at half the original dose level.  Treatment will still end at the time the final dose 
was originally scheduled to occur. 
If treatment is restarted, the MRI schedule returns to the frequency done at entry into the 
study.  That is, “reset” MRIs will be done after the second, fourth, sixth, ninth, etc., dose 
after dosing resumes.  However, because an MRI is required after the Week 104 visit, in 
some cases a “reset” MRI is not required after the Week 96 or Week 104 visits.  If a 
second ARIA-E finding occurs, treatment will be permanently discontinued.  
If possible, an LP (additional to those already specified) should be done near the time of 
identification of an ARIA-E finding to aid in understanding the mechanism of these 
findings.
5.1.3.1.2
New ARIA-H Findings (Microbleeds or Areas of 
Leptomeningeal Hemosiderosis) in Part 1 of the Study
Approximately 20% of MCI subjects will have one or more microbleeds on a standard 
1.5 Tesla T2* MRI [25].  Because microbleeds may develop spontaneously in prodromal 
AD subjects, it is reasonable to allow for the occurrence of occasional microbleeds 
without altering the treatment regimen.  The following describes the management of 
dosing in cases of new ARIA-H.
1)
If the cumulative number of new ARIA-H within the last 12 months is more than 
4, treatment must be immediately discontinued.  This is the case no matter what 
the dosing was over the prior 12-month period (e.g., full dose, half dose, dose 
held).
If the above is not met, dosing will be changed according to the following:
2)
If on a full dose and the cumulative number of new ARIA-H within the last 
12 months is more than 2, the dose will be halved.
3)
If on a half dose, treatment will be discontinued if the cumulative number of new 
ARIA-H is more than 2 within the shorter of the last 12 months or since the dose 
was halved.
These limits apply for both 1.5T and 3T magnets.
After any new ARIA-H findings
(microbleed or new area of leptomeningeal 
hemosiderosis), dosing can continue as long as the criteria for dose discontinuation is not 
met.  However, the dose due after the 4 week follow-up MRI should not be given until 


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the MRI result is known.  If criteria for dose alteration due to ARIA-H was not met, then 
no further action is needed after the 4 week follow-up MRI unless suggested by the 
MRI-C.
5.1.3.1.3
New Non-ARIA MRI Findings in Part 1 of the Study
In the case of new non-ARIA MRI findings (e.g., cases of ischemia, cerebral infarction, 
or other lesions) the MRI-C may propose further actions, if deemed appropriate 
(e.g., dose modification, additional MRI sequences, or recommendations for additional 
testing for diagnostic purposes).
5.1.4
Part 2 - Extension Period for Continued Double-Blind 
Treatment
Subjects who complete Part 1 of the study, up to and including the Week 104 visit, may 
continue to receive double-blind study medication during the optional Part 2 of the study 
after signing informed consent for the additional treatment.  
Subjects may receive up to 26 additional SC administrations of their originally 
randomized study drug over the course of 2 years with a 4-week interval between each 
dose.  On each dosing day, after all assessments indicated in the schedule of assessments 
to be done prior to dosing are completed, the gantenerumab or matching placebo will be 
administered SC at room temperature. 
The schedule Table 3 and Table 4) shows visits during Part 2 of the study by the number 
of weeks since the first dose.  It also shows when assessments should be done relative to 
the time of the injections.  Visits at which the subject receives study medication may take 
place within 7 days of the exact date.  However, all visits should be scheduled as close 
as possible to the exact day. It is preferred that all assessments for a visit be done on the 
same day, but if necessary, assessments may be done over more than 1 day.  Preferably, 
all clinical scales should be performed on the same day.
As noted in Section 5.1.4.3 below, dosing at certain visits during the extension may not 
require the subject to come to the study center.
The investigator may choose to repeat the informed consent process if the subject has had 
appreciable cognitive decline during the study.
5.1.4.1
Procedures to Follow for Subjects who reach the Week 104 
Visit prior to Approval of Amendment D
If a subject completes the Week 104 visit prior to approval of protocol amendment D, the 
subject may still continue in the optional Part 2 of the study once approval is received.
If Week 104 has been completed, and approval of amendment D is received prior to 
Week 112, the subject can be assessed and dosed as for the appropriate week (Week 108 
or 112) in Table 3.  In this case, the original visit schedule relative to baseline will be 
maintained as if the subject had not missed a dose and/or visit, as the case applies.  
If amendment D approval is not received by the time the subject completes the follow-up 
Week 112 visit in the main study, the subject may still receive extended treatment once 
approval is received.  In this case, the original visit schedule relative to baseline will be 


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maintained as if they had not missed a dose and/or visit, as the case applies.  However, 
the assessments for Week 104Ext must be performed with the exceptions of RCR plasma 
and RNA, LP/CSF (with plasma PK and matching serum sample), RCR CSF, CANTAB, 
and MRI (which were already performed at Week 104/FU1 visit.
5.1.4.2
Procedures to Follow for Subjects who reach the Week 104 or 
112 Visit without having made a Decision to Continue in Part 2 
of the Study
If the amendment has been approved and the decision to continue double-blind treatment 
is not taken at Week 104, the schedule in Table 1 should be followed.  If the decision is 
not made by the time of the Week 112 visit, the subject should have the final visit and 
must be discontinued from the study.  
5.1.4.3
Dosing during Part 2 of the Study
For sites and subjects where this is practical, visits that require only dosing, vital signs 
and C-SSRS assessments may be done at the subject’s residence conducted by 
appropriate site staff. 
5.1.4.4
Procedures for new MRI findings in Part 2 of the Study
The procedures are the same as for Part 1 except for the following:
The MRI-C is not required to review new MRI findings that are typical of ARIA.  The 
MRI-C will review findings where any of the following apply:
•
The finding is not a typical ARIA finding (e.g., ischemic lesion)
•
The subject has one or more new CNS adverse events which the investigator 
assesses as possibly related to the MRI finding 
•
Review by the Committee is requested by the central reading center, investigator, 
Sponsor, or iDMC 
5.1.5
Treatment-Free Follow-up
Subjects are considered to be on treatment until 4 weeks after the last dose.  All subjects
(including premature withdrawals) will be followed for 12 weeks and, optionally, 1 year 
(52 weeks) after the last dose.  These assessments (see Table 2 and Table 4 - FU1/DO1, 
FU2/DO2, and FU3/DO3 visits) should also be done if possible in case a subject 
prematurely withdraws consent for the study or is withdrawn early for other reasons.  
FU3/DO3 visit is optional for subjects who do not continue in the open-label extension 
and not needed for those entering Part 3, as all relevant assessments will be performed 
during Part 3 prebaseline and baseline (Table 5 and Table 6).  For subjects continuing in 
Part 3, treatment–free follow-up is estimated to last approximately between 12 and 
18 months, depending on the approval of study protocol WN25203G by local Competent 
Authorities (CAs).  During this period, unscheduled assessments may be performed at 
any time.
5.1.6
Part 3 – the Open-Label Extension
Subjects who received double-blind treatment and had at least one follow-up/drop-out 
visit will be eligible to enter Part 3 after signing an informed consent for the additional 
treatment with higher doses of gantenerumab.  Subjects who meet any of the criteria 


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outlined in Section 4.4 will not be eligible for Part 3.  Eligibility for Part 3 should be 
confirmed within 8 weeks prior to the first dose administered (see Table 5 and Table 6 ). 
APOE ε4 status will be communicated to subjects, and appropriate counseling will be 
offered.
Subjects may receive up to 39 SC administrations over the course of the 3-year 
open-label extension with a 4-week interval between each dose.  All subjects who 
complete 3 years of open-label treatment will be given the option of extending 
open-label treatment beyond the initial 3 years until July 2020  and may receive 
up to 21 additional administrations every 4 weeks during Years 4 and 5 (up to a 
maximum of an additional 19 months).  The final number of SC administrations 
will depend on when a subject enters Part 3 and receives the first dose of 
open-label gantenerumab.
On each dosing day, after all scheduled assessments to be done prior to dosing are 
completed, gantenerumab will be administered SC at room temperature. For the first 
4 doses, subjects should be observed for a minimum of 2 hours after dosing.  For 
doses 5 and beyond, subjects should be observed for a minimum of 1 hour after 
dosing (if the subject appears to be tolerating the injections).  Rescue 
medications and equipment to treat anaphylactic and anaphylactoid reactions 
must be available at the site or at the dosing location for home nursing visits.  
Subjects and study partners will be alerted to watch for signs of 
anaphylactic/anaphylactoid reactions and to contact the study center as soon as 
possible if any such signs are noted.
The schedule of assessments in Part 3 (Table 5, Table 6, Table 7, Table 8, and Table 9) 
displays when assessments should be done relative to the time of gantenerumab 
administration.  It includes separate schedules for Year 1 for APOE 4 carriers previously 
on placebo and 105 mg gantenerumab (Table 5) and for APOE 4 carriers previously on 
225 mg gantenerumab and for the non-carriers (Table 6).  All visits should be scheduled 
relative to the first dosing visit (“Day 1- baseline”) in the open-label extension, as close 
as possible to the exact day.  As in the Parts 1 and 2, all visits on which the subject 
receives study medication may take place within 7 days of the scheduled date.  It is 
preferred that all assessments for a visit are performed on the same day, but if necessary, 
assessments may be done over more than 1 day.  Preferably, all clinical scales should be 
performed on the same day.  For the PK analysis, it is important to capture date and time 
of dosing and PK sampling correctly.  In Part 3 for certain dosing visits, the subject 
may not be required to return to the study center.  At select sites and specified 
visits, study drug administration and limited safety assessments may be 
performed by home nursing staff.
The investigator may choose to repeat the informed consent process if the subject has had 
appreciable cognitive decline during the study.


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5.1.6.1
Procedures for new MRI findings in Part 3 of the Study
MRI scans in Part 3 will  be performed according to the schedule of assessments, prior to 
each increase in gantenerumab dose (Table 5 and Table 6) and then at regular intervals 
thereafter (Table 7, Table 8, and Table 9).  
All MRI scans will be read and reported by the central MRI reader in alignment with the 
processes from Parts 1 and 2 of the trial.  When the central reader identifies a new MRI 
finding, the study center medical staff and the Sponsor will be notified, and in the case of 
relevant new MRI findings (as defined in the MRI-C Charter), the Sponsor, in turn, 
notifies the MRI-C concurrently.  The MRI-C is actively involved in review and has the 
remit to make recommendations that may deviate from the protocol guidelines, as 
deemed necessary.  
MRI findings are classified as ARIA-E, ARIA-H, and non-ARIA.  Information about 
potential symptoms will be collected prospectively (i.e., the site will contact the subjects 
up to 1 week before each MRI to ask if they experience CNS adverse events, as described 
in Section 7.1.4).  
Management of MRI findings are presented in sections below. 


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5.1.6.1.3
New Non-ARIA MRI Findings
The MRI-C may be alerted in cases of new non-ARIA MRI findings (e.g., cases of
hematoma, large cerebral infarction, or other lesions), if the central reader or sponsor 
requests the committee to review the MRI.
5.2
Assessments and Procedures
5.2.1
CDR
The CDR is used to characterize six domains of cognitive and functional performance 
applicable to Alzheimer disease and related dementias:  Memory, Orientation, Judgment 
& Problem Solving, Community Affairs, Home & Hobbies, and Personal Care.  The 
necessary information to make each rating is obtained through a semi-structured 
interview of the subject and a reliable informant or collateral source (e.g., family 
member). 
 
Details 
of 
the 
CDR 
can 
be 
found 
at 
the 
website:  
http://www.biostat.wustl.edu/~adrc/cdrpgm/index.html.  The scale will not be 
administered beyond the initial 3 years of Part 3.
5.2.2
Functional Activities Questionnaire (FAQ)
The FAQ [26] is an informant-based assessment which presents a forced choice of 
4 levels of functioning for 10 activities of daily living (ADL).  The scale will not be 
administered beyond the initial 3 years of Part 3.
5.2.3
MMSE
The MMSE consists of a set of standardized questions to assess a subject’s mental status 
and identifies the individual’s general level of impairment [27].  The questions target 
5 areas; orientation, short term memory retention, attention, short term recall and 
language.  The MMSE is the only scale that will be collected beyond the initial 
3 years of Part 3.
5.2.4
Neuropsychiatric Inventory (NPI-Q)
The NPI-Q [28] was developed to assess a wide range of behaviors encountered in 
dementia patients, to provide a means of distinguishing severity of behavioral changes, 


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and to facilitate rapid behavioral assessment through the use of screening questions.  It is 
an informant-based instrument in which 10 behavioral domains are evaluated on a 3-point 
scale (mild, moderate, and severe).  The caregiver distress portion of the scale will not be 
used in this study.  The scale will not be administered during Part 3.
5.2.5
Alzheimer Disease Assessment Scale-Cognition (ADAS-Cog)
The modified version will be used which has 13 items.  The modified items are: addition 
of delayed word recall and number cancellation and use of only one trial for word 
recognition.  This is the version used in the ADNI protocol (http://www.adni-
info.org/Scientists/ADNIGrant/ADNIProtocol.aspx).  Equivalent alternate forms of the 
word recall and word recognition and number cancellation subtests will be used in 
successive test administrations.  The scale will not be administered beyond the 
initial 3 years of Part 3.
5.2.6
Free and Cued Selective Reminding Test (FCSRT-IR)
The version of FCSRT-IR to be used will use written words and immediate recall after 
each card with four words is completed [29].  The FCSRT-IR is a measure of memory 
under conditions that control attention and cognitive processing in order to obtain an 
assessment of memory unconfounded by normal age related changes in cognition.  
FCSRT-IR performance has been associated with preclinical and early dementia in 
several longitudinal epidemiological studies [30].  The scale will not be administered 
beyond the initial 3 years of Part 3.
5.2.7
Cambridge Neuropsychological Test Automated Battery
The CANTAB is a computerized assessment battery consisting of tests for 
neuropsychological 
function. 
 
Details 
of 
CANTAB 
can 
be 
found 
at: 
www.cantab.com/camcog/default.asp.  The tests selected for this study are listed in 
8.1.2.1 and additional information on the CANTAB can be found in Appendix 2.  The 
scale is administered during the first 2 years of double-blind treatment only.
5.2.8
Dementia Assessment
This is to assess if the subject has progressed to a diagnosis of dementia.  It should 
involve the assessor who completes the CDR and is done during the visit after reviewing 
the results of all scales done at that visit.  It is done even if the subject was judged to have 
dementia at a prior assessment.  In most cases, to meet criteria for dementia, worsening 
from baseline should be seen on one or more domains of the CDR, the FAQ and on 
cognition (as assessed by ADAS, MMSE, and during the first 2 years of treatment by 
CANTAB).  If dementia is judged to be present, an additional determination will be made 
as to whether it is considered to be dementia of the Alzheimer's type.  Dementia 
assessment will not be performed beyond the initial 3 years of Part 3.
5.2.9
Modified Hachinski Ischemia Scale
This is a simple clinical tool currently used for helping to differentiate different types of 
dementia (primary degenerative, vascular or multi-infarct, mixed type).


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5.2.10
MRI
The MRI should be performed using a 1.5 Tesla magnet.  In exceptional circumstances if 
a 1.5 T magnet is not available in reasonable proximity to the study center, a 3 T magnet 
may be used.  
MRI will be conducted for subject screening, for safety monitoring and to determine 
potential treatment effects on brain volume according to the Schedule of Assessments.
The screening MRI will be used to help in determining whether the exclusion criteria are 
met (e.g., number of microbleeds, presence of mass lesions, etc.).  MRI will be used 
during the course of this study to help assess safety such as the occurrence of microbleeds 
or signs potentially indicative of inflammation or vasogenic edema.  Additional 
unscheduled MRIs may be utilized to better understand relevant CNS-related AEs (such 
as increased confusion) or to follow a sign which emerged at a scheduled scan; contrast 
agent may be used in such a case of follow-up if administration of contrast agent is 
considered safe for the subject according to local standards.  MRIs done at screening, 
after the 12th and 26th dose in Part 1 of the study, and after the 39th and 52nd dose in 
Part 2, will be used for volumetric analysis.  In Part 3, MRIs performed before the first 
dose, after 13th, 26th, and 39th dose will be used for volumetric analysis.  The following 
MRI sequences will be acquired every time an MRI is scheduled:

3D T1 - weighted gradient echo scans

T2* - weighted gradient echo scans

T2 - weighted spin echo scans

T2 - weighted Fluid attenuated inversion recovery (FLAIR) scans

Diffusion weighted scans, if available
The MRI will take approximately 30 minutes to complete.
MRI should not be done unless at least 3 days have passed since a lumbar puncture.  
Further instructions regarding the MRI can be found in the separate MRI Manual.  Scans 
will be reviewed by a central MRI Core Lab and it will be the assessment of the data as 
done by the central reader that will be used in the analysis.
5.2.10.1
Healthy Volunteer MRI Scans for Site Qualification
MRI acquisition of phantoms provides some information regarding how the proposed 
sequences are standardized at a site as well as the resultant quality of scans.  However, 
this data is often not suitable enough to provide clarity on important aspects of the image 
quality for quantitative analysis of brain atrophy.  Such issues include tissue contrast, 
susceptibility artifacts, and the effects of motion on the quality of scans.  Thus as part of 
site qualification, 1 or 2 volunteers at each site should be recruited and scanned using the 
same machine and the same sequences to be used for the study before any subject is 
scanned in this study.  These volunteers must not have any contraindications for MRI 
scanning (evaluation as per local procedures at the imaging site), and they will not be 
enrolled in the study nor 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 scans acquired after certain events as follows:  Upon a major 
upgrade to the site’s scanner, 4 months without any subject scans occurring at a site, or 


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any other event deemed significant enough to affect image quality, additional scans with 
the same volunteer should be acquired.  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.
5.2.11
Pharmacokinetic [PK] Sampling
5.2.11.1
Plasma Gantenerumab
Blood samples will be collected to evaluate the pharmacokinetics of gantenerumab in 
plasma as noted in the Schedule of Assessments Table 1, Table 2, Table 3, and Table 4 in 
Parts 1 and 2.
Samples from patients receiving placebo will not be assessed in the first instance, but 
retained for subsequent analysis if appropriate.
In Part 3, the PK sampling schedule follows the separate titration schedules for the 
APOE 4 carriers and non-carriers during the first year (Table 5 and Table 6).  Collection 
of plasma samples for pharmacokinetics during Years 2 and 3 of Part 3 for all 
participants is outlined in Table 7 and Table 8, respectively.  The PK sampling 
schedule during Years 4 and 5 is outlined in Table 9.
Unused sample material may also be used for the purposes of current gantenerumab assay 
improvement. 
5.2.11.2
CSF Gantenerumab (Parts 1 and 2)
An aliquot of CSF collected by lumbar puncture as detailed in section 5.2.14.2  (Table 1, 
Table 2, Table 3, and Table 4) will be allocated for the measurement of gantenerumab 
concentration.
Samples from patients 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 gantenerumab assay 
improvement.
5.2.12
Anti-Drug Antibody Sampling
Blood samples will be collected to assess the possible development of ADAs in all 
subjects as noted in the Schedule of Assessments Table 1, Table 2, Table 3, and Table 4.  
The procedures for the collection, handling and shipping of PK and ADA samples are 
specified in the Sample Handling and Logistics Manual supplied to the site by the 
Sponsor.  The total volume of blood taken for PK and ADA assessments will be 
approximately 85 mL in Part 1 of the study and approximately 12 mL each year that the 
subject continues in Part 2.
In Part 1 of the study, analysis of samples will be limited initially to those collected at the 
Baseline (pre-dose), Dose 6 (Week 20) and Follow-up (Week 112) occasions. For 
subjects participating in Part 2, sample analysis will be limited initially to Baseline 


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(pre-dose), Dose 6 (Week 20), Dose 29 (Week 112), Dose 43 (Week 168), Dose 52 
(Week 204) and FU2 (Week 216).  
For subjects participating in Part 3, blood samples for ADA will be collected during the 
first year as indicated in Table 5 for the APOE 4 carriers and Table 6 for the non-APOE 
4 carriers.  Collection of blood samples for ADA during Years 2 and 3 of Part 3 for all 
participants is outlined in Table 7 and Table 8, respectively.  Collection of blood 
samples for ADA during Years 4 and 5 of Part 3 for all participants is outlined 
in Table 9.  The analysis of the remaining samples for Parts 1, 2, and 3 of the study may 
be requested for some individuals as appropriate, dependent on the initial results. 
Unused sample material may also be used for the purposes of current ADA assay 
improvement. 
5.2.13 
Clinical Genotyping 
During screening, a mandatory 3 mL whole blood sample will be taken for DNA 
extraction from every subject who has consented to participate in the study.  All subjects 
will be evaluated for ApoE 4 status and Fc receptor genotype.  Subjects will be 
assigned to study treatment based on ApoE 4 status.  Fc receptor genotype may play a 
role in PK and PD variability of antibody-based therapeutics and predict response/non 
response.  ApoE 4 status and Fc receptor genotype information will not be shared with 
the Investigator or the subject until the study is unblinded unless required by the relevant 
health authority or EC/IRB.  Data arising from these analyses will be subject to the same 
confidentiality as the rest of the study.  The procedures for the collection, handling and 
shipping of Clinical Genotyping samples are specified in the Laboratory Manual.  
The APOE ε4 genotype information will be communicated to subjects continuing in the 
open-label extension (Part 3), and appropriate counseling will be offered. 
5.2.14 
CSF and Plasma Biomarker Sampling (Parts 1 and 2) 
Samples will be collected from all subjects 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 Alzheimer’s Disease and related diseases. 
5.2.14.1 
Plasma Biomarkers Sampling 
Approximately 5 mL blood sample for biomarker analysis will be collected according to 
the Schedule of Assessments Table 1, Table 2, Table 3, and Table 4.  A total of 
4560 mL of plasma will be collected throughout the course of the study (30–35 mL in 
Part 1 and an additional 15 mL in Part 2).  These samples will be used for analysis of 
markers of amyloid deposition and clearance (e.g., Aβ1-40 and Aβ1-42, potentially 
-amyloid pyroglutamate).  The procedures for collection, handling and shipping of 
plasma biomarker samples are specified in the Sample Handling and Logistics Manual. 
5.2.14.2 
CSF Sampling 
CSF samples will be collected according to the Schedule of Assessments Table 1, 
Table 2, Table 3, and Table 4.  The lumbar puncture will be performed by an individual 


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who meets all local requirements and is proficient in the procedure.  Post lumbar 
puncture care will be done in accordance with local practice.  
CSF sampling will be done in the morning (between 8 AM and noon) to minimize 
potential diurnal variation of CSF parameters [31].  CSF and, in addition, matching blood 
samples (serum and plasma) will be taken at screening and Weeks 52, 104 (FU1 or 
104Ext), 156, 208/FU1, and/or drop-out visits (as applicable).  Serum samples may be 
used if required 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.  Plasma samples will be 
collected for pharmacokinetics.  Procedures for the processing of the CSF samples can be 
found in the Sample Handling and Logistics Manual. 
Approximately 12 mL of CSF will be collected at each timepoint.  The sample will be 
aliquoted on-site and used for:

Local lab testing for cell count (erythrocytes and leukocytes with differential)

Measuring the CSF gantenerumab levels (see Section 5.2.11.2), and biomarker 
analysis including A42, T-tau and P-tau, tentatively A40, and markers of 
inflammation.  This sample may also be used to support the development of 
biomarker assays for patient selection/stratification (i.e., Atau, P-tau). 
Normal ranges for CSF cell counts will be sent to the sponsor by the site for data entry. 
Unused CSF sample (up to 6 mL) will be kept for future Biomarker Research if the 
subject gives consent to RCR (see RCR CSF, below).  The procedures for handling and 
shipping of CSF samples for biomarker analyses are specified in the Sample Collection, 
Handling and Logistics Manual.
5.2.15
Roche Clinical Repository Specimen(s)
Specimens for dynamic (non-inherited) biomarker discovery and validation will be 
collected from consenting subjects in Parts 1 and 2. 
These specimens will be used for research purposes to identify dynamic biomarkers that 
are predictive of response to gantenerumab treatment (in terms of dose, safety, and 
tolerability) and will help to better understand the pathogenesis, course and outcome of 
Alzheimer’s Disease and related diseases.  They may also be used to support the 
development of biomarker and diagnostic assays. 
Three types of specimens will be collected: RCR CSF (samples remaining from the CSF 
analysis described in Section 5.2.14.2 above) RCR plasma, and RCR RNA. 
Analysis of plasma and CSF samples may include determination of markers of amyloid 
deposition and/or clearance, oxidative stress, neurodegeneration, inflammation, and other 
processes implicated in the pathogenesis of AD.  RNA samples may be tested using 
techniques such as high-density microarray profiling and/or quantitative RT-PCR to 
study the expression profile of genes known to be involved in AD, and any other 
differentially expressed genes relative to treatment or dose response. 


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Specimens for dynamic biomarker discovery will be single coded like any other clinical 
sample (labeled and tracked using the subject’s study identification number 
(see Section 17).
Specimens for genetic (inherited) biomarker discovery and validation will also be 
collected from consenting subjects (RCR DNA).  Theses samples may be used to explore 
the associations of variants of genes implicated in susceptibility and pathogenesis of AD, 
such as Clusterin and PICALM, and therapy response or adverse events.
The pharmacogenetic information gathered through the analysis of specimens in the RCR 
is hoped to improve subject outcome by predicting which subjects are more likely to 
respond to specific drug therapies, predicting which subjects are susceptible to 
developing adverse side effects and/or predicting which subjects are likely to progress to 
more severe disease states.  Such genetic samples collected for analysis of heritable DNA 
variations will be double coded: a new independent code will be added to the first code to 
increase confidentiality and data protection (see Section 17). 
The results of specimen analysis from the RCR will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for subjects in the future.
All RCR specimens will be destroyed no later than 15 years after the final lock of the 
respective clinical database unless regulatory authorities require that specimens be 
maintained for a longer period.  The specimens in the RCR will be made available for 
future biomarker research towards further understanding of treatment with gantenerumab, 
of Alzheimer’s Disease, related diseases and adverse events and for the development of 
potential associated diagnostic assays.  The implementation and use of the RCR 
specimens is governed by the Roche Clinical Repository policy to ensure the appropriate 
use of the RCR specimens.
5.2.15.1
Specimen Types [the following list is not exhaustive]
Plasma assays
Blood (one approximately 6.0 mL sample in EDTA) for plasma isolation will be obtained 
at various time points as shown in Table 1, Table 2, Table 3, and Table 4.  For sampling 
procedures, storage conditions and shipment instructions see study Sample Handling and 
Logistics Manual.
Blood Sample for RNA Expression Profiling
Blood for RNA isolation (two 2.5 mL samples collected in PAXgene vacutainers) will be 
collected from consenting patients at various time points according to the Schedule of 
Assessments Table 1, Table 2, Table 3, and Table 4.  Date of consent and specimen 
collection should be recorded on the associated RCR page of the eCRF.  For sampling 
procedures, storage conditions and shipment instructions see study Sample Handling and 
Logistics Manual. 


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Blood sample for genetic analysis (RCR DNA)
Blood (approximately 6 mL in K3 EDTA) for DNA isolation will be collected as shown 
in Table 1.  If, however, the RCR genetic blood sample is not collected during the 
scheduled visit, it may be collected at any time (after randomization) during the conduct 
of the clinical study.  See study Sample Handling and Logistics Manual for more details.
5.2.16
Safety
5.2.16.1
Physical Examination
A general physical examination will be carried out at the time points listed in the 
Schedule of Assessments (for Part 3, please refer to Table 5, Table 6, Table 7, Table 8, 
and Table 9).  Weight and height measurements will be done as part of the screening 
physical exam.
5.2.16.2
Neurological Examination
A neurological examination will be performed at time points listed in the Schedule of 
Assessments (for Part 3, please refer to Table 5, Table 6, Table 7, Table 8, and 
Table 9).
5.2.16.3
GDS
The Geriatric Depression Scale (short form) [32] is a self-report scale designed to 
identify symptoms of depression in the elderly.  The scale consists of 15 questions which 
are answered yes or no on the basis of how the subject felt over the past week.  Total 
scores of 05 are considered normal and scores of 615 are considered depressed.  The 
scale will not be administered in Part 3.
5.2.16.4
Vital Signs
Vital signs (systolic and diastolic blood pressure and pulse rate) will be measured after 
the subjects have been in a supine position for at least 5 minutes at time points listed in 
the Schedule of Assessments (for Part 3, please refer to Table 5, Table 6, Table 7, 
Table 8, and Table 9).
5.2.16.5
ECG
After 5 minutes in a supine position, 12-lead ECG single read will be performed at the 
time points indicated in the Schedule of Assessments (for Part 3, please refer to Table 5, 
Table 6, Table 7, Table 8, and Table 9).  Triplicate ECGs will be recorded at certain 
visits as indicated in the Schedule of Assessments during Parts 1 and 2 only.  Triplicates 
should be done 25 minutes apart (i.e., 3 readings within 10 minutes).  All ECGs will be 
recorded/digitized using a validated device.  All ECGs will be read by the central reader.  
The investigator or designee must review the outputs to ensure there are no clear alerts 
for quality or clinical issues and then sign, and date the outputs.


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5.2.16.6
Laboratory Assessments
Blood Chemistry: AST/SGOT, ALT/SGPT, alkaline phosphatase, total protein, total 
bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, 
BUN/urea and serum creatinine (and creatinine clearance calculated by central lab).  
During the screening period, Week 53, Week 101 or DO1 in Part 1, Week 204, or 
Ext DO1 in Part 2, and at all visits with scheduled blood chemistry in Part 3, HbA1C, 
folic acid, B12, thyroxine (T4), free T4, and thyroid-stimulating hormone levels will also 
be assessed. 
Hematology: hemoglobin, hematocrit, red blood cell (with morphology), white blood 
cell, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBC–other 
total counts.
Coagulation: prothrombin time (PT)
Urine for Drugs of Abuse:  at screening only, urine samples will be analyzed for the 
presence of the following drugs: amphetamine, benzodiazepines, cannabinoids, opiates, 
cocaine, barbiturates, and methadone.  Results will be used to verify subject eligibility 
pertaining to drug abuse.
Urinalysis: performed during Parts 1 and 2 only at the site by dipstick for blood, protein, 
glucose and pH.  Microscopic examination will be performed by the central lab if blood 
and/or protein results are positive or strong positive.
Urinalysis for Pregnancy: urine pregnancy testing will be performed at the site for 
women of childbearing potential, and at the site for any other female participants if 
required by local regulations.  Women who are of child-bearing potential must have a 
pregnancy test conducted at the site prior to each dose.
The total volume of blood taken for laboratory assessments will be approximately 130 to 
215 mL over the course of Part 1 of the study and an additional 3040 mL during each 
year of Part 2.  During Part 3, the total volume of blood taken at scheduled visits will be 
approximately 111 mL during the initial 3 years, and up 40 mL during Years 4 
and 5.
The procedures for the collection, handling and shipping of laboratory samples are
specified in the manual provided by the central laboratory.
5.2.16.7
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS (http://www.cssrs.columbia.edu) is an assessment tool used to assess the 
lifetime suicidality of a subject (C-SSRS 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/potential lethality.  The C-SSRS baseline will be collected at baseline and the 
C-SSRS since last visit will be collected at subsequent visits during Parts 1 and 2. 
The C-SSRS will be done at visits indicated in the Schedule of Assessments (for Part 3, 
please refer to Table 5, Table 6, Table 7, Table 8, and Table 9).  It will be completed by 
the clinician after interviewing the subject and also the study partner when in attendance 
at the visit. 


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6.
INVESTIGATIONAL MEDICINAL PRODUCT
6.1
Formulation, Packaging and Labeling
A 
 antibody-producing cell line was established 
 
by fermentation of a recombinant 
 cell line and subsequent purification of 
the antibody.  
 
 
 
 
  
The study drug must be stored according to the details on the product label.  RO4909832 
Drug Product should be stored at 28°C and protected from light.  Study drug packaging 
will be overseen by the Roche clinical trial supplies department and will bear labeling 
with identification required by law, the protocol number, drug identification, and dosage.
The packaging and labeling of the study medication will be in accordance with Roche 
standard and local regulations.
Upon arrival of investigational products at the site, site personnel should check them for 
damage and verify proper identity, quantity, integrity of seals and temperature conditions, 
and report any deviations or product complaints to the monitor upon discovery.
6.2
Dose and Schedule of IMP
For details on dosing schedule see Sections 5.1.2, 5.1.4, and 5.1.6.
6.2.1
Dose Modifications, Interruptions, and Delays
Strict adherence to the planned dose regimen is required.  However, a single missed dose 
may not automatically result in study withdrawal. If cognitive assessments were to have 
been done at a missed visit, these may be rescheduled to the next visit.
For details on dose modification due to MRI findings see Section 5.1.3.1.
6.3
Preparation and Administration of the IMP
6.3.1
Preparation and Administration of the IMP in Parts 1 and 2
Prior to administration, each vial of test drug or placebo needs to be reconstituted with 
Water for Injection using a sterile needle and syringe.  
 
DO NOT SHAKE AND DO NOT FREEZE VIAL CONTENTS.
 
  Vials will contain either gantenerumab or placebo depending on the dose to be 
delivered. 
 
 
If reconstitution of the product has taken place in controlled and aseptic conditions 
(including the use of a laminar flow hood), the solution can be stored for up to 24 hours 


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at 2°C8°C and 6 hours at ambient temperature.  Otherwise, the product should be used 
immediately (within 2 hours) after reconstitution.
The study medication will be administered as  SC injections in the abdominal area.  The 
SC injections are to be administered slowly 
 
 
Exposure of the study medication to direct sunlight in the vial or syringe should be 
avoided.
Parenteral Drug Products should be inspected visually for particulates prior to 
administration.  Partially used vials should NOT be re-used.
Other parenterally administered medications should not be mixed with the study drug. 
Personnel involved in reconstitution of and filling syringes with study medication must 
not be involved with subject care in the study nor communicate any observations made 
during the study drug preparation to any personnel involved in the care of the subject.  
Personnel who reconstitute and/or fill syringes may also give the injections but must 
observe the rules above for those involved in study drug preparation.
6.3.2
Preparation and Administration of the IMP in Part 3
Gantenerumab will be available in 2 drug product formulations during Part 3:
 
, containing 105 or 225 mg gantenerumab 
ready for SC administration
.
Gantenerumab doses of 105 and 225 mg will be administered SC
  
 
  The 1200-mg gantenerumab dose will be administered SC 
 
 
 
 
All formulations should be stored at 2C–8°C and protected from light.  The liquid 
formulation in 
 can be stored for up to 6 hours at ambient temperature.  If withdrawal 
from the vial (for the liquid formulation in vial) has taken place in controlled and aseptic 
conditions (including the use of a laminar flow hood), the solution can be stored for up to 
24 hours at 2C–8°C and 4 hours at ambient temperature once prepared; otherwise, the 
product should be used immediately after withdrawal from the vial.  All drug product 
solutions should be brought to room temperature prior to administration to minimize 
discomfort during the injection.
6.4
Randomization, Blinding, and Unblinding
Randomization will be performed centrally using an interactive system (IxRS).  After 
being screened, those subjects who meet all eligibility criteria will be randomly assigned, 
within each ApoE 4 genotype group (i.e., 04, 14, 24), to one of three treatment 
groups (gantenerumab 105 mg, gantenerumab 225 mg, or placebo).  The ratio will be 


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2 active to 1 placebo.  Within the 24 genotype all subjects receiving gantenerumab will 
receive 105 mg. Based on the ADNI data, it is expected that for the 04 and 14 
genotypes receiving gantenerumab, approximately 40% will receive 105 mg and 60% 
will receive 225 mg.  Except in circumstances where a health authority, EC or IRB 
requires the subject be told of his/her ApoE genotype, the individual patient ApoE 
genotype results will be blinded to the subjects, investigators, and the Sponsor, and will 
be supplied directly to the IxRS vendor by the testing lab so that the information can be 
incorporated at the time of randomization.
Randomization to treatment allocation will also be stratified by geographical region of 
the study center. 
Subjects participating in the PET substudy will also be allocated to a study treatment as 
described above to achieve the ratio 2 active to 1 placebo.
The study is conducted in a double-blind manner in order to minimize potential bias from 
investigators and subjects.  Except as described in Section 10, the Sponsor will be blinded 
to the study treatments (randomized and actually given).  Treatment allocation for 
patients who continue in the optional Part 2 of the study will continue to be 
double-blinded. 
The Master Randomization or Master Medication list will not be available at the study 
center, to the Roche monitors, 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 impact subject treatment.  The Investigator should make 
every effort to contact Roche before unblinding a patient’s treatment assignment, but 
must contact Roche within 1 working day of the event.  Any request from the investigator 
for information about the treatment administered to study subjects for another purpose 
must be discussed with Roche.
When required, unblinding will be performed by means of an Interactive Voice Response 
System (IVRS) or an equivalent method. 
As per regulatory reporting requirement, Roche will unblind the identity of the study 
medication for all unexpected serious adverse events that are considered by the 
Investigator to be related to study drug.  Details of subjects who are unblinded during the 
study will be included in the Clinical Study Report (CSR).
The password-protected and/or encrypted electronic Master Randomization or Master 
Medication List is kept by Clinical Supply in their secure system and is only accessible to 
the Randomization List Managers.  No open key to the code will be available at the study 
center, to the Roche monitors, project statisticians, or to the project team at Roche.
Unblinding for MRI-C, iDMC, and PK/PD analysis groups (which are independent from 
the project team) will be performed according to Roche standard procedures.
During the open label Part 3, gantenerumab treatment will be allocated by IxRS based on 
the titration schedule assigned for the APOE 4 carriers (i.e., 14 and 24) and 
non-carriers (04).


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6.5
Accountability of IMP and Assessment of Compliance
6.5.1
Accountability of IMP
The Investigator is responsible for the control of drugs under investigation.  Adequate 
records for the receipt (e.g., Drug Receipt Record) and disposition (e.g., Drug Dispensing
Log) of the study drug must be maintained.  Accountability will be assessed by maintaining 
adequate drug dispensing and return records. 
Accurate records must be kept for each study drug provided by the sponsor.  These 
records must contain the following: 

Documentation of drug shipments received from the Sponsor (date received and 
quantity)

Disposition of unused study drug not dispensed to subject
A Drug Dispensing Log must be kept current and should contain the following 
information:

The identification of the subject to whom the study medication was dispensed

The date[s], quantity of the study medication dispensed to the subject
All records and drug supplies must be available for inspection by the Monitor at every 
monitoring visit.
When the study is completed, the Investigator will return all empty, partially used, and 
unused containers of study drug to Roche unless site has received alternate authorization 
from Roche.  The completed Drug Dispensing Log and Drug Return Record(s) will be 
returned to Roche unless alternate destruction has been authorized by Roche or required 
by local or institutional regulations (Section 6.5.2).  The Investigator's copy of the Drug 
Return Record(s) must accurately document the return of all study drug supplies to 
Roche.
6.5.2
Assessment of Compliance
Subject compliance will be assessed by maintaining adequate study drug dispensing 
records.  The Investigator is responsible for ensuring that dosing is administered in 
compliance with the protocol.  Delegation of this task must be clearly documented and 
approved by the Investigator.
6.6
Destruction of the IMP/Comparator
Local or institutional regulations may require immediate destruction of used 
investigational medicinal product (IMP) for safety reasons.  In these cases, it may be 
acceptable for investigational site staff to destroy dispensed IMP before a monitoring 
inspection provided that source document verification is performed on the remaining 
inventory and reconciled against the documentation of quantity shipped, dispensed, 
returned and destroyed.  Written authorization must be obtained from the Sponsor at 
study start up before destruction.
If there are any issues with the drug it should be returned to the appropriate Roche 
clinical trial supplies department for long-term storage and not destroyed.


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Written documentation of destruction must contain the following:

Identity (batch numbers or participant identification numbers) of IMP and 
comparator destroyed

Quantity of IMP destroyed

Date of destruction

Method of destruction

Name and signature of responsible person who destroyed investigational products.
7.
SAFETY INSTRUCTIONS AND GUIDANCE
7.1
Adverse Events (AEs)
7.1.1
Clinical Adverse Events
According to the International Conference of Harmonization (ICH), an AE is any 
untoward medical occurrence in a subject or clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An AE 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 
[investigational] product, whether or not considered related to the medicinal 
[investigational] product.  

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition)

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)
A consistent methodology of non-directive questioning should be adopted for 
eliciting adverse event information at all patient 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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7.1.1.1
Intensity 
All clinical AEs encountered during the clinical study will be reported on the AE eCRF.  
Intensity of AEs will be graded on a three-point scale [mild, moderate, severe] and 
reported in detail on the AE eCRF.
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 7.1.1.3).
7.1.1.2
DrugAdverse Event Relationship (Assessment of Causality of 
Adverse Events)
Relationship of the AE to the treatment should always be assessed by the investigator. 
Investigators or their designees should use their knowledge of the patient, the 
circumstances surrounding the event, and an evaluation of any potential 
alternative causes to determine whether or not an adverse event is considered 
related to the study drug, indicating “yes” or “no” accordingly.
To ensure consistency of causality assessments, investigators should apply the following 
general guidelines:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where 
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 patient 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 
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Causal Attribution Guidance
Is the AE/SAE suspected to be caused by the investigational product based on facts, 
evidence, science-based rationales, and clinical judgment?
Yes
There is a plausible temporal relationship between the onset of the 
adverse event and administration of the study drug, and the adverse 
event cannot be readily explained by the patient's clinical state, 
intercurrent illness, or concomitant therapies; and/or the adverse event 
follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study 
drug or dose reduction and, if applicable, reappears upon re challenge.  
No
An adverse event will be considered related, unless it fulfills the 
criteria specified below.  
Evidence exists that the adverse event has an etiology other than the 
study drug (e.g., preexisting medical condition, underlying disease, 
intercurrent illness, or concomitant medication); and/or the adverse 
event has no plausible temporal relationship to administration of the 
study drug (e.g., cancer diagnosed 2 days after first dose of study 
drug).
7.1.1.3
Serious Adverse Events [Immediately Reportable to Sponsor]
A Serious Adverse Event is any AE that at any dose fulfils at least one of the following 
criteria:

is fatal; [results in death; NOTE: death is an outcome, not an event] 

is Life-Threatening [NOTE: the term "Life-Threatening" refers to an event in 
which the subject was at immediate risk of death at the time of the event; it does 
not refer to an event which could hypothetically have caused a death had it been 
more severe]

requires in-patient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal 
life functions)

is a congenital anomaly/birth defect born to a mother exposed to study drug

is medically significant in the investigator’s judgment (e.g., may jeopardize 
the patient or may require intervention to prevent one or other 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, see 
Section 7.1.1.1); 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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The study will comply with all local regulatory requirements and adhere to the full 
requirements of the ICH Guideline for Clinical Safety Data Management, Definitions and 
Standards for Expedited Reporting, Topic E2.
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 this section), 
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 for a pre-existing condition, provided that the following criterion
is 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 a disease present at baseline

The study subject has not suffered an adverse event
In centers where it is standard practice to hospitalize a subject for an LP for observation, 
this hospitalization itself would not be considered a serious adverse event.  If the 
hospitalization is extended due to an adverse event, this would be considered an SAE.
7.1.1.4
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 7.2.2 for reporting instructions).  Adverse events of special 
interest for this study are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT 
or AST in combination with either an elevated bilirubin or clinical 
jaundice, as defined by Hy's Law (see Section 7.1.2)

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 patient exposed to a 
medicinal product.  This term applies only when a contamination of 
the study drug is suspected.


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7.1.2
Laboratory Test Abnormalities
Laboratory test results will appear on electronically produced laboratory reports 
submitted directly from the central laboratory. 
Any laboratory result abnormality fulfilling the criteria for a serious adverse event should 
be reported as such on the AE eCRF.  Any treatment-emergent abnormal laboratory result 
which is clinically significant, i.e., meeting one or more of the following conditions, 
should be recorded as a single event on the AE eCRF:

Accompanied by clinical symptoms

Leading to a change in study medication [e.g., dose modification, interruption or 
permanent discontinuation]

Requiring a change in concomitant therapy [e.g., addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy or 
treatment].

Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) 

Is clinically significant in the investigator's judgment
This applies to any protocol and non-protocol specified safety and efficacy laboratory 
result from tests performed after signing of the informed consent, which falls outside the 
laboratory reference range and meets the clinical significance criteria.
It is the investigator's responsibility to review all laboratory findings.  Medical 
and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or 
syndrome (e.g., alkaline phosphatase and bilirubin 5 ULN associated with 
cholestasis), only the diagnosis (i.e., cholestasis) should be recorded on the 
Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or 
syndrome, the abnormality itself should be recorded on the Adverse Event eCRF, 
along with a descriptor indicating whether the test result is above or below the 
normal range (e.g., "elevated potassium," as opposed to "abnormal potassium").  
If the laboratory abnormality can be characterized by a precise clinical term per 
standard definitions, the clinical term should be recorded as the adverse event.  
For example, an elevated serum potassium level of 7.0 mEq/L should be recorded 
as "hyperkalemia." 
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 of 
special interest (Section 7.1.1.4) if the occurrence of either of the following:


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
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.
If a patient develops moderate to severe neutropenia (ANC 1000/mm3) in the absence 
of an identified cause, investigators should consider temporary discontinuation of the 
study drug.  Neutrophil counts should be monitored according to the local guidelines.  
Reintroduction of study drug could be done only after the investigator discusses the case 
with the Sponsor's Medical Monitor.
7.1.2.1
Follow-up of Abnormal Laboratory Test Values
In the event of medically significant unexplained abnormal laboratory test values, the 
tests should be repeated and followed up until they have returned to the normal range 
and/or an adequate explanation of the abnormality is found.  
Observations of the same clinically significant laboratory abnormality from visit 
to visit should only be recorded once on the Adverse Event eCRF.
7.1.3
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.
7.1.4
MRI Observations
Any treatment-emergent MRI observations, ARIA-E, and ARIA-H, as well as other 
clinically relevant findings that are clinically significant (i.e., meeting one or more 
of the following conditions) should be recorded as a single event on the AE eCRF:

Accompanied by clinical symptoms


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
Leading to a change
in study medication (e.g., dose modification, 
interruption or permanent discontinuation)

Requiring a change in concomitant therapy (e.g., addition of, interruption 
of, discontinuation of, or any other change in a concomitant medication, 
therapy or treatment)

Results in a medical intervention

Is clinically significant in the investigator’s judgment
All such MRI observations will also be compiled in a separate MRI report.  In addition, 
adverse events considered to be symptoms of ARIA will be marked as such in the eCRF.  
These events will be summarized separately in the CSR.  To further elucidate potential 
clinical implications of ARIA findings, patients will be asked within 1 week before each 
MRI, by non-directive, unbiased questioning, if they experience CNS adverse events.  
The adverse events collected in this prospective fashion will be distinct from other 
adverse events and summarized separately in the clinical study report.  Additional data on 
associated symptoms (as defined on the eCRF) and safety MRI scans will be collected for 
these adverse events.
7.1.5
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of any 
drug including 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 serious criteria, the event should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning 
of the event; see Section 7.1.1.3).
Any study drug overdose or incorrect administration of study drug should be 
noted on the Study Drug Administration eCRF.
7.1.6
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 7.1.1), regardless of relationship to study drug, must be recorded on 
the Adverse Event eCRF and immediately reported to the Sponsor (see 
Section 7.2.2).  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 


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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.
7.2
Handling of Safety Parameters
7.2.1
Reporting of Adverse Events
Collection of adverse events begins at the time the informed consent is signed and 
continues throughout the study, including the follow-up period.  All AEs will be recorded 
in detail on the source documents and on the AE eCRF for subjects who are randomized 
to study treatment.
7.2.2
Reporting of Serious Adverse Events and Adverse Events of 
Special Interest [Immediately Reportable]
For reports of serious adverse events and adverse events of special interest, 
investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours) 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, a paper Serious Adverse Event 
Reporting Form and fax cover sheet should be completed and faxed to Roche 
Safety Risk Management or its designee immediately (i.e., no more than 24 hours 
after learning of the event).  Once the EDC system is available, all information 
will need to be entered and submitted via the EDC system.
After informed consent has been obtained, but prior to initiation of study medication, 
only SAEs caused by a protocol-mandated intervention will be collected (e.g., SAEs 
related to MRIs or invasive procedures such as lumbar punctures).  After initiation of 
study drug, all adverse events, regardless of relationship to study drug, will be 
reported until the last visit.  After this period, the investigator should report any 
serious adverse events that are believed to be related to study drug treatment.
Related Serious Adverse Events MUST be collected and reported regardless of the time 
elapsed from the last study drug administration, even if the study has been closed.
Unrelated Serious Adverse Events must be collected during the study until the last 
study visit.
If the study is closed but a SAE occurs within required reporting period, the SAE 
worksheet is used to report the event to the sponsor.
This study adheres to the definition and reporting requirements of ICH Guideline for 
Clinical Safety Data Management, Definitions and Standards for Expedited Reporting, 
Topic E2.  Complete information can be found in Appendix 1.


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7.2.3
Reporting of Pregnancy
A female subject must be instructed to immediately inform the Investigator if she 
becomes pregnant during the study.  She will then be discontinued from study 
medication.  The Investigator should report all pregnancies within 24 hours to the 
Sponsor.  The Investigator should counsel the subject; discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus.  Monitoring of the subject 
should continue until conclusion of the pregnancy.  Pregnancies that occur up to 
16 weeks after the last dose of study medication must also be reported to the Investigator.
The site must report the pregnancy on the Pregnancy Report eCRF for randomized 
subjects.  If the study is closed but pregnancy occurs within required reporting period, the 
Pregnancy Report worksheet is used to report the event to the sponsor.
Any spontaneous abortion should be classified as a serious adverse event 
(because the Sponsor considers spontaneous abortions to be medically significant 
events), recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event).
Any congenital anomaly/birth defect in a child born to a female patient 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).
7.2.4
Reporting Requirements for Medical Device Complaints
The investigator must report all medical device complaints (e.g., devices for 
study drug administration) to the Sponsor.  The investigator should document as 
much information as possible on the IMP Deviation Form, including the product 
batch number, and forward the form to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event) (refer to the pharmacy manual for 
further details).  If the medical device results in an adverse event to the study 
patient, 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).
7.2.5
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees
Any treatment-emergent SAE deemed related to gantenerumab will be reported 
as a suspected unexpected serious adverse reaction (SUSAR) and will be reported 
to investigators at each site and associated Institutional Review Boards
(IRBs)/Ethics Committees (ECs).
The Sponsor will promptly evaluate all serious adverse events and adverse events 
of special interest against cumulative product experience to identify and 


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expeditiously communicate possible new safety findings to investigators, IRBs, 
ECs, and applicable health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor 
will assess the expectedness of the events using the Gantenerumab IB.
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 
Gantenerumab IB.
Reporting requirements will also be based on the investigator’s assessment of 
causality and seriousness, with allowance for upgrading by the Sponsor as 
needed.
7.2.6
Recording Adverse Events on the eCRF
Investigators should use correct medical terminology/concepts when recording AEs or 
SAEs on the AE eCRF.  Avoid colloquialisms and abbreviations.
Only one medical concept should be recorded in the event field on the AE eCRF.
In general, adverse events that are secondary to other events (e.g., cascade events 
or clinical sequelae) should be identified by their primary cause, with the 
exception of severe or serious secondary events.  A medically significant 
secondary adverse event that is separated in time from the initiating event 
should be recorded as an independent event on the Adverse Event eCRF.  For 
example:

If vomiting results in mild dehydration with no additional treatment in a 
healthy adult, only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should 
be reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it 
is unclear as to whether the events are associated.
A persistent adverse event is one that extends continuously, without resolution, 
between patient evaluation timepoints.  Such events should only be recorded once 
on the Adverse Event eCRF, unless the severity increases.  If a persistent adverse 
event becomes more severe, it should be recorded as a separate event on the 
Adverse Event eCRF.  The initial (less severe) adverse event report should be 


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updated to indicate that the event resolved on the date just prior to the day the 
event became more severe.  If a persistent adverse event becomes serious, it 
should be recorded as a separate event on the Adverse Event eCRF and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning that the 
event became serious; see Section 7.2.2 for reporting instructions).  The initial 
(non-serious) adverse event report should be updated to indicate that the event 
resolved on the date just prior to the day the event became serious.
A recurrent adverse event is one that resolves between patient evaluation 
timepoints and subsequently recurs.  Each recurrence of an adverse event should 
be recorded separately on the Adverse Event eCRF.
Individual signs and symptoms of injection-site reactions (e.g., erythema, 
pruritus, pain) should be reported on the dedicated Injection Site Reaction eCRF.  
The overall diagnosis of injection site reaction should be captured on the Adverse 
Event eCRF.  Systemic reactions should be recorded as a single diagnosis.
For adverse events other than injection-related reactions, 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.  Ifa 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
7.2.7
Follow-up of Patients after Adverse Events
7.2.7.1
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 
patient is lost to follow-up, or the patient 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 patient's medical record to 
facilitate source data verification.
All pregnancies reported during the study should be followed until pregnancy 
outcome.


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7.2.7.2
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.
7.3
Safety Plan
To date, ARIA findings and injection site reactions are the identified risks of 
gantenerumab. 
Detailed information about ARIA findings is provided in Section 1.3.3.  
 
  In case of 
clinical symptoms, the use of IV glucorticosteroids may be considered.
Concerning injection site reactions, gantenerumab is generally well tolerated by 
patients.  Injection-site reactions have been observed in up to one-third of 
healthy volunteers after SC administration (Section 1.1.2.2).  As of 13 February 
2018, injection site reactions have been reported in 25.3% and 29.8% of patients 
treated with gantenerumab in the OLE periods of Study WN25203 and Study 
WN28745, respectively.  All injection site reactions were non-serious, with the 
majority being mild and resolving without treatment.  Approximately 10% of 
patients who had injection site reactions required treatment, which included 
topical steroids and antihistamines.
No gantenerumab-related immunogenicity reactions of major clinical relevance 
have emerged to date.  Patients should be monitored for and alerted to the risk of 
any symptoms of hypersensitivity reactions.
Refer to the Gantenerumab IB for information about identified and potential 
risks.
8.
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN
The plans for the statistical analysis of the data recorded during Part 1, the first 
24 months of double-blind treatment are summarized below.  The plans for the analysis 
of the data recorded during Part 2, the extension are described in section 8.6.  The plans 
for the analysis of the data recorded during Part 3, the open-label extension are described 
in Section 8.7.
8.1
Primary and Secondary Study Endpoints 
8.1.1
Primary Efficacy Endpoint
Change from baseline in CDR-SOB score at Week 104.


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8.1.2
Secondary Efficacy Endpoints
8.1.2.1
Cognition – Change from Baseline at Week 104 in the 
Following

Alzheimer’s Disease Assessment Scale – Cognition (ADAS-Cog) total score

Mini Mental State Exam (MMSE) total score

CANTAB – selected subtest scores

Simple Reaction Time (RTI) 

Simple Movement Time (RTI) 

5- Choice Reaction Time (RTI) 

Delayed Match to Sample (DMS) 

Spatial Working Memory (SWM) 

Pattern Recognition Memory (PRM) immediate

Pattern Recognition Memory (PRM) delayed

Rapid Visual Information Processing (RVP)

Paired Associates Leaning (PAL)

FCSRT-IR
8.1.2.2
Global

CDR global score at Week 104
8.1.2.3
Functioning

FAQ total score change from baseline at Week 104
8.1.2.4
Neuropsychiatric Functioning

Neuropsychiatric Inventory (NPI-Q) –total and domain scores change from 
baseline at Week 104
8.1.2.5
Dementia Assessment

Time from baseline to development of dementia
8.1.2.6
MRI Volumetric Measures

Hippocampal volume change from baseline

Whole brain volume change from baseline

Ventricular enlargement change from baseline

Change from baseline in other volumetric measures such as cortical thickness 
8.1.2.7
Cerebrospinal Fluid Biomarker Measures

Change from baseline in CSF T-tau, P-tau, and A1-42 levels


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8.1.3
Safety

MRI safety findings: inflammation (such as that found on FLAIR sequences), 
microbleeds and other.

Adverse events

Physical and neurological examination

GDS

C-SSRS

Vital signs

ECG

Clinical laboratory results
8.1.4
Pharmacokinetics 

Cmax

Time to peak concentration (Tmax)

Trough plasma concentration at steady state (Cmin)

Area under the time-plasma concentration curve at steady state (AUC0-τ)
Other parameters determined from the pharmacokinetic model will be regarded as 
secondary.  Potential covariates for the model will be explored as appropriate.
8.1.5
Exploratory Endpoints
8.1.5.1
Plasma Biomarkers

Plasma A1-40 and A1-42 change from baseline
8.1.5.2
Genotype
The following information will be used to assess its impact on efficacy and safety:

ApoE genotype

FcR genotype
8.2
Statistical and Analytical Methods
All efficacy data in Part 1, up to week 104 will be evaluated in the following manner:

Each of the two gantenerumab dose groups (i.e., 105 mg or 225 mg) versus 
placebo.  The gantenerumab 225 mg group will include only subjects with the 
ApoE 04 and 14 types; therefore, for the primary comparison of the 
gantenerumab 225 mg group to placebo, the comparator group will include the 
subset of placebo subjects who have the ApoE 04 and 14 types.  For the 
primary comparison of the gantenerumab 105 mg group to placebo, the 
comparator group will be the entire set of subjects randomized to placebo.  The 
primary inferential statistics will be applied to the pairwise comparisons of each 
of the 2 gantenerumab dose groups to the corresponding placebo group.

All gantenerumab dose groups combined (i.e., 105 mg plus 225 mg) versus 
placebo for overall assessments regardless of the ApoE genotype.  All placebo 
subjects will be pooled. 
All analyses in Part 2 will be considered exploratory.


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8.2.1
Efficacy Data
8.2.1.1
Primary Efficacy Variable
For the assessment of differences between each gantenerumab group and placebo with 
regard to the mean change from baseline in the CDR SOB score at week 104, a 
mixed-effects MMRM analysis incorporating data up to 104 weeks of treatment will be 
used to utilize all the data collected over time with consideration of the variance-
covariance matrix of the repeated measures.  This method allows a general unstructured 
variance-covariance matrix and enables to include data from subjects with incomplete 
data across scheduled time points. 
The following null (H0) and alternative (Ha) hypotheses will be tested to compare the
mean change values between each of the gantenerumab groups and placebo group:
H0: MEANRO   =   MEANplacebo   versus 
Ha: MEANRO   ≠   MEANplacebo
where MEANRO and MEANplacebo refer to mean change of gantenerumab and placebo, 
respectively.
The model will include the change from baseline in the CDR–SOB score as the 
dependent variable.  The effects in the model will include independent variables of the 
fixed, categorical effects of treatment, assessment weeks relative to the first dose of study 
medication (i.e., time), and treatment-by-time interaction, and ApoE status (carrier vs. 
non-carrier), along with covariates of the baseline value and hippocampal volume at 
baseline.  Time will be treated as the repeated variable within a subject.  Subject, 
treatment, and time will be treated as class variables.  An unstructured 
variance-covariance structure will be applied to model the within-subject errors. 
As a sensitivity analysis for the primary efficacy variable, the MMRM model excluding 
the hippocampal volume at baseline covariate will also be run.  Sensitivity analyses will 
also be performed excluding the ApoE4 genotype carrier status as an additional fixed 
effect in the statistical model in order to assess the impact of this factor on the primary 
and selected secondary efficacy variables.
Sensitivity analyses to assess the impact of missing data on the primary efficacy endpoint 
results will be performed using multiple imputation and pattern-mixture method models.
Additional details will be provided in the Statistical Analysis Plan.
A treatment-by-time interaction contrast will be constructed to estimate the difference 
between each of the gantenerumab doses and placebo in mean change from baseline to 
week 104.  Based on the analysis above, least square means, standard errors, and the 
95% confidence intervals of treatment difference will be reported for each dose of 
gantenerumab against placebo.
In order to adjust for the multiplicity in the pairwise comparisons of each gantenerumab 
dose to placebo, a hierarchical testing procedure will be used.


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8.2.1.2
Secondary Efficacy Variables
Continuous Variables
The secondary efficacy variables of the continuous type with multiple post-baseline 
scheduled assessments will be analyzed using the same methods described above for the 
primary efficacy variable:  MMRM including the covariate of hippocampal volume at 
baseline. 
Time-to-Event Variable
The time-to-onset of dementia from baseline will be analyzed using an un-stratified log 
rank test.  The following hypothesis will be tested:
H0: There is no difference in the survival functions between the gantenerumab (RO) and 
placebo (pbo) group: 
         
SURRO = SURpbo,      where SUR denoted the distribution function.
Ha: there is a difference in the survival function between the gantenerumab (RO) and 
placebo (pbo) group: 
     
SURRO ≠ SURPBO,   where SUR denoted the distribution function.
In addition, a stratified log rank test of treatment difference will be performed as an 
exploratory analysis of this variable, using ApoE genotype status (carrier vs. non-carrier) 
as a stratification factor.  If the number of events observed in any treatment-by-genotype 
status cell is less than 2, then this exploratory analysis will not be performed.  Additional 
exploratory analyses will be performed as appropriate using clinically relevant covariates 
such as baseline biomarker variables.  For this variable, the principal analysis results will 
be those generated using the unstratified log-rank test.
When comparing time-to-event endpoints between treatment groups, it is important to 
assess whether there are systematic differences in the completeness and duration of 
follow-up.  Summaries of follow-up duration by treatment group will be provided for all 
subjects and for subjects who have not had an event yet.  The duration of follow-up will 
be calculated as the interval (days) from the first day of study treatment to the event or 
date last known to have not the event.  
8.2.2
Safety Data 
All safety variables will be summarized for each assessment time (including follow-up) 
using descriptive statistics.  Incidence of adverse events will be summarized by treatment 
group based on body systems and dictionary preferred terms.  Incidence of marked 
abnormal lab test results will be summarized.  All the GDS ratings, anti-drug antibody, 
lab tests, ECG, and vital signs will be summarized (e.g., mean, median, SD or frequency
of abnormalities) for each assessment time by treatment group. ECG data will also be 
analyzed to evaluate treatment effect on QT parameters as described in the FDA guidance 
document. 
All the safety data collected during the follow-up period (i.e., after discontinuation of 
study treatment) will be summarized separately from the data collected during the 
treatment period.


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Number (%) of subjects with MRI safety findings will be summarized at each scheduled 
visit by treatment and MRI safety finding types.  In addition, number (%) of subjects with 
MRI findings will be summarized by ApoE genotypes and MRI safety finding types.
8.2.3
Exploratory Analysis
The following 2 types of analyses will be performed to explore association of the 
treatment effect with the subject’s genotypes and biomarkers:

To assess influence of the ApoE and FCγR genotypes on the gantenerumab 
treatment effect, the primary efficacy variable and selected safety parameters will 
be summarized by each of the genotypes.  Inferential statistics may be applied in 
case the difference is clinically relevant.

To evaluate effect of gantenerumab treatment on changes in plasma A1-40 and 
A1-42 biomarkers; changes will be summarized for each treatment group, 
i.e., each dose of gantenerumab and placebo.  
8.2.4
Subgroup Analyses
The results of selected efficacy and safety variables will be summarized within subgroups 
using descriptive statistics.  Additional exploratory analyses of efficacy results may be 
performed using an MMRM model, with the subgroup, a treatment-by-subgroup 
interaction, and a subgroup-by-time interaction terms included along the independent 
effects described above.  Such exploratory analyses will be performed primarily in the 
case where the descriptive statistics results indicate substantial differences between the 
subgroups.
The following variables will be used to define the subgroups for these analyses:

Sex

Age

Race

ApoE status

FcR genotype

Region
8.3
Sample Size
The comparison of the gantenerumab 225 mg arm to the placebo arm will include 
primary efficacy results from the approximately 257 subjects randomized to 
gantenerumab 225 mg, and the approximately 213 ApoE 04 and 14 subjects 
randomized to placebo.  A total of 770 subjects will warrant at least 80% power in 
demonstrating an effect size of 0.35 (gantenerumab 225 mg vs. placebo) at the 
type I error level of p0.05 (2-sided).  In order to protect the overall type I error at the 
0.05 level, a hierarchical testing procedure will be used in which the first hypothesis to be 
tested will be the comparison of the gantenerumab 225 mg group to the corresponding 
placebo group.  The second test, comparing the gantenerumab 105 mg group to the 
placebo group, will be carried out only if the first test is statistically significant at the 
2-sided 0.05 level. 


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The power calculation was based on simulations of the MMRM analysis planned for 
analysis of the primary efficacy variable.  The following assumptions were included:

4 post-baseline assessment visits at Weeks 24, 52, 76, and 104.

Overall dropout rate of 30% at Week 104 for both placebo and active treatment 
group, incremental rates over the 104 week period.

Effect sizes of 0.35 (gantenerumab 225 mg vs. placebo) and 0.25 (gantenerumab 
105 mg vs. placebo) at Week 104 assuming increasing magnitude of treatment 
difference over the 104 weeks period. 

A correlation structure with stronger correlations for assessments that are adjacent 
in time and weaker between assessments that are further apart.

About 5% reduction in sample size with hippocampal volume at baseline as a 
covariate in the analysis.
The sample size was confirmed following a planned blinded evaluation of the variance in 
the change in the CDR-SOB at Week 76 (Section 10.2.2).
8.3.1
Analysis Populations
8.3.1.1
Safety Population
The safety population will consist of all subjects who have received any dose of study 
medication, whether withdrawn prematurely or not.  All safety data will be analyzed 
according to the medication actually taken.
8.3.1.2
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all subjects who received any dose of 
study treatment and had at least 1 post-baseline assessment of CDR SOB.  The ITT 
analysis will be done by randomized treatment. 
The ITT population will be the primary population for all analyses of primary and 
secondary efficacy variables as well as the imaging and biomarker and clinical efficacy 
variables.
8.3.1.3
Per-Protocol Population
The per-protocol (PP) population may be defined as a subset of the intent-to-treat 
population.  Definition of the PP population will be finalized before the clinical database 
closure and will be documented in the analysis plan.  The definition will include those 
who did not have any major protocol violations that affect efficacy evaluation.  For the 
PP population analysis, data will be analyzed according to the treatment actually taken.  
The primary efficacy variables will be analyzed including the PP population when there 
is a more than 10% difference in number of subjects between ITT and PP population.
8.4
Interim Analysis 
Two interim analyses will be performed, as described in Section 10.2. 
8.5
Other Analyses
8.5.1
Pharmacokinetic Analysis
Nonlinear mixed effects modeling will be used to analyze the dose-concentration-time 
data of gantenerumab.  Information from other studies in humans may be incorporated to 


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establish the pharmacokinetic model.  The selection of parameters and the derivation of 
individual measures of exposure, such as AUC0-τ, Cmax, and trough concentrations 
(Ctrough) will depend on the final pharmacokinetic model used for this analysis.  All 
pharmacokinetic parameters will be presented by listings and descriptive summary 
statistics including arithmetic mean (for AUC0-τ, Cmax, and Ctrough), median, range, 
standard deviation, and CV.  Results of this analysis will be reported separately. 
If appropriate, concentration-effect relationships may be explored and modeled post hoc 
for pharmacodynamic, efficacy or safety measures.
8.6
Analysis Considerations for Data Collected during Part 2, 
the Extension Period for Continued Double-Blind 
Treatment
All data collected during Part 2 the extension will be summarized using descriptive 
statistics as described above.  No formal hypothesis testing or inferential statistics will be 
performed for the data collected during this extension period.
All subjects included in the safety and ITT populations (as defined in Sections 8.3.1.1
and 8.3.1.2) who choose to continue double-blind treatment after dose 26 will be included 
in the respective analysis populations for the analysis of the extension period data.
For all analyses of efficacy data collected during Part 2, the extension period, a sensitivity 
analysis will be performed in which subjects who start symptomatic treatments for 
Alzheimer’s disease will be censored for purposes of analysis at the time at which the 
treatment is initiated.  Any efficacy assessments made after the start of such symptomatic 
treatments will be flagged as such in data listings. 
8.7
Analysis Considerations for Data Collected during Part 3 –
the Open-Label Extension
Statistical analyses will primarily focus on safety aspects during and after the up-titration 
phase in Part 3 of the trial.  In addition, it is planned that efficacy analyses will be 
conducted on cognitive and functional measures as well as biomarkers.  It is planned that 
efficacies will be calculated using both, the original, drug-naïve baseline as well as the 
baseline that gets available before start of Part 3.  Results of these analyses will be 
interpreted in an exploratory fashion.  The number of subjects enrolled in Part 3 
is 154.
9.
DATA COLLECTION, MANAGEMENT AND QUALITY ASSURANCE
The overall procedures for quality assurance of clinical study data are described in the 
Roche Standard Operational Procedures.
Electronic Case Report Forms are to be completed by the site using the Medidata Rave 
Electronic Data Capture (EDC) system.  Sites will transcribe data from source documents 
onto the eCRFs.  In no case is the eCRF to be considered as source data for this trial.  
Sites will receive training and help text for appropriate eCRF completion.  eCRFs will be 
electronically transmitted to Roche and should be handled in accordance with instructions 
from Roche.


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In the event of discrepant data, Roche will electronically request data clarification from 
the sites, which the sites will resolve electronically, in the EDC system.  Roche will 
produce an EDC Study Logic and Check Specification document that describes the data 
quality checking to be performed on the data in Rave.
Accurate and reliable data collection will be assured by verification and cross–check of 
the eCRFs against the Investigator’s source documents by the study monitor (source 
document verification), and the maintenance of a drug–dispensing log by the 
Investigator.
A comprehensive validation check program utilizing front-end checks in the eCRF and 
back-end checks in the Roche data base will verify the data and discrepancies will be 
generated accordingly.  These are transferred electronically to the eCRF at the site for 
resolution by the Investigator.
Throughout the study the study management team (SMT) will review data according to 
the SMT Integrated Data Review Plan.
9.1
Assignment of Preferred Terms and Original Terminology
For classification purposes, preferred terms will be assigned by the Sponsor to the 
original terms entered on the eCRF, using the most up-to-date version of the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology for adverse events and 
diseases and the Genentech Drug Dictionary for treatments and surgical and medical 
procedures.
10.
REVIEW OF RESULTS DURING THE CONDUCT OF THE STUDY
10.1
Review of Safety Data
The study will have 2 committees for the purpose of reviewing and recommending 
actions to be taken on the basis of safety data.  There will be an independent MRI-C as 
well as a separate iDMC.  Each committee is described briefly below and each will have 
a separate charter providing specifics on the operations of the committee, including how 
the treatment disclosures will be managed.
10.1.1
MRI Review Committee
The MRI-C will review any relevant new MRI findings identified by the MRI central 
reader and will provide guidance on the management of subjects, taking into account the 
guidelines in the protocol.  The committee may request that measures in addition to those 
in the protocol be undertaken (e.g., a repeat MRI earlier than 4 weeks).  The committee 
can also make recommendations to alter the protocol procedures for the management of 
subjects with MRI abnormalities as well as recommendations for amendments to the 
protocol.  During Parts 1 and 2, the committee reviewed MRI findings as described in 
Section 5.1.3 and 5.1.4.3, respectively.  In Part 3, the committee will review relevant 
MRI findings as defined in the MRI-C Charter.  
10.1.2
Independent Data Monitoring Committee
An external fully iDMC, composed of three physicians and one statistician, met 
periodically as specified in the Charter to review the safety and key efficacy results from 


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the double-blind treatment phase.  This committee was also provided with all new 
significant safety data events as they occurred, including relevant new MRI findings, and 
could have ad hoc meetings as necessary.  This committee could request the study to be 
amended or terminated based on their findings (see also Section 10.2.3 Futility Analysis). 
During the Part 3, the iDMC reviewed safety findings until the majority of 
subjects had reached the target dose.  Significant MRI findings during Part 3 
will continue to be reviewed by the IMC and by the MRI-C as documented in the 
MRI-C charter.  Any new relevant findings identified either through the IMC or 
MRI-C may be submitted to the Phase III studies (WN29922 and WN39658) 
iDMC.
10.2
Interim Analysis 
Two interim analyses, and one blinded sample size assessment, were planned.  The 
specifics of each analysis were documented prior to its conduct in the Statistical Analysis 
Plan.
10.2.1
Administrative Interim Analysis
The administrative interim analysis was conducted approximately when the Week 52 
visit for the 200th subject randomized was scheduled to occur.  The main purpose of this 
review was to assess whether preparations for an additional adequate and well-controlled 
study should begin.
The review included unblinded PET scan results, safety (including safety MRI), ADA, 
biomarkers and pharmacokinetics.  No efficacy data were included in this administrative 
interim analysis.
The type I error rate was not to be adjusted for this interim analysis as it is administrative 
(i.e., to gate the next steps of the development program).
The results will not be communicated to any of the study team members.  The interim 
analysis results will be evaluated by the independent data monitoring committee and by a
Roche review board that includes only senior Roche managers/scientists who are entirely 
separate from the study team.  The Roche review board will not communicate any of the 
interim analysis results to any Roche personnel involved in the conduct of 
Study WN25203.
10.2.2
Sample Size Adjustment
At the time of the administrative interim analysis, a blinded evaluation of the observed 
variability in the absolute change from baseline in CDR-SOB at Week 76 was also 
performed.  The analysis time point of Week 76 was selected for this analysis, as the 
number of subjects with available data at Week 104 would be insufficient to perform a 
meaningful analysis at this time.
Based on the data available at the time of the interim analysis, a point estimate and 
1-sided 80% confidence bound for the standard deviation of the absolute change from 
baseline in CDR-SOB at Week 76 was  calculated with the following assumption:  if 
these results indicate a value substantially higher than the assumed value for this standard 


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deviation that was used in the process of determining the sample size (for example, if the 
lower bound of the confidence interval exceeds the assumed standard deviation value of 
1.44), then the Sponsor will consider increasing the sample size of the study in order to 
maintain the desired power.  The increase in sample size resulting from this analysis 
would be no more than 190 subjects (i.e., an increase from 770 to no more than 
960 subjects), with the magnitude of the sample size increase depending on the number 
of subjects needed to maintain at least 80% power for the hypothesis testing of the 
primary endpoint.  Based on the results of this analysis, the sample size remained as 
originally calculated (770 subjects).
10.2.3
Futility Analysis
A futility interim analysis was performed approximately when 50% of the sample size 
was scheduled to complete the Week 104 visit.  This analysis was performed by the 
independent data coordinating center (iDCC) that generates the unblinded results 
reviewed by the iDMC on a regular basis, as described in Section 10.1.2.  The iDMC 
reviewed the unblinded results for the primary efficacy endpoint (absolute change from 
baseline in CDR-SOB at Week 104).  The analysis of the primary endpoint results at the 
time of this interim analysis indicated that the predictive probability of success for the 
trial is less than a pre-specified threshold, and the committee recommended that the trial 
could be terminated for futility. The iDMC communicated to the Roche Data Review 
Board only this recommendation (whether or not to either stop the study for futility); 
detailed results of the primary efficacy analysis were not shared with the Sponsor.  The 
Roche Data Review Board has accepted this recommendation, and the dosing was 
suspended on 19 December 2014.  
No adjustment for multiple comparisons was to be made to the α-level for this analysis, 
as the decision rules for the futility analysis will not allow for the opportunity to stop the 
study early for overwhelming efficacy.
The specifics of the analysis were documented prior to its conduct in an Interim Data 
Analysis Plan. 


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11.
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Crane-PK, Doody-RS Donepezil Treatment of Patients with MCI: A 48-Week 
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Cordonnier-C, van der Flier-WM, Sluimer-JD, Leys-D, Barkhof-F and Scheltens-
P.  Prevalence and severity of microbleeds in a memory clinic setting. Neurology 
2006;66;1356-1360.
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Pfeffer-RI, Kurosaki-TT, Harrah-CH, Jr., Chance-JM, Filos-S.  Measurement of 
Functional Activities of Older Adults in the Community.  J Gerontol. 1982 37(3): 
323-329.
27.
Folstein-ME, Folstein-SE & McHugh-PR. “Mini-mental State”. A practical 
Method for Grading the Cognitive State of Patients for the Clinician. J Psych Res 
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28.
Kaufer-DI, Cummings-JL, Ketchel-P, Smith-V, MacMillan-A, Shelley-T, Lopez-
OL, DeKosky-ST.  Validation of the NPI-Q, a Brief Clinical Form of the 
Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci. 2000; 12:233-239.
29.
Sarazin-M, Berr-C, DeRotrou-J, Fabrigoule-C, Pasquier-F, Legrain-S, Michel-B, 
Puel-M, Volteau-M, Touchon-J, Verny-M, Dubois-B. Amnestic Syndrome of the 
Medial Temp[oral Type Identifies Prodromal AD. Neurology, Nov 6, 2007, vol. 
69, p. 1859-1867.
30.
Grober-E, Buschke-H. Genuine memory deficits in dementia. Dev Neuropsychol. 
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Mulder-Cees,Nicolaas A. Verwey- Nicolaas A, van der Flier- Wiesje M., 
Bouwman- Femke H., Kok- Astrid, van Elk- Evert J., Scheltens- Philip, and 
Blankenstein- Marinus A. Amyloid-_(1– 42), Total Tau, and Phosphorylated Tau 
as Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease. 
Clinical Chemistry 2010, vol. 56, no. 2, p. 248–253.
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Sheikh-JI and Yesavage-JA. Geriatric Depression Scale (GDS): Recent evidence 
and Development of a shorter version.  Clinical Gerontology: A Guide to 
Assessment and Intervention 165-173, NY: The Haworth Press, 1986.
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Sperling-RA, Jack, Jr.-CR, Black-SE, Frosch-MP, Greenberg-SM, Hyman-BT, 
Scheltens-P, Carrillo-MC, Thies-W, Bednar-MM, Black-RS, Brashear-HR, 
Grundman-M, Siemers-ER, Feldman-HH, Schindler-RJ.  Amyloid-related 
imaging abnormalities in amyloid-modifying therapeutic trials: Recommendations 
from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimer’s 
& Dementia, July, 2011, vol. 7, p. 367-385.
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Albert-M, 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. 
Alzheimer’s & Dementia 2011 vol. 7 p. 270–279.
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De Meyer G, et al., Diagnosis-Independent Alzheimer Disease Biomarker 
Signature in Cognitively Normal Elderly People. Arch Neurol
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Hertze J, et al., Evaluation of CSF Biomarkers as Predictors of Alzheimer’s 
Disease: A Clinical Follow-Up Study of 4.7 Years. J Alzheimers Dis. 
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Mesterton J, et al., Cross sectional observational study on the societal costs of 
Alzheimer’s disease. Cur Alzheimer Res 2010;7:358–67.
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Neugroschl J and Sano M., Current treatment and recent clinical research in 
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Sevigny J., et al., Randomized, Double-Blind, Placebo-Controlled, Phase Ib Study 
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Hutmacher M, et al. Pharmacokinetic-Pharmacodynamic Modeling of Amyloid-
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PART II:
ETHICS AND GENERAL STUDY ADMINISTRATION
12.
ETHICAL ASPECTS
12.1
Local Regulations/Declaration of Helsinki
The Investigator will ensure that this study is conducted in full conformance with the 
principles of the “Declaration of Helsinki” or with the laws and regulations of the country 
in which the research is conducted, whichever affords the greater protection to the 
individual.  The study must fully adhere to the principles outlined in “Guideline for Good 
Clinical Practice” ICH Tripartite Guideline or with local law if it affords greater 
protection to the subject.  For studies conducted in the EU/EEA countries, the 
Investigator will ensure compliance with the EU Clinical Trial Directive [2001/20/EC].  
For studies conducted in the USA or under US IND, the Investigator will additionally 
ensure adherence to the basic principles of “Good Clinical Practice” as outlined in the 
current version of 21 Code of Federal Regulations, subchapter D, part 312, 
“Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human 
Subjects”, and part 56, “Institutional Review Boards”.
In other countries where a “Guideline for Good Clinical Practice” exists, Roche and the 
Investigators will strictly ensure adherence to the stated provisions.
12.2
Informed Consent 
12.2.1
Main Study Informed Consent
It is the responsibility of the Investigator, or a person designated by the Investigator 
[if acceptable by local regulations], to obtain signed informed consent from each subject 
prior to participating in this study after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study.
The Investigator or designee must also explain that the subjects are completely free to 
refuse to enter the study or to withdraw from it at any time, for any reason.  
The clinical database for this study includes an eCRF for documenting subject informed 
consent, and this must be completed appropriately.  If new safety information results in 
significant changes in the risk/benefit assessment, the consent form should be reviewed 
and updated if necessary.  All subjects (including those already being treated) should be 
informed of the new information, given a copy of the revised form and give their consent 
to continue in the study.
12.2.2
Written Informed Consent from the Study Partner
It is a requirement for this study that the subject has a study partner considered reliable by 
the Investigator to provide accurate information as to the subject's cognitive and 
functional abilities and who agrees to accompany the subject to clinic visits which require 
their input for scale completion.  Therefore separate study partner consent will be 
requested.
12.2.3
RCR Informed Consent
It is the responsibility of the Investigator, or a person designated by the Investigator 
(if acceptable under local regulations), to obtain written informed consent from each 


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individual who has consented to RCR sampling after adequate explanation of the aims, 
methods, objectives and potential hazards.  Subjects must receive an explanation that they 
are completely free to refuse to provide the RCR specimen(s) and may withdraw his/her 
sample at any time and for any reason during the 15 year storage period of the 
specimen(s).  The Informed Consent for an optional specimen donation will be 
incorporated as a specific section into the main Clinical Trial ICF.  A second, separate, 
specific signature consenting to specimen donation will be required to document the 
study participant’s agreement to provide an optional specimen; if the participant declines, 
he/she will check a “no” box in the appropriate section and not provide a second 
signature.
The clinical database for this study includes an eCRF for documenting subject informed 
consent to the RCR, and this must be completed appropriately.
12.2.4
Death or Loss of Competence of Participant who Has Donated 
a Specimen(s) That Is Stored in the RCR
In case of death or loss of competence, specimen and data will continue to be used as part 
of RCR research.
12.3
Independent Ethics Committee(IEC)/Institutional Review 
Board(IRB)
The protocol, informed consent and any accompanying material provided to the subject 
in the U.S. will be submitted by the Investigator to an IRB for review.  For EEA member 
states, the Sponsor will submit to the Competent Authority and IEC, the protocol and any 
accompanying material provided to the subject.  In both the U.S. and EEA member states, 
the accompanying material may include subject information sheets, descriptions of the 
study used to obtain Informed Consent and terms of any compensation given to the 
subject as well as advertisements for the trial.
An approval letter or certificate (specifying the protocol number and title) from the 
IEC/IRB must be obtained before study initiation by the Investigator specifying the date 
on which the committee met and granted the approval.  This applies whenever subsequent 
amendments/modifications are made to the protocol.
Any modifications made to the protocol, Informed Consent or material provided to the 
subject after receipt of the IEC/IRB approval must also be submitted by the Investigator 
in the U.S. and by the Sponsor in the EEA member states in accordance with local 
procedures and regulatory requirements.
When no local review board exists, the investigator is expected to submit the protocol to 
a regional committee.  If no regional committee exists, Roche will assist the Investigator 
in submitting the protocol to the European Ethics Review Committee.
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.  In the U.S. Roche submits an IND Annual Report to the FDA according to 
local regulatory requirements and timelines.


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Sampling for the RCR is contingent on review and approval for the exploratory 
biomarker assessments and written informed consent by an appropriate regulatory body 
(depending on the country where the study is performed) and a site’s Institutional Review 
Board (IRB)/Ethics Committee (EC). If a regulatory or site’s IRB/ EC does not approve 
the sampling for the exploratory assessments the section on biomarker sampling will not 
be applicable.
12.4
Role of the Science and Ethics Advisory Group (SEAG)
A Science and Ethics Advisory Group (SEAG), consisting of experts in the fields of 
biology, ethics, sociology, and law will advise Roche regarding the use of specimens 
stored in the RCR and on the scientific and ethical aspects of handling genetic 
information. The SEAG is independent of Roche.
13.
CONDITIONS FOR MODIFYING THE PROTOCOL
Requests from Investigators to modify the protocol to ongoing studies will be considered 
only by consultation between an appropriate representative of the Sponsor and the 
Investigator [Investigator representative[s].  Protocol modifications must be prepared by 
a representative of the Sponsor and initially reviewed by all relevant functions and 
approved by the Disease Area Chair.
All protocol modifications must be submitted to the appropriate Independent Ethics 
Committee or Institutional Review Board for information and approval in accordance with 
local requirements, and to Regulatory Agencies if required.  Approval must be obtained 
before any changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to trial subjects.
The investigator should document and explain any protocol deviations. 
The 
investigator should promptly report any deviations that might have an impact on 
patient safety and data integrity to the Sponsor and to the IRB/EC in accordance 
with established IRB/EC policies and procedures.  The Sponsor will review all 
protocol deviations and assess whether any represent a serious breach of Good 
Clinical Practice guidelines and require reporting to health authorities.  As per 
the Sponsor's standard operating procedures, prospective requests to deviate 
from the protocol, including requests to waive protocol eligibility criteria, are 
not allowed. 
14.
CONDITIONS FOR TERMINATING THE STUDY
Both the sponsor and the Investigator reserve the right to terminate the study at any time.  
Should this be necessary, both parties will arrange the procedures on an individual study 
basis after review and consultation. In terminating the study, Roche and the Investigator 
will assure that adequate consideration is given to the protection of the subjects’ interests.  
The appropriate IRB/EC and Regulatory Agencies should be informed accordingly.


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15.
STUDY DOCUMENTATION, ECRFS AND RECORD KEEPING
15.1
Investigator's Files / Retention of Documents
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified.  These 
documents should be classified into 2 different separate categories [1] Investigator's 
Study File, and [2] subject clinical source documents.
The Investigator's Study File will contain the protocol/amendments, and schedule of 
assessments, 
Independent 
Ethics 
Committee/Institutional 
Review 
Board 
and 
governmental approval with correspondence, sample Informed Consent, drug records, 
staff 
curriculum 
vitae 
and 
authorization 
forms 
and 
other 
appropriate 
documents/correspondence, etc.  In addition at the end of the study the Investigator will 
receive the subject data, which includes an audit trail containing a complete record of all 
changes to data, query resolution correspondence and reasons for changes, in human 
readable format on CD which also has to be kept with the Investigator’s Study File.
Subject clinical source documents may include subject hospital/clinic records, physician's 
and nurse's notes, appointment book, original laboratory reports, ECG, signed ICFs, 
consultant letters, and subject screening and enrollment logs. 
The Investigator must keep the 2 categories of documents as described above (including 
the archival CD) on file for at least 15 years after completion or discontinuation of the 
study.  After that period of time the documents may be destroyed, subject to local
regulations.
Should the Investigator wish to assign the study records to another party or move them to 
another location, Roche must be notified in advance.
If the Investigator cannot guarantee this archiving requirement at the investigational site 
for any or all of the documents, special arrangements must be made between the 
Investigator and Roche to store these in a sealed container[s] outside of the site so that 
they can be returned sealed to the Investigator in case of a regulatory audit.  Where 
source documents are required for the continued care of the subject, appropriate copies 
should be made for storing outside of the site.
ICH Good Clinical Practice guidelines require that Investigators maintain information in 
the study subject’s records which corroborate data collected on the eCRF(s).
15.2
Source Documents and Background Data
The Investigator shall supply the Sponsor on request with any required background data 
from the study documentation or clinic records.  This is particularly important when 
errors in data transcription are suspected.  In case of special problems and/or 
governmental queries or requests for audit inspections, it is also necessary to have access 
to the complete study records, provided that subject confidentiality is protected.
15.3
Audits and Inspections
The investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Roche Pharma Development 


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Quality Assurance Unit or its designees or to health authority inspectors after appropriate 
notification.  The verification of the eCRF data must be by direct inspection of source 
documents.
15.4
Electronic Case Report Forms
Data for this study will be captured via an EDC system. The data collected in the source 
documents is entered by the site onto the eCRFs.  An audit trail will maintain a record of 
initial entries and changes made; reasons for change; time and date of entry; and user 
name of person performing entry or change.
For each subject enrolled, the eCRFs should be reviewed and electronically signed and 
dated by the principal investigator or authorized delegate from the study staff.  This also 
applies to records for those subjects who fail to complete the study.  If a subject 
withdraws from the study, the reason must be noted on the eCRF.  If a subject is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome.
The Investigator should ensure the accuracy, completeness and timeliness of the data 
reported to the sponsor in the eCRFs and in all required reports.
15.5
Financial Disclosure
The Investigator(s) will provide the Sponsor with sufficient accurate financial 
information (PD35) to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. 
The 
investigator is responsible to promptly update any information provided to the Sponsor if 
relevant changes occur in the course of the investigation and for 1 year following the 
completion of the study (last subject, last visit).
16.
MONITORING THE STUDY
It is understood that the responsible Roche monitor [or designee] will contact and visit 
the Investigator regularly and will be allowed, on request, to inspect the various records 
of the trial [eCRFs and other pertinent data] provided that subject confidentiality is 
maintained in accord with local requirements.
It will be the monitor's responsibility to inspect the eCRFs at regular intervals throughout 
the study, to verify the adherence to the protocol and the completeness, consistency and 
accuracy of the data being entered on them.  The monitor must verify that the subject 
received the study drug assigned by the randomization center (by controlling the written 
confirmation of the randomization by IVRS).  The monitor should have access to all 
records needed to verify the entries on the eCRF.  The Investigator [or deputy] agrees to 
cooperate with the monitor to ensure that any problems detected in the course of these 
monitoring visits are resolved.
Roche Clinical Repository  specimens will at all times be tracked in a manner consistent 
with Good Clinical Practice, by a quality controlled, auditable and validated Laboratory 
Information Management System, to ensure compliance with data confidentiality as well 
as adherence to authorized use of specimens as specified in the study protocol and ICF, 
respectively.  Roche monitors and auditors will have direct access to appropriate parts of 


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records relating to subjects participating in this study for the purposes of verifying the 
data provided to Roche.  The site will permit monitoring, audits, Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) review, and regulatory inspections by 
providing direct access to source data and documents related to the RCR Research 
Project.
17.
CONFIDENTIALITY OF TRIAL DOCUMENTS AND SUBJECT 
RECORDS
The Investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties.  On eCRFs or other documents 
submitted to the Sponsor, subjects should not be identified by their names, but by an 
identification code.  The Investigator should keep a subject enrollment log showing 
codes, names and addresses.  The Investigator should maintain documents not for 
submission to Roche, e.g., subjects' written consent forms, in strict confidence.
Roche already maintains rigorous confidentiality standards for clinical studies by 
“coding” (i.e., assigning a unique patient identifier number at the Investigator site) all 
subjects enrolled in Roche clinical studies.  This means that subject names are not 
included in data sets that are transmitted to any Roche location. Given the sensitive 
nature of genetic data, Roche has implemented a number of additional processes to assure 
subject confidentiality.  All specimens taken for inherited genetic research that will be 
stored in the RCR (see 5.6.1) undergo a second level of “coding”. At Roche, the 
specimen is transferred to a new tube and labeled with a new random number.  This is 
referred to as “Double Coding (De-Identification)”.  Data generated following the use of 
these specimens and all clinical data transferred from the clinical database and considered 
relevant, will also be labeled with this same code.  The “linking key” between the 
participant’s identification number and this new independent code will be stored in a 
secure database system.  Access to the table linking the participant identification number 
to the specimen code will be strictly limited and monitored by audit trail.  Legitimate 
operational reasons for accessing the “linking key” will be documented in a standard 
operating procedure.  Access to the “linking key” for any other reason will require 
written approval from the Governance Committee responsible for the specimen(s).
18.
CLINICAL STUDY REPORT (CSR)
A CSR will be written and distributed to Health Authorities as required by applicable 
regulatory requirements.  To fulfil the requirement of the EU Directive No 75/318/EEC 
the CSR will be signed by a coordinating Investigator who will be designated at a later 
stage.
19.
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS
Roche will comply with the requirements for publication of study results.
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to Roche prior to 
submission.  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.


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In accordance with standard editorial and ethical practice, Roche 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 (ICMJE) authorship requirements.  Any formal 
publication of the study in which contribution of Roche personnel exceeded that of 
conventional monitoring will be considered as a joint publication by the investigator and 
the appropriate Roche personnel.
Data derived from RCR specimen analysis on individual subjects will not be provided to 
study Investigators, except where explicitly stipulated in a study protocol (e.g., if the 
result is an enrollment criterion).  Exceptions may be granted (e.g., if biomarker data 
would be linked to safety issues).  The aggregate results of any research conducted using 
RCR specimens will be available in accordance with the effective Roche policy on study 
data publication.
Any inventions and resulting patents, improvements and/or know- how originating from 
the use of the RCR will become and remain the exclusive and unburdened property of 
Roche, except where agreed otherwise. 


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Appendix 1
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2
A serious adverse event is any experience that suggests a significant hazard, 
contraindication, side effect or precaution.  It is any AE that at any dose fulfills at least 
one of the following criteria:
–
is fatal; [results in death] [NOTE: death is an outcome, not an event]
–
is Life-Threatening    [NOTE: the term “Life-Threatening” refers to an event in 
which the subject was at immediate risk of death at the time of the event; it does 
not refer to an event which could hypothetically have caused a death had it been 
more severe]
–
requires in-subject hospitalization or prolongation of existing hospitalization
–
results in persistent or significant disability/incapacity
–
is a congenital anomaly/birth defect
–
is medically significant or requires intervention to prevent one or other of the 
outcomes listed above.
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate in other situations, such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the subject or may require intervention to prevent one of the 
outcomes listed in the definitions above.  These situations should also usually be 
considered serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
An unexpected AE is one in which the nature or severity is not consistent with the 
applicable product information.
Causality is initially assessed by the Investigator.  For Serious Adverse Events, possible 
causes of the event is indicated by selecting one or more options.  (Check all that apply) 
–
Pre-existing/Underlying disease - specify 
–
Study treatment - specify the drug(s) related to the event
–
Other treatment (concomitant or previous) - specify
–
Protocol-related procedure
–
Other (e.g., accident, new or intercurrent illness) – specify


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Appendix 1
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2
[Cont.]
The term severe is a measure of intensity, thus a severe AE is not necessarily serious.  For 
example, nausea of several hours’ duration may be rated as severe, but may not be 
clinically serious.
A serious adverse event occurring during the study or which comes to the attention of the 
Investigator within 15 days after stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, whether considered treatment-related or not, must be 
reported.  In addition, a serious adverse event that occurs after this time, if considered 
related to test “drug”, should be reported.
Such preliminary reports will be followed by detailed descriptions later which will 
include copies of hospital case reports, autopsy reports and other documents when 
requested and applicable.
For serious adverse events, the following must be assessed and recorded on the AEs 
eform of the eCRF: intensity, relationship to test substance, action taken, and outcome to 
date.
The Investigator must notify the Ethics Review Committee/Institutional Review Board of 
a serious adverse event in writing as soon as is practical and in accordance with 
international and local laws and regulations.
ROCHE LOCAL COUNTRY CONTACT for SAEs: Local Monitor:
See attached Protocol Administrative and Contact Information & List of Investigators 
Form, [ gcp_for000227], for details of administrative and contact information.
ROCHE HEADQUARTERS CONTACT for SAEs and other medical emergencies: 
Clinical Operations/Clinical Science:
See attached Protocol Administrative and Contact Information & List of Investigators 
form, [gcp_for000227], for details of administrative and contact information.
24 HOUR MEDICAL COVERAGE:  
Identification of a contact for 24 Hour Medical Coverage is mandatory to be compliant 
with worldwide regulatory agencies and to ensure the safety of study subjects.
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 the Roche medical contact for this study and 
track all calls.  The Emergency Medical Call Center Help Desk will be manned 24 hours 
7 days a week.  Toll free numbers will be distributed to all Investigators running Roche 
Pharma Development clinical trials.  The Help Desk will be used for medical 
emergencies outside regular business hours, or when the regular Clinical Science 
Leader/Clinical Pharmacology Leader cannot be reached.


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Appendix 1
ICH Guidelines for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2 
[Cont.]
See the attached Protocol Administrative and Contact Information & List of Investigators 
form [gcp_for000227], for details of administrative, contact information, and Emergency 
Medical Call Center Help Desk toll-free numbers.  


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Appendix 2
CANTAB – Descriptions of tests used in this study
Motor Screening Test (MOT)
The Motor Screening test is a training procedure designed to introduce the subject to the 
computer and touch screen.  It should always be given at the beginning of a session. 
It simultaneously screens for difficulties with vision, movement and comprehension and 
ascertains that the subject can follow simple instructions.
A series of crosses is shown in different locations on the screen.  The rater demonstrates 
with the first 3 crosses, the correct way to point using the forefinger of their dominant 
hand, then the subject must touch the next set of crosses in turn.
Test duration:  approximately 3 minutes
Reaction Time (RTI)
Reaction Time (RTI) is a latency task with a comparative history (the 5 choice task) and 
uses a procedure to separate response latency from movement time.  It is more useful 
than CRT or SRT where it is necessary to control for tremor.
The task is divided into 5 stages, which require increasingly complex chains of responses.  
In each case, the subject must react as soon as a yellow dot appears.  In some stages the 
dot may appear in 1 of 5 locations, and the subject must sometimes respond by using the 
press-pad, sometimes by touching the screen, and sometimes both.
The four outcome measures in RTI are divided into reaction time (simple and 5-choice) 
and movement time (simple and five-choice).
Test duration:  approximately 5 minutes
Pattern Recognition Memory ([PRM] Immediate and Delayed)
This is a test of visual pattern recognition memory in a 2-choice forced discrimination 
paradigm.  The subject is presented with a series of 12 visual patterns, one at a time, in 
the center of the screen.  These patterns are designed so that they cannot easily be given 
verbal labels.  In the recognition phase, the subject is required to choose between a 
pattern they have already seen and a novel pattern.  In this phase, the test patterns are 
presented in the reverse order to the original order of presentation.  This is then repeated, 
with 12 new patterns.  The second recognition phase can be given either immediately or 
after a 20 minute delay.
Test duration:  approximately 5 minutes
Delayed Match to Sample (DMS)
DMS is a test of simultaneous and delayed matching to sample.  This test is primarily 
sensitive to damage in the medial temporal lobe area, with some input from the frontal 
lobes.
The subject is shown a complex visual pattern (the sample) and then, after a brief delay, 
4 patterns.  Each pattern is made up of 4 sub-elements, each of a different colour. 


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CANTAB – Descriptions of tests used in this study (Cont.)
The subject is instructed to touch the pattern that matches the sample.  In some trials the 
sample and the choice patterns are shown simultaneously, whereas in others a delay (of 0, 
4, or 12 seconds) is introduced between covering the sample pattern and showing the 
choice patterns.  If the first choice is incorrect, the subject must make a second choice, 
and so on, until a correct choice is made.
Test duration:  approximately 7 minutes
Spatial Working Memory (SWM)
This is a test of the subject’s ability to retain spatial information and to manipulate 
remembered items in working memory.  This test is a sensitive measure of frontal lobe 
and executive dysfunction.
The test begins with a number of coloured squares (boxes) being shown on the screen. 
The subject must touch each box in turn until one opens with a blue token.  When a blue 
token has been found, the subject has to place it in the black column (‘home’) by 
touching the right-hand side of the screen.  The subject must then begin a new search for 
the next blue token.  It may be in any of the boxes that so far have been empty.  This is 
repeated, until a blue token has been found in every box on the current screen.  Touching 
any box in which a blue token has already been found is an error.  The test consists of 
stages which increase in difficulty according to the number of boxes that must be opened. 
Test duration:  approximately 8 minutes
Rapid Visual Information Processing (RVP)
This test is sensitive to dysfunction in the parietal and frontal lobe areas of the brain and 
is also a sensitive measure of general performance.
RVP is a test of visual sustained attention.  A white box appears in the centre of the 
computer screen, inside which digits, from 2 to 9, appear in a pseudo-random order, at 
the rate of 100 digits per minute.  The test is in 2 parts; a ‘warm-up’ practice stage which 
lasts for 2 minutes and is not scored, and a test stage which lasts for 7 minutes.
Subjects are requested to detect target sequences of digits (for example, 2-4-6, 3-5-7, 
4-6-8) and to register responses by touching the screen. 
Test duration:  approximately 9 minutes
Paired Associates Learning (PAL)
The PAL test assesses visual memory and new learning.  This test is primarily sensitive 
to changes in medial temporal lobe functioning.
Boxes are displayed on the screen.  All are opened in a randomised order.  One or more 
of them will contain a pattern.  The patterns shown in the boxes are then displayed in the 
middle of the screen, one at a time, and the subject must touch the box where the pattern 
was originally located.


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CANTAB – Descriptions of tests used in this study (Cont.)
The test consists of stages which increase in difficulty during the test as more patterns are 
hidden in the boxes.  If an error is made the patterns are re-presented to remind the 
subject of their locations.  At each stage the subject may have up to 6 attempts in total 
(the first presentation of all the shapes, then up to 5 repeat presentations).  When the 
subject gets all the locations correct, they proceed to the next stage.  If the subject cannot 
complete a stage correctly, the test terminates.
Test duration:  approximately 10 minutes


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SAP_001.pdf: 
 
Official Title: 
 
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel- 
Group Two Year Study to Evaluate the Effect of Subcutaneous 
RO4909832 on Cognition and Function in Prodromal Alzheimer's 
Disease With Option for up to an Additional Two Years of Treatment 
and an Open-Label Extension With Active Study Treatment 
NCT Number: NCT01224106 
Document Date: Statistical Analysis Plan Version 1: 18-November-2014  
Statistical Analysis Plan Version H: 13-November-2020 
 
 
 


Name
Reason for Signing
Date and Time
(UTC)
18-Nov-2014 15:07:51
Company Signatory
STATISTICAL ANALYSIS PLAN APPROVAL 
 
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 WN25203 
STATISTICAL ANALYSIS PLAN 
TITLE: 
MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP TWO YEAR 
STUDY TO EVALUATE THE EFFECT OF SUBCUTANEOUS 
RO4909832 ON COGNITION AND FUNCTION IN 
PRODROMAL ALZHEIMER’S DISEASE WITH OPTION FOR 
AN ADDITIONAL TWO YEARS OF TREATMENT 
PROTOCOL NUMBER: 
WN25203 
STUDY DRUG: 
Gantenerumab (RO4909832) 
VERSION NUMBER: 
1 
IND NUMBER: 
102266 
EUDRACT NUMBER: 
2010-019895-66 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
, Ph.D. 
DATE FINAL: 
See electronic date stamp below. 


 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Protocol Synopsis.................................................................... 5 
2.2 
Outcome Measures ................................................................. 5 
2.2.1 
Primary Efficacy Outcome Measure ........................................ 5 
2.2.2 
Secondary Efficacy Outcome Measures.................................. 6 
2.2.2.1 
Alzheimer’s Disease Assessment Scale–
Cognition ................................................................................. 6 
2.2.2.2 
Mini Mental State Exam Total Score ....................................... 6 
2.2.2.3 
Cambridge Neuropsychological Test Automated 
Battery, Selected Subset Scores............................................. 6 
2.2.2.4 
Clinical Dementia Rating−Global Score................................... 7 
2.2.2.5 
Functional Activities Questionnaire.......................................... 8 
2.2.2.6 
Neuropsychiatric Inventory−Questionnaire.............................. 8 
2.2.2.7 
Dementia Assessment............................................................. 8 
2.2.2.8 
Free and Cued Selective Reminding 
Test−Immediate Recall............................................................ 8 
2.2.2.9 
Magnetic Resonance Imaging Volumetric 
Measures................................................................................. 8 
2.2.3 
Exploratory Efficacy Outcome Measures................................. 8 
2.2.4 
Pharmacokinetic Outcome Measures...................................... 8 
2.2.5 
Safety Outcome Measures ...................................................... 9 
2.3 
Determination of Sample Size ................................................. 9 
2.3.1 
Blinded Sample Size Assessment ......................................... 10 
2.4 
Analysis Timing ..................................................................... 10 
3. 
STUDY CONDUCT..................................................................................... 10 
3.1 
Randomization....................................................................... 10 
3.2 
Data Monitoring ..................................................................... 11 
4. 
STATISTICAL METHODS .......................................................................... 11 
4.1 
Analysis Populations ............................................................. 11 
4.1.1 
Intent-to-Treat Population...................................................... 11 
4.1.2 
ECG-Evaluable Population.................................................... 11 
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4.1.3 
Safety Population .................................................................. 12 
4.2 
Analysis of Study Conduct..................................................... 12 
4.2.1 
Disposition of Subjects .......................................................... 12 
4.3 
Analysis of Treatment Group Comparability .......................... 12 
4.3.1 
Demographic Data and Baseline Characteristics .................. 12 
4.3.2 
Medical Events ...................................................................... 13 
4.4 
Efficacy Analysis.................................................................... 13 
4.4.1 
Primary Efficacy Endpoint...................................................... 13 
4.4.2 
Statistical Models and Methods of Primary 
Outcome Analysis.................................................................. 13 
4.4.3 
Secondary Efficacy Endpoints............................................... 15 
4.4.3.1 
Key Secondary Efficacy Endpoint.......................................... 15 
4.4.3.2 
Cognition ............................................................................... 15 
4.4.3.3 
Global .................................................................................... 16 
4.4.3.4 
Functioning............................................................................ 16 
4.4.3.5 
Neuropsychiatric Functioning ................................................ 16 
4.4.3.6 
MRI Volumetric Measures ..................................................... 16 
4.4.4 
Statistical Models and Methods of Secondary 
Efficacy Analyses .................................................................. 16 
4.4.5 
Sensitivity Analyses............................................................... 17 
4.4.6 
Subgroup Analyses ............................................................... 17 
4.5 
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 18 
4.6 
Safety Analyses..................................................................... 18 
4.6.1 
Exposure of Study Medication............................................... 19 
4.6.2 
Adverse Events ..................................................................... 19 
4.6.3 
MRI Safety Findings and Injection-Site Reactions................. 20 
4.6.4 
Laboratory Data..................................................................... 21 
4.6.5 
Vital Signs.............................................................................. 21 
4.6.6 
Electrocardiograms................................................................ 21 
4.6.7 
Deaths ................................................................................... 22 
4.7 
Missing Data.......................................................................... 23 
4.8 
Interim Analyses .................................................................... 23 
5. 
REFERENCES ........................................................................................... 25 
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LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 26 
Appendix 2 
Schedules of Assessments......................................................... 30 
Appendix 3 
Alzheimer’s Disease Assessment Scale–Cognition.................... 35 
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1. 
BACKGROUND 
This document describes the statistical methodology to be applied to the data that will be 
reported in the Clinical Study Report (CSR) for Study WN25203.  Study WN25203 was 
originally designed as a proof-of-efficacy trial with safety data review to be performed by 
an internal safety monitoring committee.  On the basis of feedback from European 
Medicines Agency/Committee for Medicinal Products for Human Use and U.S. Food and 
Drug Administration, the study has been modified to an adequate and well-controlled 
study to support the marketing registration of gantenerumab.  The efficacy and safety 
endpoints that will be the basis for treatment comparison of 225 mg and 105 mg 
gantenerumab with placebo will be fully defined in this document along with the subject 
populations to be included in the analyses. 
Although it is anticipated that there will be reporting of study data in a variety of contexts 
beyond that of the CSR, such as to the independent Data Monitoring Committee (iDMC), 
this document will not cover those contexts. 
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. 
2. 
STUDY DESIGN 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedules of 
Assessments in Appendix 2. 
2.2 
OUTCOME MEASURES 
2.2.1 
Primary Efficacy Outcome Measure 
The primary outcome measure is the change from baseline in the Clinical Dementia 
Rating−Sum of Boxes (CDR-SOB) score at Week 104. 
The CDR is obtained through semi-structured interviews of subjects and informants.  
The cognitive functioning is rated in six domains:  memory, orientation, judgment and 
problem solving, community affairs, home and hobbies, and personal care.  Each 
domain is rated on a 5-point scale of functioning as follows:  0, no impairment; 0.5, 
questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe 
impairment (personal care is scored on a 4-point scale, without a 0.5 rating available). 
The CDR-SOB score is obtained by summing the scores for each of the domain box; 
thus, the CDR-SOB score for a subject has a range of 0−18. 
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2.2.2 
Secondary Efficacy Outcome Measures 
The change from baseline at Week 104 will be assessed for the following secondary 
outcome measures. 
2.2.2.1 
Alzheimer’s Disease Assessment Scale–Cognition 
The Alzheimer’s Disease Assessment Scale-cognition (ADAS-Cog) with 11-item total 
score and its modified version with 13-item total score are used in the study.  The item 
scores are derived per description in Appendix 3.  The 13-item total score is calculated 
using the sum of all the 13-item scores, whereas the 11-item total score is calculated 
using the sum of all-item scores except Item 4 (delayed word recall task) and Item 13 
(number cancellation).  If any item score is missing or is invalid, the total score will be set 
to missing.  The 13-item ADAS-Cog total score has a range of 0−85, whereas the 
11-item ADAS-Cog total score has a range of 0−70.  Higher scores indicate greater 
pathology. 
2.2.2.2 
Mini Mental State Exam Total Score 
The Mini Mental State Exam (MMSE) comprises 11 items to assess a subject’s mental 
status and identifies the individual’s general level of impairment in five areas:  
orientation, short-term memory retention, attention, short-term recall, and language.  The 
total score is calculated by summing the scores of all 11 items; the maximum total score 
is 30. 
2.2.2.3 
Cambridge Neuropsychological Test Automated Battery, 
Selected Subset Scores 
The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a 
computerized assessment battery that consists of tests for neuropsychological function.  
CANTAB is evaluated by Cambridge Cognition Ltd independent of this study.  The 
following tests were selected for this study and will be summarized descriptively: 
• 
Simple reaction time (SRT):  the duration between the onset of the stimulus and the 
time when a subject released the button in correct, assessed trials in which the 
stimulus could appear in one location only 
• 
Simple movement time (SMT):  the length of time to touch the stimulus after the 
button has been released, calculated in correct, assessed trials in which the 
stimulus could appear in one location only 
• 
Five-choice reaction time (RTI):  the duration between the onset of the stimulus and 
the release of the button, calculated in correct, assessed trials in which the stimulus 
could appear in any one of five locations 
• 
Delayed match to sample (DMS) latency (the subject’s speed of response):  the 
numbers of correct patterns selected and statistical analysis measuring the 
probability of an error after a correct or incorrect response 
• 
Spatial working memory (SWM):  the ability to remember the location in which 
something is perceived and in addition, the ability to recall a series of visited 
locations 
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• 
Pattern recognition memory (PRM) immediate:  a test of visual pattern recognition 
memory in a two-choice forced discrimination paradigm 
• 
PRM delayed:  a test of visual pattern recognition memory in a two-choice forced 
discrimination paradigm 
• 
Rapid visual information processing (RVP):  a signal-detection measure of 
sensitivity to the target, regardless of response tendency (expected range is 
0.000−1.000 [bad to good]) 
• 
Paired associates learning (PAL):  the errors made by the subject, the number of 
trials required to locate the pattern(s) correctly, memory scores, and stages 
completed 
 
2.2.2.4 
Clinical Dementia Rating−Global Score 
The CDR global score is calculated on the basis of Washington University’s CDR 
assignment algorithm.  Investigators enter scores from each of the six categories (“box 
scores”), and the CDR global score is calculated using a calculator available at 
http://www.biostat.wustl.edu/~adrc/cdrpgm/index.html.  The global scores are recorded 
on the electronic Case Report Form (eCRF) by investigators and are the basis of 
analyses of CDR global scores in this study. 
The global CDR score is derived from the scores in each of the six categories (“box 
scores”) and is determined as follows (Memory [M] is considered the primary category, 
and all others are secondary): 
• 
CDR = M if at least three secondary categories are given the same scores as 
memory. 
• 
CDR = score of majority of secondary categories with at least three secondary 
categories given a score greater or less than the memory score on one side of M, 
except in the case of CDR = M (see the subsequent point). 
• 
CDR = M when three secondary categories are scored on one side of M and two 
secondary categories are scored on the other side of M. 
• 
If M = 0.5, then CDR cannot be 0 and it can only be 0.5 or 1; CDR = 1 if at least three 
of the other categories are scored ≥ 1. 
• 
If M = 0, then CDR = 0; if there are impairments (≥ 0.5) in two or more secondary 
categories, then CDR = 0.5. 
• 
When there are ties in the secondary categories on one side of M, the chosen tied 
score for CDR is the closest score to M (e.g., If M and another secondary 
category = 3, two secondary categories = 2, and two secondary categories = 1, then 
CDR = 2). 
• 
When only one or two secondary categories are given the same score as M, then 
CDR = M as long as no more than two secondary categories are on either side of M. 
• 
When M ≥ 1, then CDR cannot be 0; in such a circumstance, CDR = 0.5 when the 
majority of secondary categories are 0. 
 
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2.2.2.5 
Functional Activities Questionnaire 
The Functional Activities Questionnaire (FAQ) is an informant-based assessment that 
presents a forced choice of four levels of functioning for ten activities of daily living.  
Total scores for FAQ will be summarized. 
2.2.2.6 
Neuropsychiatric Inventory−Questionnaire 
The Neuropsychiatric Inventory−Questionnaire (NPI-Q) is an informant-based instrument 
in which 10 behavioral domains are evaluated on a 3-point scale (mild, moderate, or 
severe).  The caregiver’s distress portion of the scale will not be used in this study. 
2.2.2.7 
Dementia Assessment 
Time to dementia is defined as the time interval between the first treatment date and the 
date that subject is assessed as having Alzheimer-type dementia by investigators. 
2.2.2.8 
Free and Cued Selective Reminding Test−Immediate Recall 
The version of the Free and Cued Selective Reminding Test−Immediate Recall 
(FCSRT-IR) uses written words and immediate recall after each card with four words 
completed.  The FCSRT-IR is a measure of memory under conditions that control 
attention and cognitive processing in order to obtain an assessment of memory not 
confounded by normal age-related changes in cognition.  The performance of the 
FCSRT-IR has been associated with nonclinical and early dementia in several 
longitudinal epidemiologic studies. 
2.2.2.9 
Magnetic Resonance Imaging Volumetric Measures 
The change in hippocampal volume from baseline will be calculated.  The change in 
whole-brain volume from baseline and the change in ventricular volume from baseline 
will be assessed.  Change from baseline in other volumetric measures such as cortical 
thickness may be assessed.  The assessment details are available in the magnetic 
resonance imaging (MRI) Charter. 
2.2.3 
Exploratory Efficacy Outcome Measures 
The following parameters will be recorded and analyzed: 
• 
Change from baseline in plasma amyloid-beta (Aβ)1−40 and Aβ1−42 levels 
• 
Change from baseline in cerebrospinal fluid (CSF) T-tau, P-tau, and Aβ1−42 levels 
 
2.2.4 
Pharmacokinetic Outcome Measures 
The following pharmacokinetic (PK) outcome measures will be assessed: 
• 
Peak plasma concentration at steady state (Cmax) 
• 
Time to peak concentration 
• 
Trough plasma concentration at steady state 
• 
Area under the time-plasma concentration curve at steady state (AUC0−τ) 
 
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Other parameters derived from the PK model will be regarded as secondary parameters.  
Potential covariates for the model will be explored as appropriate. 
2.2.5 
Safety Outcome Measures 
MRI safety findings such as amyloid-related imaging abnormalities (ARIA) of the 
microhemorrhage (ARIA-H) and effusive or edematous (ARIA-E) and any other findings 
are: 
• 
Adverse events (AEs) 
• 
Physical and neurologic examination findings 
• 
Geriatric Depression Scale 
• 
Columbia-Suicide Severity Rating Scale 
 
2.3 
DETERMINATION OF SAMPLE SIZE 
A total of 770 subjects (257 for each gantenerumab dose group and 256 for the placebo 
group) were planned to be randomized in a 2:1 ratio to receive either gantenerumab 
(high or low dose, depending on Apolipoprotein E [ApoE] genotype groups) or placebo.  
The power calculation was based on simulations of the mixed-effects model repeated 
measures (MMRM) analysis planned for analysis of the primary outcome variable.  The 
following assumptions were included: 
• 
80% power in demonstrating an effect size of 0.35 (225 mg of gantenerumab vs. 
placebo) 
• 
Overall Type I error at the 0.05 level 
• 
Four post-baseline assessment visits at Weeks 24, 52, 76, and 104 
• 
Overall dropout rate of 30% at Week 104 for both the placebo and active treatment 
groups, incremental rates over the 104-week period 
• 
Effect sizes of 0.35 (225 mg of gantenerumab vs. placebo) and 0.25 (105 mg of 
gantenerumab vs. placebo) at Week 104, with the assumption of increasing 
magnitude of the treatment difference over the 104-week period 
• 
A correlation structure with stronger correlations for assessments that are adjacent 
in time and weaker between assessments that are further apart 
• 
Approximately 5% reductions in sample size with hippocampal volume at baseline 
as a covariate in the analysis 
 
In order to protect the overall Type I error at the 0.05 significance level, a hierarchical 
testing procedure will be used in which the first hypothesis to be tested will be the 
comparison of the 225-mg gantenerumab group with the corresponding placebo group. 
The second test, which compares the 105-mg gantenerumab group to the placebo 
group, will be carried out only if the first test is statistically significant at the two-sided 
0.05 level. 
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2.3.1 
Blinded Sample Size Assessment 
A blinded assessment of the variance of the absolute change from baseline in CDR-SOB 
at Months 6, 12, 18, and 24 will be conducted in order to assess whether the assumed 
SDs of this variable at these timepoints are appropriate.  The sample size and power 
considerations for the study were developed on the basis of simulations of an MMRM 
analysis with use of absolute change from baseline in CDR-SOB values at these 
scheduled timepoints.  The assumed SD values of these CDR-SOB values used in these 
simulations (estimated on the basis of the Alzheimer Disease Neuroimaging Initiative-1 
database) are 0.96 at Month 6, 1.20 at Month 12, 1.44 at Month 18, and 2.00 at 
Month 24. 
A blinded sample size assessment was conducted approximately 6 months prior to the 
completion of recruitment of the planned sample size of 770 subjects.  At that time, the 
observed SD of the absolute change from baseline in CDR-SOB at each timepoint was 
calculated.  This calculation was done on a completely blinded basis, with no results 
generated by treatment group.  The observed SDs at these timepoints did not differ 
substantially from the assumptions described above.  As a consequence, no sample size 
adjustment was made to ensure at least 80% power of the study.  
2.4 
ANALYSIS TIMING 
The final analysis will be performed after all randomized subjects have been treated for 
at least 2 years. 
Safety data and selected efficacy data are being reviewed approximately once every 
3−4 months by the iDMC. 
An administrative interim analysis was conducted in June 2013 to assess whether 
preparations for an additional adequate and well-controlled study should begin.  For this 
interim analysis, the review included unblinded results for positron emission tomography 
(PET) scan, safety, anti-drug antibody (ADA), biomarkers, and pharmacokinetics.  
Details of this administrative interim analysis are documented in a separate interim 
Statistical Analysis Plan. 
A 2-level futility interim analysis will be performed when approximately 50% of the 
sample size is scheduled to complete the Week 104 visit.  Further details of the futility 
analysis are provided in Section 4.8. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION 
Randomization was performed centrally with use of an interactive system (interactive 
voice/Web response system).  The randomization ratio was 2 active (gantenerumab 
105 mg, gantenerumab 225 mg) to 1 placebo.  Within the 2ε4 genotype, all subjects 
randomized to gantenerumab are receiving 105 mg.  A dynamic randomization scheme 
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was applied.  The algorithm for dynamic patient allocation to treatment was based on 
minimization with biased coin assignment (Pocock and Simon 1975).  The randomization 
was stratified by PET substudy participation, ApoE4 genotype (0ε4 vs. 1ε4 vs. 2ε4), and 
region (Europe vs. rest of world). 
3.2 
DATA MONITORING 
An external iDMC was created to review the safety and selected efficacy data once 
every 3 months, starting in mid-July 2012.  The iDMC Charter describes the roles of the 
iDMC and the frequency and conduct of the planned review meetings in detail. 
4. 
STATISTICAL METHODS 
Details about the statistical models for the various types of endpoints (continuous, 
categorical, and time-to-event endpoints) are provided in Section 4.4.2. 
In the following sections, for all continuous variables for which descriptive statistics are 
indicated, the following statistics will be reported:  the number of observations, including 
the mean, median, SD, and minimum and maximum.  The 25th and 75th percentiles (Q1 
and Q3) will also be reported for selected outputs. 
4.1 
ANALYSIS POPULATIONS 
4.1.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all subjects who have received any dose 
of study treatment and had at least one post-baseline assessment of CDR-SOB.  The 
ITT analysis will be performed by randomized treatment. 
The ITT population will be the primary population for all analyses of primary and 
secondary outcome variables as well as for the imaging and biomarker and clinical 
efficacy variables. 
4.1.2 
ECG-Evaluable Population 
The ECG-evaluable analysis population will consist of subjects who meet all of the 
following criteria: 
• 
Received at least one dose or a partial dose of gantenerumab or placebo 
• 
Have at least one interpretable predose ECG measurement prior to dosing 
• 
Have at least one interpretable postdose ECG measurement on any of the 
post-baseline timepoints 
 
All ECG analyses will be based on this population. 
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4.1.3 
Safety Population 
The safety population will consist of all subjects who have received at least one dose of 
study drug, regardless of whether a subject withdrew prematurely or not.  All safety data 
will be analyzed according to study drug actually received. 
4.2 
ANALYSIS OF STUDY CONDUCT 
4.2.1 
Disposition of Subjects 
The number of subjects randomized, the duration of the study, and the number and 
percentage of subjects who prematurely withdraw from the study, including the reasons 
for discontinuation, will be summarized. 
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
4.3.1 
Demographic Data and Baseline Characteristics 
Baseline comparability of the placebo and gantenerumab treatment groups will be 
assessed for the ITT population and discussed in the CSR.  The comparisons will be 
made on patient demographic and baseline variables, including the following: 
• 
Sex 
• 
Age 
• 
Race 
• 
Years of education 
• 
Female reproductive status 
• 
Weight 
• 
Height 
• 
Body mass index 
• 
ApoE status 
• 
FcγR genotype 
• 
FCSRT-IR, total recall at baseline 
• 
MMSE, total score at baseline 
• 
ADAS-Cog total score (sum of 11-item scores) at baseline 
• 
ADAS-Cog total score (sum of 13-item scores) at baseline 
• 
CDR-SOB at baseline 
• 
CDR-Memory at baseline 
 
All comparisons will be based on descriptive statistics. 
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4.3.2 
Medical Events 
All listings and summaries will include only the preferred terms (PTs) or superclass 
terms (SCTs). 
Medical events (such as AEs, treatments, procedures, diseases) will be assigned as 
previous or concomitant on or after a reference date (such as index event date, 
randomization date, start date of study drug) on the basis of start and end dates.  The 
reference date must always be a complete and valid date. 
If the medical event does not have complete or valid start and end dates, the following 
rules will be applied: 
• 
If the medical event start date is 1) completely missing, 2) has only the year 
specified and this is the same as the year of the reference date, or 3) has only the 
month/year specified and these are the same month/year of the reference date, then 
the medical event will be assumed to have started before the reference date. 
• 
If the medical event end date is 1) completely missing, 2) has only the year specified 
and this is the same as the year of the reference date, or 3) has only the month/year 
specified and these are the same month/year of the reference date, then the 
medical event will be assumed to have ended after the reference date. 
• 
Otherwise, partial medical start and end dates (month/year or year only) will be 
compared with the corresponding part of the reference date to determine whether 
strictly before or strictly after the reference date (no other possibility exists because 
this is covered by the two previous bullet points). 
 
With use of these data handling rules, when needed, each event will be classified as one 
of the following: 
• 
Previous event:  A medical event with an end date (applying the rules above if 
necessary) strictly before the reference date will be considered as previous to the 
reference date. 
• 
Concomitant event:  A medical event with a start date (applying the rules above if 
necessary) before the reference date and end date (imputed as above if necessary) 
on or after the reference date will be considered as present concomitant at the 
reference date. 
 
4.4 
EFFICACY ANALYSIS 
4.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline in the CDR-SOB score at 
Week 104. 
4.4.2 
Statistical Models and Methods of Primary Outcome Analysis 
The primary inferential statistics will be applied to the pairwise comparisons of each of 
the two gantenerumab dose groups with the placebo group.  To protect the overall 
Type I error at the 0.05 significance level, a hierarchical testing procedure will be used in 
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which the first hypothesis to be tested will be the comparison of the 225-mg 
gantenerumab group with the matching subgroup of placebo patients with ApoE 0ε4 and 
1ε4 genotypes.  The second test, which compares the 105-mg gantenerumab group with 
the entire placebo group, will be performed only if the first test is statistically significant at 
the two-sided 0.05 level. 
For the assessment of differences between each gantenerumab group and placebo with 
regard to the mean change from baseline in the CDR-SOB score at Week 104, an 
MMRM analysis, which incorporates data up to 104 weeks of treatment, will be used to 
utilize all the data recorded over time with consideration of the variance-covariance 
matrix of the repeated measures.  This method allows a general unstructured 
variance-covariance matrix and enables the inclusion of data from subjects with 
incomplete data across scheduled timepoints. 
Independent MMRM models will be fitted for the comparisons of the two gantenerumab 
dose group with the placebo group.  For each comparison, the following null (H0) and 
alternative (Ha) hypotheses will be tested to compare the mean change values between 
the gantenerumab group and placebo group: 
H0:  MEANRO = MEANplacebo   versus 
Ha:  MEANRO ≠ MEANplacebo 
 
for which the MEANRO and MEANplacebo refer to the mean change of gantenerumab and 
placebo from baseline to Week 104, respectively. 
The model will include the change from baseline in the CDR-SOB score as the 
dependent variable.  The effects in the model will include independent variables of the 
fixed, categorical effects of treatment, assessment weeks relative to the first dose of 
study drug (i.e., time), treatment-by-time interaction, and ApoE status (carrier vs. 
non-carrier), along with baseline CDR-SOB and hippocampal volume at baseline.  
Hereby, the ApoE status “carrier” comprises all patients with ApoE status 1ε4 or 2ε4,  
and patients with ApoE status 0ε4 are non-carriers.  Time will be treated as the repeated 
variable within a subject.  Subject, treatment, and time will be treated as class variables.  
An unstructured variance-covariance structure will be applied to model the within-subject 
errors.  The model will be fitted using the restricted maximum likelihood method.  
Denominator degrees of freedom will be estimated using Satterthwaite’s approximation.  
A treatment-by-time interaction contrast will be constructed to estimate the difference 
between the respective gantenerumab dose group and placebo in the mean change 
from baseline to Week 104.  On the basis of the above analysis, p-values, least square 
means, SEs, and the 95% CIs of treatment difference will be reported for each dose of 
gantenerumab relative to placebo. 
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4.4.3 
Secondary Efficacy Endpoints 
In light of the yet-to-be defined considerations arising from continuing scientific and 
regulatory evolution that could impact Alzheimer’s disease drug development activities in 
the near future, the planned secondary endpoints specified in this Statistical Analysis 
Plan might need to be adjusted to accommodate these considerations as they emerge.  
Additionally, presentation and analysis of the biomarker data from this trial are planned 
and are expected to be critical to the interpretation of the overall dataset.  The plans for 
evaluation of these biomarkers will be addressed in the future as scientific understanding 
on the appropriate biomarkers to be used continues to evolve. 
4.4.3.1 
Key Secondary Efficacy Endpoint 
Ongoing discussions within the Sponsor’s organization and between the Sponsor and 
Regulatory Authorities are being conducted to establish the optimal endpoint and 
analytic process to implement for the key secondary efficacy endpoint for 
Study WN25203 (hereby “key secondary efficacy endpoint” is used to refer to the first 
secondary endpoint in the hierarchical testing and the results of which the Sponsor 
would propose to present in the prescribing information). 
The Sponsor is exploring Dementia Assessment (time to dementia), as performed by 
investigators every 6 months, as a potential key secondary efficacy endpoint.  Emerging 
composites to examine clinical decline are also being evaluated as a potential key 
secondary efficacy endpoint.  The Sponsor is currently conducting the analyses on the 
performance of the Dementia Assessment (and potential emerging composites) outside 
of this study to determine its clinical characteristics (such as median time to event, 
number of events, etc.) compared with other measures of clinical assessment before 
final proposal to Regulatory authorities for inclusion as the key secondary efficacy 
endpoint in Study WN25203. 
4.4.3.2 
Cognition 
The change from baseline at Week 104 in the following will be assessed: 
• 
ADAS-Cog total score (13 items and 11 items) 
• 
MMSE total score 
• 
CANTAB with selected subtest scores: 
SRT 
SMT 
Five-choice RTI 
DMS latency 
SWM 
PRM immediate 
PRM delayed 
RVP 
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PAL 
• 
FCSRT-IR 
 
4.4.3.3 
Global 
• 
CDR global score 
4.4.3.4 
Functioning 
• 
The change from baseline in FAQ total score 
 
4.4.3.5 
Neuropsychiatric Functioning 
• 
The change from baseline in the total and domain scores of the NPI-Q 
 
4.4.3.6 
MRI Volumetric Measures 
• 
The change from baseline in hippocampal volume 
• 
The change from baseline in whole brain volume 
• 
The change from baseline in ventricular volume 
• 
The change from baseline in other volumetric measures such as cortical thickness, 
if adequate 
 
4.4.4 
Statistical Models and Methods of Secondary Efficacy 
Analyses 
Continuous Variables 
The secondary efficacy variables of the continuous type with multiple post-baseline 
scheduled assessments will be analyzed using the same methods described above for 
the primary outcome variable:  MMRM including the covariates of baseline CDR-SOB 
and hippocampal volume at baseline. 
Time-to-Event Variables 
Time to event in the gantenerumab group and the placebo group will be compared using 
a two-sided log-rank test stratified by ApoE status (carrier vs. non-carrier).  The 
proportion of patients with the event given the treatment group and time will be 
estimated using Kaplan-Meier methodology.  
In order to estimate the overall hazard ratio, a proportional hazards model will be 
assumed with respect to time-to-event variables.  Under the following model, the hazard 
function for the jth subject is expressed as: 
λj (t) = λ0 (t) exp(zj β) 
 
where λ0 (t) is the baseline hazard function and zj is the vector of explanatory variables 
for the jth subject who has received treatment.  For time-to-event variables, the 
explanatory variables included in the regression model will be treatment, ApoE genotype 
status (carrier vs. non-carrier), baseline CDR-SOB, and hippocampal volume at 
baseline.  The treatment effect is then the hazard ratio for gantenerumab versus placebo, 
which is assumed to be constant over time.  
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Subjects will be considered to be at risk for an event until the database cutoff for the 
primary analysis is reached.  Subjects who are lost to follow-up or who withdraw consent 
(while event-free) will be censored at the time that they are last known to be event-free.  
Point estimates and two-sided 95% CIs will be determined for treatment effects and will 
be based on the estimate (and SD) for the treatment effect term in a Cox proportional 
hazard model. 
Hierarchical Testing 
Only if both tests for the primary efficacy endpoint result in statistically significant 
outcomes will a statistical test for the key secondary efficacy endpoint be conducted in a 
confirmatory manner.  Hereby, the overall Type I error will be controlled at the 0.05 level. 
4.4.5 
Sensitivity Analyses 
If statistically significant treatment effects are demonstrated in the analysis of the primary 
outcome measure, the robustness of the results will be evaluated with respect to their 
potential dependence on the assumptions made and definitions of the composite 
endpoint components and subject populations. 
• 
Analysis of the primary outcome measure, excluding hippocampal volume as a 
covariate 
The MMRM model excluding the hippocampal volume at baseline covariate will 
also be performed to compare each gantenerumab dose group with the 
corresponding placebo group to assess the effect of this factor on the primary 
outcome measure. 
• 
Analysis of the primary outcome measure excluding the ApoE4 genotype carrier 
status as a covariate 
The MMRM model excluding the ApoE4 genotype will also be performed to 
compare each gantenerumab dose group with the corresponding placebo group 
to assess the effect of this factor on the primary outcome measure. 
 
Pattern mixture models and multiple imputation methods, as described in Section 4 of 
the National Research Council report, will be performed as additional sensitivity 
analyses. 
4.4.6 
Subgroup Analyses 
The primary variable (i.e., the change from baseline in the CDR-SOB score at 
Week 104) and ADAS-Cog will be summarized within subgroups defined by the following 
baseline characteristics.  Inferential statistics may be applied in case the difference is 
clinical relevant. 
• 
Sex 
• 
Age 
• 
Race 
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• 
ApoE status 
• 
FcγR genotype 
• 
Region (North American [America and Canada] vs. others) 
Descriptive statistics for baseline-demographics and disease-characteristics variables, 
as well as for the primary outcome variable, will also be generated for the subgroups of 
subjects randomized prior to and after the CSF Aβ inclusion-criterion cutoff was 
modified and the expansion of the study sample size with an effective date of 14 March 
2012, submission date of Protocol Study WN25203C for the IND, 29 March 2012 
(S-0020).  The subgroup analyses will be used to evaluate the consistency of the data 
between the two study populations over time. 
4.5 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
Nonlinear mixed-effects modeling (using the software NONMEM®) will be used to 
analyze the dose concentration-time data of gantenerumab.  Information from other 
studies in humans may be incorporated to establish the PK model.  The selection of 
parameters and the derivation of individual measures of exposure, such as AUC0−τ, Cmax, 
and steady-state concentration at the end of a dosing interval (Ctrough) will depend on the 
final PK model used for this analysis.  All PK parameters will be presented in listings and 
descriptive summary statistics, including the arithmetic mean (for AUC0−τ, Cmax, and 
Ctrough), median, range, SD, and coefficient of variation.  Results of this analysis will be 
reported separately. 
In this study, PET using the amyloid tracer AV-45 will be used as a pharmacodynamic 
(PD) measurement of potential effects of gantenerumab on amyloid load in the brains of 
subjects with early (prodromal) Alzheimer’s disease.  The primary PET variable, percent 
change from screening in cortical composite standard uptake value ratio (SUVR), will be 
summarized using descriptive statistics and analyzed using the MMRM method.  The 
effects in the model will include independent variables of the fixed, categorical effects of 
treatment, assessment time, and treatment-by-time interaction.  Time will be treated as 
the repeated variable within a subject.  Subject, treatment, and time will be treated as 
class variables.  An unstructured variance-covariance structure will be applied to model 
the within-subject errors.  Similar analyses may be performed for absolute change and 
percent change from screening in regional SUVR values. 
4.6 
SAFETY ANALYSES 
Descriptive statistics will be used to analyze all safety data.  Wherever possible, Roche’s 
safety reporting system will be used to present safety evaluations.  The outputs defined 
in this section will be produced using the safety analysis population, unless otherwise 
specified. 
Selected safety outcome measures will also be reported by ApoE genotype.  
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For all safety analyses, Day 1 will be defined as the start date of double-blind 
randomized treatment.  For all safety data (laboratory findings, ECG results, vital sign 
measurements), the baseline value will be the last available value before the start of 
dosing. 
4.6.1 
Exposure of Study Medication 
Exposure to study drug will be summarized using the following using descriptive 
statistics: 
• 
Duration of treatment (defined as the time from the date of first treatment to date of 
last treatment) 
• 
Cumulative dose 
• 
Dose intensity (%) (defined as total amount of study treatment administrated relative 
to total amount of study treatment assigned per protocol) 
 
4.6.2 
Adverse Events 
AEs will be coded using the MedDRA, Version 15.0.  For each treatment group, the 
frequency of each AE preferred term will be defined as the number of subjects 
experiencing at least one occurrence of the event.  The incidence rate will be calculated 
as the frequency count divided by the total number of subjects in the population and 
treatment group specified. 
Each table will also present the overall number of subjects experiencing at least one AE 
and the total number of AEs reported.  Subject listings will contain PTs and comments 
for each event.  In summary tables, AEs will be sorted by body system and then by PT 
(both in decreasing order of overall incidence). 
All AEs will be summarized separately for the following two study periods and include 
the specified AEs: 
• 
Treatment period includes 1) the AEs for which the onset date is on or after the start 
of dosing and on or prior to 4 weeks after the last dose day or 2) the AEs for which 
the onset date is prior to the first dosing day and the end date is on or after the first 
dose day or is unresolved. 
• 
Follow-up period includes 1) the AEs for which the onset date is 28 days or more 
after the last dose day or 2) the AEs for which onset date is during the treatment 
period and the end date is after the last dose day or is unresolved.  When the last 
dose date is not available (e.g., for subjects who are still in the study), all the AEs 
reported will be considered as occurring during the “treatment period.” 
 
The following safety information will be summarized: 
• 
AEs 
• 
Serious AEs 
• 
Study drug−related AEs 
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• 
Study drug−related serious AEs 
• 
AEs leading to discontinuation of study treatment 
• 
AEs leading to dose reduction 
• 
AEs leading to dose held 
In addition, summaries of AEs will be provided by age, race, and sex. 
The following data handling rules will be applied for all AE summary tables: 
• 
Multiple occurrences of the same AE in 1 subject will be counted only once. 
• 
For administrative analysis and iDMC (due to potentially incomplete coding of the 
terms), missing PTs will be presented as the investigator’s terms, preceded by 
″NO_PT_Found″ in all outputs.  Missing SCTs will be presented as 
″<NO_SCT_FOUND>″ in all outputs.  All cases of missing PTs should be resolved 
at the time of the final database closure. 
• 
Events that are missing both onset and end dates will be considered treatment 
emergent, 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 treatment emergent. 
• 
If the end date is missing and the onset date is on or after the first dosing date, then 
the event will be considered treatment emergent. 
 
The following data handling rules will also be applied for specific tables: 
• 
An AEs will be included in the summary table of AEs leading to study drug 
discontinuation if the “study drug adjustment” tick box on the Adverse Event CRF is 
checked “discontinued.” 
• 
In the summary table of AEs by intensity, if a subject 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 subjects with the event by intensity. 
• 
In the summary table of AEs by relationship to study drug, if a subject has more 
than one occurrence of an event, the most closely related event will be counted.  If 
the relationship 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 subjects with the event by 
relationship. 
 
4.6.3 
MRI Safety Findings and Injection-Site Reactions 
The incidence of ARIA-E, ARIA-H, and other MRI findings as well as injection-site 
reactions will be listed and summarized by treatment group.  In addition, the MRI data 
will be summarized by ApoE4 genotype. 
Both, ARIA and injection-site reactions will be also captured as AEs, but respective 
listings and reports will be summarized in a separate subchapter. 
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4.6.4 
Laboratory Data 
Laboratory data will be summarized for each assessment with use of descriptive 
statistics (e.g., mean, SD, and median).  The proportion of subjects who develop marked 
abnormalities during study treatment on the basis of National Cancer Institute Common 
Terminology Criteria for Adverse Events, Version 4.0 will be summarized. 
4.6.5 
Vital Signs 
Vital sign assessments include systolic blood pressure, diastolic blood pressure, and 
pulse measured throughout the study.  Summaries of vital sign measurements at each 
assessment timepoint using descriptive statistics will be presented for each group with 
respect to both the actual values and changes from baseline. 
Categorical analysis will include number of subjects exceeding a systolic blood pressure 
of 160−179 and ≥ 180 or a diastolic blood pressure of 95−109 and ≥ 110 mm Hg or with 
blood pressure of < 90 mm Hg systolic and < 60 mm Hg diastolic.  The number of 
subjects with changes in systolic and/or diastolic blood pressure by 5 to < 10, 10 to < 15, 
and ≥ 15 mm Hg will also be provided. 
With respect to heart rate (HR), the number of subjects with an HR of > 100 bpm or 
< 60 bpm and the number of subjects with a change in HR by 5 to < 10, 10 to < 15 and 
≥ 15 bpm will be provided. 
4.6.6 
Electrocardiograms 
An average of the three values of QT interval (QT), QTcF (Fridericia’s correction), and 
HR from each ECG triplicate reading will be used as a single observation at the 
timepoint for all analyses except the T-wave and U-wave morphology. 
Duration of the QT interval is inversely correlated with the corresponding HR so it has to 
be corrected relative to HR to allow a reliable interpretation of changes in the QTc 
interval independent of the changes in the HR.  The QT intervals will be corrected for the 
HR with use of Bazett’s (QTcB) and QTcF formulae as follows:  The QTcB value will be 
calculated as the QT interval (in milliseconds) divided by the squared root of the RR 
interval (in seconds).  The QTcF value will be calculated as the QT interval (in 
milliseconds) divided by the cubed root of the RR interval (in seconds). 
Descriptive statistics will be generated for the actual values and the change from 
baseline for the two visits at which ECGs are scheduled for all subjects (baseline and 
end of treatment). 
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The following parameters will be summarized: 
• 
HR 
• 
PQ (PR) interval 
• 
QRS interval 
• 
QT interval 
• 
RR interval 
• 
QTcB and QTcF 
 
Additional categorical analyses will include the number and percentage of subjects at 
each timepoint whose ECG recordings meet any of the following criteria: 
• 
Absolute QT/QTc values:  > 450 to < 480 ms, ≥ 480 to < 500 ms, and ≥ 500 ms 
• 
Change from baseline in QTc interval:  20 to < 30 ms, ≥ 30 to < 60 ms, and ≥ 60 ms 
• 
PR changes from baseline are ≥ 50% if absolute baseline value was ≤ 200 ms and 
are ≥ 25% if absolute baseline value was > 200 ms. 
• 
QRS changes from baseline are ≥ 50% if absolute baseline value was ≤ 100 ms and 
≥ 25% if absolute baseline value was > 100 ms. 
• 
New incidence of abnormal U waves (a morphology abnormality in any lead will be 
scored as the result with use of three individual ECG tracings from each triplicate as 
three observations) 
• 
New incidence of abnormal T waves (a morphology abnormality in any lead will be 
scored as the result with use of three individual ECG tracings from each triplicate as 
three observations) 
• 
Number and percentage of subjects with abnormal ECG findings overall 
 
4.6.7 
Deaths 
Deaths will be categorized by study phase (between start date of study drug and 
30 days after end date of study drug or > 30 days after end date of study drug) and 
summarized. 
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4.7 
MISSING DATA 
For the efficacy rating scales with multiple items, the overall total and domain scores 
(i.e., “summed scores”) will be set to missing for the primary analysis when at least one 
item score that contributes to the “summed scores” is missing.  In addition, an 
exploratory analysis will be performed with imputed missing “summed score” (in case 
there are > 10% of subjects who have a missing “summed score” for a given test at a 
given assessment time) with use of various imputation rules as long as < 25% of the 
items involved in the given summed score are missing.  When ≥ 25% of item scores are 
missing, the summed score will remain as missing.  Imputation rules will include the 
following simple algorithm: 
Total score from the non-missing items in a domain (or total) multiplied by 
(maximum possible scores for items involved in the domain [or total] divided by 
maximum possible scores for items with non-missing score) 
 
A more complex method may be explored, such as the two-way imputation (based on a 
linear model) method, proposed by Bernaards and Sijtsma (2000).  The authors impute 
item j of subject i by PMi + IMj − OM, for which PMi is the subject’s mean across all of his 
or her available item responses, calculated for each subject. 
• 
IMj is the mean of item j across all available scores, calculated for each item 
• 
OM is the overall mean across all subjects and items. 
 
4.8 
INTERIM ANALYSES 
In addition to the regularly scheduled safety monitoring reviews by the iDMC as 
described in Section 10.1.2 of the Protocol, one administrative interim analysis was 
conducted in June 2013.  For this interim analysis, unblinded summary tables showing 
results for selected safety parameters (such as MRI findings) and selected PET PD 
parameters collected in the PET substudy were generated.  Unblinded summary tables 
showing results for PK and ADA data were also generated. 
The results of the administrative interim analysis were generated by the same 
independent data coordinating center (iDCC) that is used for the quarterly safety 
reviews.  The interim analysis results were reviewed by both the iDMC and the 
Sponsor’s Data Review Board (DRB).  The details of the composition of the DRB and 
the data outputs to be reviewed are described in the iDMC Charter and a separate 
interim Statistical Analysis Plan. 
The iDMC recommendation on the basis of the results of the administrative interim 
analysis was used by the DRB to determine whether to initiate activities for additional 
clinical trials, and no efficacy data was provided to DRB for review.  The Type I error rate 
has not been adjusted for this interim analysis because the study team has remained 
blinded to the data.  The results of the interim analysis have not been used to inform the 
future conduct of this trial and therefore there is no risk to introduce operational bias. 
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A 2-level futility interim analysis will be performed when approximately 50% of the 
sample size is scheduled to complete the Week 104 visit.  This analysis will be 
performed by the iDCC that generates the unblinded results to be reviewed by the iDMC 
on a regular basis.  For the 2-level futility analysis, the iDMC will review the unblinded 
results for the primary and secondary efficacy endpoints (absolute change from baseline 
at Week 104) as well as emerging safety data.  The specifics of the futility analysis will 
be documented prior to its conduct in an Interim Statistical Analysis Plan. 
No adjustment for multiple comparisons will be made to the α level for this analysis 
because the decision rules for the futility analysis will not allow for the opportunity to stop 
the study early for overwhelming efficacy. 
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5. 
REFERENCES 
Bernaards CA, Sijtsma K. Influence of imputation and EM methods on factor analysis 
when item nonresponse in questionnaire data is nonignorable. Multivariate Behav Res 
2000;35:321−64. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic 
factors in the controlled clinical trial. Biometrics 1975;31:103−15. 
 
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Appendix 1  
Protocol Synopsis 
SYNOPSIS OF PROTOCOL NUMBER WN25203F 
 
TITLE 
Multicenter, Randomized, Double-Blind, Placebo-Controlled, 
Parallel-Group Two Year Study to Evaluate the Effect of 
Subcutaneous RO4909832  on Cognition and Function in 
Prodromal Alzheimer's Disease with Option for an Additional 
Two Years of Treatment 
SPONSOR 
Roche 
Clinical Phase 
3 
INDICATION 
Prodromal Alzheimer’s Disease 
OBJECTIVES  
Primary 
 
 
 
Secondary 
Cognition, global, and functioning 
 
 
 
 
 
 
 
 
 
 
 
 
Safety 
 
 
 
 
 
MRI volumetry 
 
     
    
 
CSF Biomarkers 
 
 
 
 
 
Pharmacokinetics/ 
Anti-Drug Antibodies 
 
 
 
 
 
 
To evaluate the effect of gantenerumab versus placebo on the 
change in the Clinical Dementia Rating scale Sum of Boxes 
(CDR-SOB), a global measure of cognition and functional 
ability. 
 
To evaluate the effect of gantenerumab versus placebo on 
cognition (assessed with the Alzheimer Disease Assessment 
Scale-Cognition [ADAS-Cog], Mini Mental State Exam 
[MMSE], Cambridge Neuropsychological Test Automated 
Battery [CANTAB], and the Free and Cued Selective 
Reminding Test-Immediate Recall [FCSRT-IR]) on global 
measures (based on the CDR global score), and on functioning 
(assessed with the Functional Activities Questionnaire [FAQ]), 
on  neuropsychiatric functioning (assessed with  the 
Neuropsychiatric Inventory Questionnaire [NPI-Q]) and on time 
to onset of dementia. 
 
To assess the safety and tolerability of gantenerumab assessed 
by magnetic resonance imaging (MRI), physical and 
neurological examinations, vital signs, blood and urine safety 
tests, ECGs, Columbia-Suicide Severity Rating Scale (C-SSRS), 
Geriatric Depression Scale (GDS), and adverse event 
monitoring. 
 
To evaluate the effect of gantenerumab versus placebo on 
hippocampal volume, whole brain volume, ventricular 
enlargement, and possibly other volumetric measures of the 
brain. 
 
To evaluate the effect of gantenerumab versus placebo on levels 
of cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease 
(AD) pathology (i.e., total tau [T-tau], phospho-tau [p-tau], and 
amyloid-beta (Aβ1-42]).  
 
To determine the relationship of plasma and CSF concentrations 
of gantenerumab on other responses. To assess incidence of 
anti-gantenerumab antibodies, and if relevant, evaluate its effect 
on the pharmacokinetic (PK), pharmacodynamic (PD), efficacy. 
and safety parameters.  
 
 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
26 


Appendix 1  
Protocol Synopsis (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
27 
Exploratory 
Plasma Biomarkers 
 
 
 
 
Clinical Genotyping 
 
 
To evaluate the effect of treatment on peripheral biomarkers of 
amyloid deposition and/or clearance, neurodegeneration, 
inflammation, and other markers known to be involved in the 
pathogenesis of AD. 
 
To evaluate the effect of gene encoding apoliprotein E (ApoE) ε4 
genotype and fragment crystalizable gamma receptor (FcγR)  
genotype on PK/PD, efficacy, and safety parameters 
TRIAL DESIGN 
Multicenter, randomized, double-blind, placebo-controlled, 
parallel-group 
NUMBER OF SUBJECTS 
Approximately a total of 770; 514 on gantenerumab and 256 on 
placebo with an option to increase to no more than 960 based on 
a blinded evaluation of the observed variability in the absolute 
change from baseline in CDR-SOB at Week 76 done at the time 
of the administrative interim analysis. 
TARGET POPULATION 
Subjects who meet memory and biomarker criteria which 
indicate a strong likelihood that they are in the prodromal phase 
of Alzheimer’s Disease 
LENGTH OF STUDY  
Part 1: Approximately 3 years and 2 months which includes 
8 weeks for screening, 2 years (104 weeks) of treatment, and 
1 year (52 weeks) of follow-up.  Part 2: additional 2 years which 
includes 1 year (52 weeks) of follow-up at the end of Year 4 
rather than Year 2.  
END OF STUDY 
The end of the study will be considered to be the date of the last 
visit (including the last scheduled follow-up visit according to 
study protocol) of the last subject in the study. 
INVESTIGATIONAL MEDICAL 
PRODUCT(S) 
DOSE/ ROUTE/ REGIMEN 
Gantenerumab (105 mg  or 225 mg for the 0ε4 and 1ε4 ApoE 
genotypes or 105 mg for the 2ε4 ApoE genotype patients) by 
subcutaneous (SC) injection, every 4 weeks 
COMPARATOR  
DOSE/ ROUTE/ REGIMEN 
Placebo,  by SC injection, every 4 weeks 
ASSESSMENTS OF: 
 
- EFFICACY 
CDR SOB, ADAS-Cog, MMSE, CANTAB, FAQ, FCSRT-IR, 
NPI-Q, onset of dementia 
 
- SAFETY 
 
MRI, physical and neurological examinations, vital signs, blood 
and urine safety tests, C-SSRS, GDS, ECGs and adverse event 
monitoring 
 
- PHARMACOKINETICS 
 
- BIOMARKERS  
 
Gantenerumab levels in plasma and CSF 
 
Peripheral and CSF biomarkers of amyloid deposition and/or 
clearance (including but not restricted to CSF and plasma Aβ1-40 
and Aβ1-42), markers of neurodegeneration (including CSF T-tau 
and P-tau), inflammatory and other markers thought to be 
involved in the pathogenesis of AD. 
 


Appendix 1  
Protocol Synopsis (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
28 
- CLINICAL GENOTYPING 
SAMPLES 
- ROCHE CLINICAL 
REPOSITORY SPECIMENS 
ApoE and FcγR  
 
Roche Clinical Repository  DNA (blood) and  non-DNA (plasma 
and RNA) specimens will be taken from consenting subjects  
The RCR sampling is optional.   
 
 
 
PROCEDURES (summary):  
Screening and baseline: After written informed consent is obtained, screening 
assessments, which include general health and cognitive testing, brain MRI, and lumbar 
puncture for CSF collection,  must be completed within 8 weeks followed by up to 
1 week for baseline assessments. (See schedule of assessments.) 
Treatment: In this study, all subjects will receive 26 treatments (drug administrations) 
with a 4-week interval between each dose. On each dosing day, gantenerumab or 
matching placebo will be administered as 
 SC injections in the abdominal area. Safety 
and efficacy evaluations will be performed according to the schedule of assessments.  
Treatment Extension: Subjects who complete the entire 2 years of treatment and the 
Week 104 follow-up visit may continue to receive the same treatment they were 
receiving at the Week 100 visit.  The double-blind treatment can resume at the Week 104 
visit after all assessments have been completed for that visit.  If this amendment was not 
yet approved at the time of the subject’s Week 104 visit, the subject can resume treatment 
at a subsequent visit; however, assessments as indicated in the Schedule of Assessments 
for Week 104Ext must be completed prior to administration of study medication. 
Follow-up: Patients will be followed for 1 year (52 weeks) after the last dose of study 
treatment.  
Futility Analysis:  A futility interim analysis will be performed approximately when 50% 
of the sample size is scheduled to complete the Week 104 visit. 
STATISTICAL ANALYSES:   
All efficacy and safety data will be evaluated in the following manner: 
• All gantenerumab dose groups combined versus placebo for overall assessments 
regardless of the ApoE genotype. All placebo patients will be pooled.  
• Each of the two gantenerumab dose groups (i.e., 105 mg vs. 225 mg) versus placebo. 
The primary inferential statistics will be applied to the pairwise comparison of each 
of the two gantenerumab dose groups to the corresponding placebo group. The 
corresponding placebo group for the comparison to the gantenerumab 105 mg group 
is the entire placebo group. The corresponding placebo group for the comparison to 
the gantenerumab 225 mg group is the subgroup of placebo patients with ApoE 0E4 
and 1E4 types (as there are no patients with ApoE 2E4 randomized to the 


Appendix 1  
Protocol Synopsis (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
29 
gantenerumab 225 mg arm). In order to adjust for the multiplicity in the pairwise 
comparisons of each gantenerumab dose to placebo, a hierarchical testing procedure 
will be used. 
 
Each of the ApoE genotypes will also be assessed separately in comparison to the 
corresponding placebo group.  
The efficacy variables of continuous type will be analyzed using a mixed-effects model 
repeated measures technique incorporating the data up to 104 weeks of treatment will be 
used to utilize all the data collected over time with consideration of the 
variance-covariance matrix of the repeated measures. Treatment difference between 
gantenerumab and placebo will be estimated for the change from baseline values at 
Week 104. 
All safety variables will be summarized for each assessment time (including follow-up) 
using descriptive statistics. 
 


Appendix 2  
Schedules of Assessments 
Table 1 Schedule of Assessments – First Year 
Visit by week # 
Screen 
Baseline 
1 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
53 
Dose Number 
(8 wks) 
1 
 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
Demographics12 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
X
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Modified Hachinski 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Genotyping 
X
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RCR Plasma and RNA 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X
 
 
RCR DNA 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
P 
X 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
X 
ECG (triple if underlined) 
X 
P 
X 
 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
X 
Blood and Urine Labs 
X13 
P 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X13 
Urine Pregnancy Test5 
X 
P 
 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
 
PK  plasma 
 
P 
X 
 
P 
 
 
P 
 
 
 
 
 
P 
 
 
X 
ADA samples 
 
P 
X 
 
P 
 
 
P 
 
 
 
 
 
P 
 
 
 
Plasma Biomarkers 
 
P 
 
 
 
 
 
P 
 
 
 
 
 
P 
 
 
 
CDR 
X 
P-1 wk 
 
 
 
 
 
 
P 
 
 
 
 
 
 
P 
 
FAQ, NPI-Q, GDS 
X 
P-1 wk 
 
 
 
 
 
 
P 
 
 
 
 
 
 
P 
 
MMSE 
X 
P-1 wk 
 
 
 
P 
 
 
P 
 
 
P 
 
 
 
P 
 
Dementia Assessment 
X
P
 
 
 
P
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADAS-Cog 
X 
P-1 wk 
 
 
 
P 
 
 
P 
 
 
P 
 
 
 
P 
 
FCSRT-IR 
X4 
P-1 wk 
 
 
 
P 
 
 
 
 
 
P 
 
 
 
 
 
CANTAB 
X 
P-1 wk 
 
 
 
 
 
 
P 
 
 
 
 
 
 
P 
 
C-SSRS 
 
P-1wk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LP/CSF, plasma PK and 
matching serum  sample3 
X2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/2
2 
0d
 
RCR CSF 
X
0d
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/2
2 
 
MRI9 
X2 
 
 
10/20d 
* 
10/20d 
* 
10/20d 
* 
 
10/20d 
* 
 
10/20d 
* 
 
 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
30 


Appendix 2  
Schedules of Assessments (cont.) 
Table 2 Schedule of Assessments – Second Year 
Visit by week # 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
101 
FU1/1047 
FU2/112 
FU3/152
Unsch.1  
FU1/DO1 
FU2/DO2
FU3/DO3 
Dose Number 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
X 
RCR Plasma and RNA 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
X6 
 
 
Vital Signs 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (triple if underlined) 
 
 
 
P 
 
 
 
P 
 
 
 
P 
X 
 
X 
 
X 
 
X 
 
Blood and Urine Labs 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X13 
 
X 
X 
X 
X13 
X 
X 
Urine Pregnancy Test5 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
 
 
X 
 
X 
 
X 
 
PK  plasma 
 
 
 
P 
 
 
 
 
 
 
 
P 
X 
 
X 
 
X 
 
X 
 
ADA samples 
 
 
 
P 
 
 
 
 
 
 
 
P 
 
 
X 
 
X 
 
X 
 
Plasma Biomarkers 
 
 
 
P 
 
 
 
 
 
 
 
P 
 
 
X 
 
X 
 
X 
 
CDR 
 
 
P 
 
 
P 
 
 
P 
 
 
 
 
X 
 
X 
X 
X 
 
X 
FAQ, NPI-Q, GDS 
 
 
 
 
 
P 
 
 
 
 
 
 
 
X 
 
X14 
X 
X 
 
X14 
MMSE 
 
 
P 
 
 
P 
 
 
P 
 
 
 
 
X 
 
 
X 
X 
 
 
Dementia Assessment 
 
 
 
 
 
P 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
ADAS-Cog 
 
 
P 
 
 
P 
 
 
P 
 
 
 
 
X 
 
 
X 
X 
 
 
FCSRT-IR 
 
 
P 
 
 
 
 
 
P 
 
 
 
 
X 
 
 
X 
X 
 
 
CANTAB 
 
 
 
 
 
P 
 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
 
LP/CSF,  plasma PK and 
matching serum sample3 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/20d2 
 
 
X 
10/20d2 
 
 
RCR CSF 
 
 
 
 
 
 
 
 
 
 
 
 
 
10/20d2 
 
 
 
10/20d2 
 
 
MRI9 
 
10/20d 
* 
 
 
 
10/20d 
* 
 
 
 
 
 
10/20d2 
 
X8 
X 
10/20d2 
 
X8 
P indicates Prior to Injections: P-1 wk is within 1 week prior the 1st dose; P is prior to the injections on the day of dosing. 
ECG readings underlined above to be done in triplicate for subjects enrolled prior to protocol amendment D. Subjects enrolled after approval of amendment D will have triplicate 
ECG done only at Screen.  All ECGs are sent for central reading.   
DO1, DO2 and DO3 are drop-out visits; FU1, FU2, and FU3 are 4, 12, and 52 weeks after last dose of study treatment. 
LP/CSF and MRI: the times are days after the visit (e.g. 10/20d is 10-20 days.  Attempt to schedule MRI closer to 10 days than 20 days as the result must be received prior to the 
next dose). 
RCR CSF:  after aliquoting the required samples, any remaining CSF fluid from consenting subjects will be saved for RCR sample. 
Visit window:  +/- 7 days for dosing days; +/- 3 days for visits that are 1 week post-dose (see Section 5.1.3). 
* The MRI result as determined by the central reader must be known before a subsequent dose can be given. 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
31 


Appendix 2  
Schedules of Assessments (cont.) 
Table 2 Schedule of Assessments – Second Year (Cont.) 
1  
Any procedure or assessment marked may be done at an unscheduled visit as required   
2  
LP performed in the morning (8 am−12 pm); MRI should not be done during the 3 days following an LP. The LPs at screening and Week 104 (FU1/104, 
FU1/DO 1 or 104 Ext) are mandatory.  The LPs at 1 year and during the extension part of the study are optional. The final LP in the extension (FU1/208 or 
ext208/DO1) is highly encouraged.  
3  
LP/CSF for biomarkers and PK assays,  plasma PK and matching serum samples: at screen, Wk 52 Wk FU1/104 (or FU1/DO 1 or Wk 104 Ext), Wk 156 and 
Wk FU1/208 (or ExtFU1/DO 1). See Section 5.2.14.2. 
4  
FCSRT-IR performed up to 1 month prior to screening can be used to satisfy inclusion criteria  
5  
Women who are of childbearing potential must have a urine pregnancy test done at the site prior to each dose. 
6  
RCR plasma and RNA samples should be taken at the same time as the blood samples taken during the LP visit.  
7  
Subjects continuing directly into the Extension, should follow Week 104 Ext schedule in Table 3. FU2/112 and FU3/152 visit in Table 2 will not be 
performed. 
8  
The final MRI should be done approximately 4 weeks before the final follow-up visit to allow review before the final visit. 
9. 
 “Reset” MRI schedule if restarted on half dose during Part 1 can be found in Appendix 3. 
10. 
“Reset” MRI schedule if entering the extension already on a “reset” MRI schedule can be found in Appendix 4. 
11. 
“Reset” MRI schedule if restarted on half dose during Part 2 can be found in Appendix 5.  
12. 
At screening, demographic data collected will include years of education. 
13   During the screening period, Week 53, the Week 101 or DO1 and, Week 204, or Ext DO1 only, HbA1C, folic acid and, B12, T4, free T4, and thyroid 
 stimulating hormone levels will also be assessed. 
14   At FU, DO3, Ext FU3 or Ext DO3, only FAQ will be administered. 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
32 


Appendix 2  
Schedules of Assessments (cont.) 
Table 3 Schedule of Assessments – Extension Year 1 
Visit by week # 
104 Ext 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
Dose Number 
27 
28 
29 
30 
31 
32 
33 
34 
35 
36 
37 
38 
39 
Physical Exam 
 
 
P 
 
 
 
 
 
 
 
 
 
 
Neurological Exam 
 
 
P 
 
 
 
 
 
 
 
 
 
 
RCR Plasma and RNA 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
ECG  
 
 
P 
 
 
 
 
 
 
P 
 
 
 
Blood and Urine Labs 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Urine Pregnancy Test5 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
PK  plasma 
 
 
P 
 
 
 
 
 
 
P 
 
 
 
ADA samples 
 
 
P 
 
 
 
 
 
 
P 
 
 
 
Plasma Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
CDR 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
 
FAQ, NPI-Q, GDS 
P 
 
 
 
 
 
P 
 
 
 
 
 
 
MMSE 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
 
Dementia Assessment 
P 
 
 
 
 
 
P 
 
 
 
 
 
 
ADAS-Cog 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
 
FCSRT-IR 
P 
 
 
P 
 
 
 
 
 
P 
 
 
 
CANTAB 
P 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LP/CSF,  plasma PK and matching 
serum sample3 
10/20d2 
 
 
 
 
 
 
 
 
 
 
 
 
RCR CSF 
10/20d2 
 
 
 
 
 
 
 
 
 
 
 
 
MRI10, 11 
10/20d 
* 
 
 
 
 
10/20d 
* 
 
 
 
 
10/20d 
Also refer to footnotes  Table 2
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
33 


Appendix 2  
Schedules of Assessments (cont.) 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
34 
Table 4 Schedule of Assessments – Extension Year 2  
Visit by week # 
156 
160 
164 
168 
172 
176 
180
184 
188 
192 
196 200 
204 
FU1/208 
FU2/216 
FU3/ 256 
Unsch.1  
ExtFU1/ 
DO1 
ExtFU2/ 
DO2 
ExtFU3/ 
DO3 
Dose Number 
40 
41 
42 
43 
44 
45 
46 
47 
48 
49 
50 
51 
52 
 
 
 
 
 
 
 
Physical Exam 
P 
 
 
 
 
 
 
 
 
 
 
 
P 
 
X 
X 
X 
 
X 
X 
Neurological Exam 
P 
 
 
 
 
 
 
 
 
 
 
 
P 
 
X 
X 
X 
 
X 
X 
RCR Plasma and RNA 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
X6 
 
 
Vital Signs 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
X 
X 
X 
X 
X 
X 
X 
ECG  
 
 
 
P 
 
 
 
 
 
P 
 
 
P 
 
X 
 
X 
 
X 
 
Blood and Urine Labs 
 
 
 
X 
 
 
 
 
 
X 
 
 
X13 
 
X 
X 
X 
X13 
X 
X 
Urine Pregnancy Test5 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
 
X 
 
X 
 
X 
 
PK  plasma 
 
 
 
P 
 
 
 
 
 
P 
 
 
P 
 
X 
 
X 
 
X 
 
ADA samples 
 
 
 
P 
 
 
 
 
 
P 
 
 
P 
 
X 
 
X 
 
X 
 
Plasma Biomarkers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
CDR 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
 
X 
 
X 
X 
X 
 
X 
FAQ, NPI-Q, GDS 
P 
 
 
 
 
 
P 
 
 
 
 
 
 
X 
 
X14 
X 
X 
 
X14 
MMSE 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
 
X 
 
 
X 
X 
 
 
Dementia Assessment 
P 
 
 
 
 
 
P 
 
 
 
 
 
 
X 
 
 
X 
X 
 
 
ADAS-Cog 
P 
 
 
P 
 
 
P 
 
 
P 
 
 
 
X 
 
 
X 
X 
 
 
FCSRT-IR 
 
 
 
P 
 
 
 
 
 
P 
 
 
 
X 
 
 
X 
X 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
LP/CSF,  plasma PK and 
matching serum sample3 
10/20d2 
 
 
 
 
 
 
 
 
 
 
 
 
10/20d2 
 
 
X 
10/20d2 
 
 
RCR CSF 
10/20d2 
 
 
 
 
 
 
 
 
 
 
 
 
10/20d2 
 
 
 
10/20d2 
 
 
MRI10,11 
* 
 
 
 
 
10/20d
* 
 
 
 
 
 
 
10/20d2 
 
X8 
X 
10/20d2 
 
X8 
Also refer to footnotes in Table 2. 
 


Appendix 3  
Alzheimer’s Disease Assessment Scale–Cognition 
The Alzheimer’s Disease Assessment Scale (ADAS)-cognition, also referred to as 
ADAS-Cog, with 11-item total score and its modified version with 13-item total score are 
used in the study.  The 13-item total score is calculated using the sum of all the 13-item 
scores shown below, whereas the 11-item total score is calculated using the sum of 
all-item scores except Item 4 (delayed word recall task) and Item 13 (number 
cancellation). 
The item scores are derived from the following: 
• 
Item 1:  word recall 
Three trials of reading and recall are given.  The item score is calculated using 
the mean number of “total not recalled” recorded on the electronic Case Report 
Form (eCRF) for the three trials.  The item score has a range of 0−10.  If the 
“total not recalled” in any of the three trials is missing, then the item score will be 
set to missing. 
• 
Item 2:  following commands 
The item score is the number of incorrect responses on commands (i.e., no) for 
Questions 2a−e on the eCRF.  The score has a range of 0−5. 
• 
Item 3:  constructional praxis 
The item score is available from Question 3e on the eCRF.  The score has a 
range of 0−5. 
• 
Item 4:  delayed word-recall task 
The item score is “total not recalled” on the eCRF.  The score has a range of 
0−10. 
• 
Item 5:  naming objects and fingers 
The item score is derived on the basis of “total incorrect” recorded on the eCRF 
and determined as follows: 
0 = 0−2 incorrect 
1 = 3−5 incorrect 
2 = 6−8 incorrect 
3 = 9−11 incorrect 
4 = 12−14 incorrect 
5 = 15−17 incorrect 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
35 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
36 
Appendix 3  
Alzheimer’s Disease Assessment Scale–Cognition (cont.) 
• 
Item 6:  ideational praxis 
The item score is equal to the “total incorrect” recorded on the eCRF for this item.  
The score has a range of 0−5. 
• 
Item 7:  orientation 
The item score is equal to the “total incorrect” recorded on eCRF for this item.  
The score has a range of 0−8. 
• 
Item 8:  word recognition 
The item score is equal to the “total incorrect” recorded on eCRF if “total 
incorrect” is ≤ 12.  If the “total incorrect” is > 12, the item score is 12.  The item 
score has a range of 0−12. 
• 
Item 9:  remembering test instructions 
The item score is derived on the basis of replies recorded on the eCRF and 
determined as follows:  0 = none, 1 = very mild, 2 = mild, 3 = moderate, 
4 = moderately severe, and 5 = severe. 
• 
Item 10:  comprehension 
The item score is derived on the basis of replies recorded on the eCRF and 
determined as follows:  0 = none, 1 = very mild, 2 = mild, 3 = moderate, 
4 = moderately severe, and 5 = severe. 
• 
Item 11:  word-finding difficulty 
The item score is derived on the basis of replies recorded on the eCRF and 
determined as follows:  0 = none, 1 = very mild, 2 = mild, 3 = moderate, 
4 = moderately severe, and 5 = severe. 
• 
Item 12:  spoken language ability 
The item score is derived on the basis of replies recorded on the eCRF and 
determined as follows:  0 = none, 1 = very mild, 2 = mild, 3 = moderate, 
4 = moderately severe, and 5 = severe. 


 
Gantenerumab—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WN25203 
37 
Appendix 3  
Alzheimer’s Disease Assessment Scale–Cognition (cont.) 
• 
Item 13:  number cancellation 
The item score has a range of 0−5 with a maximum score of 5, given if the item is 
not performed for cognitive reasons.  The item score is derived from the 
cancellation score, which is equal to the number of target hits (minus) the 
number of errors (minus) the number of times reminded of task, and is 
determined as shown below: 
0 = cancellation score is > 23 
1 = cancellation score is 18−22 
2 = cancellation score is 13−17 
3 = cancellation score is 9−12 
4 = cancellation score is 5−8 
5 = cancellation score is 0−4 
 
This 45-second version of scoring rule is the scoring rule that Alzheimer Disease 
Neuroimaging Initiative is using and is based on the proposal of the ADAS 
Instrument Committee. 


STATISTICAL ANALYSIS PLAN APPROVAL
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 WN25203: Part 3 
STATISTICAL ANALYSIS PLAN
TITLE:
MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP TWO YEAR 
STUDY TO EVALUATE THE EFFECT OF SUBCUTANEOUS
RO4909832 ON COGNITION AND FUNCTION IN 
PRODROMAL ALZHEIMER'S DISEASE WITH OPTION FOR 
UP TO AN ADDITIONAL TWO YEARS OF TREATMENT AND 
AN OPEN-LABEL EXTENSION WITH ACTIVE STUDY 
TREATMENT; PART III: OPEN-LABEL EXTENSION FOR 
PARTICIPATING PATIENTS
PROTOCOL NUMBER:
WN25203
STUDY DRUG:
Gantenerumab (RO4909832)
VERSION NUMBER:
H
IND NUMBER:
102,266
EUDRACT NUMBER:
2010-019895-66
SPONSOR:
Hoffmann-La Roche Ltd
PLAN PREPARED BY:
DATE FINAL:
See electronic date stamp below.
Date and Time(UTC)        Reason for Signing                              Name
13-Nov-2020 10:42:15
Company Signatory


Gantenerumab—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan WN25203: Part 3
TABLE OF CONTENTS
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Protocol Synopsis.................................................................... 7
2.2
Outcome Measures ................................................................. 7
2.2.1
Efficacy Outcome Measures.................................................... 7
2.2.1.1
Clinical Dementia Rating ......................................................... 8
2.2.1.2
Functional Activities Questionnaire.......................................... 8
2.2.1.3
Mini Mental State Exam........................................................... 8
2.2.1.4
Dementia Assessment............................................................. 9
2.2.1.5
Alzheimer Disease Assessment Scale-Cognition.................... 9
2.2.1.6
Free and Cued Selective Reminding Test –
Immediate Recall..................................................................... 9
2.2.2
Safety Outcome Measures ...................................................... 9
2.2.3
Pharmacokinetic Outcome Measures.................................... 10
2.2.4
Biomarker Outcome Measures.............................................. 10
2.3
Determination of Sample Size ............................................... 10
2.4
Analysis Timing ..................................................................... 10
3.
STUDY CONDUCT..................................................................................... 10
3.1
Randomization....................................................................... 10
3.2
Independent Imaging Review Facility .................................... 11
3.3
Data Monitoring ..................................................................... 11
4.
STATISTICAL METHODS .......................................................................... 11
4.1
Analysis Populations ............................................................. 11
4.1.1
Safety Population .................................................................. 11
4.1.2
Safety Population with Post OLE Baseline MRI..................... 12
4.2
Analyses of Study Conduct.................................................... 12
4.3
Analyses of Treatment Group................................................ 12
4.3.1
Demographic Data and Baseline Characteristics .................. 12
4.3.2
Previous and Concomitant Medications and 
Medical History...................................................................... 13
4.4
Efficacy Analyses .................................................................. 13


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4.4.1
Efficacy Endpoint................................................................... 14
4.5
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 14
4.5.1
PK and ADA Analysis ............................................................ 14
4.5.2
PD and Exploratory Biomarker Analyses............................... 14
4.5.3
Magnetic Resonance Imaging Volumetric 
Measures............................................................................... 15
4.6
Safety Analyses..................................................................... 15
4.6.1
Exposure to Study Medication............................................... 15
4.6.2
Adverse Events ..................................................................... 15
4.6.3
MRI Safety Findings and Injection-Site Reactions................. 16
4.6.4
Laboratory Data..................................................................... 17
4.6.5
Vital Signs and Electrocardiograms....................................... 17
4.6.6
Deaths ................................................................................... 18
4.6.7
Subgroup Analyses ............................................................... 18
4.7
Interim Analyses .................................................................... 18
4.8
Analyses Related to COVID-19 ............................................. 18
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ...................................................................... 19
Appendix 2
Schedule of Assessments.......................................................... 25
Appendix 3
Alzheimer’s Disease Assessment Scale - Cognition.................. 32


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GLOSSARY OF ABBREVIATIONS
AD
Alzheimer’s disease
ADAS-Cog
Alzheimer Disease Assessment Scale - Cognition
AE
adverse event
AESI
adverse event of special interest
APOE
apolipoprotein E
ARIA
amyloid-related imaging abnormality
ARIA-E
amyloid-related imaging abnormality – edema
ARIA-H
amyloid-related imaging abnormality – hemosiderin 
AUC0-T
area under the plasma concentration-time curve
CCOD
clinical cutoff date 
CDR
Clinical Dementia Rating
CDR-SOB
Clinical Dementia Rating – Sum of Boxes
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CSF
cerebrospinal fluid
CSR
clinical study report
C-SSRS
Columbia−Suicide Severity Rating Scale
DO
dropout
ECG
electrocardiogram
eCRF
electronic Case Report Form
FAQ
Functional Activities Questionnaire
FCSRT-IR
Free and Cued Selective Reminding Test – Immediate 
Recall
FU
follow-up
iDMC
independent Data Monitoring Committee
IMC
Internal Monitoring Committee
LEAP
Learning Embeddings for Atlas Propagation
MedDRA
Medical Dictionary for Regulatory Activities
MMSE
Mini Mental State Exam
MRI-C
MRI Review Committee 
OLE
open-label extension
PD
pharmacodynamic
PET
positron emission tomography 
PK
pharmacokinetic
PT
preferred term


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Q4W
every 4 weeks
QTcB
QT corrected using Bazett’s formula
QTcF
QT corrected using Fridericia’s formula
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SE
safety-evaluable 
SOC
system organ class 
SUVR
standard uptake value ratio


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1.
BACKGROUND
This document describes the planned statistical analyses that will be reported in the final 
Clinical Study Report (CSR) for open-label extension (OLE) treatment (Part 3) of Study
WN25203.  
Study WN25203 was originally designed as a double-blind placebo-controlled proof-of-
efficacy trial with safety data review to be performed by an independent Data Monitoring 
Committee (iDMC). As stated in Protocol Version H, the study has 3 parts:

In Part 1 (double-blind), participants were randomized to gantenerumab or placebo, 
with 26 planned treatments every 4 weeks (Q4W).

Participants who completed Part 1 of the study through the Week 104 visit could 
enter the optional (blinded) extension part of the study (Part 2) and continue 
receiving the same treatment for up to 2 additional years. However, dosing was 
suspended on 19 December 2014 after an interim analysis showed that the study 
was unlikely to meet the primary endpoint.  Details are available in the published 
CSR (January 2016, with clinical cutoff date (CCOD) 22 June 2015).

After a treatment-free follow-up period (approximately 12-18 months based on the 
approval of Protocol Version G), participants had the option to enter an open-label 
extension (Part 3) and receive higher doses of gantenerumab treatment.
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 final CSR 
are not within the scope of this document and will be covered in the CSR content map. 
The language used in this statistical analysis plan (SAP) supersedes that in the protocol 
and protocol synopsis.
2.
STUDY DESIGN
Study WN25203 is a Phase III, multicenter, randomized, double-blind, placebo-
controlled, parallel-group study, followed by an open-label extension with active study 
drug treatment for participants with prodromal Alzheimer’s disease (AD).  A total of 799 
participants were randomized and 797 participants received gantenerumab or placebo. 
In Part 1, there were 266 participants in the placebo group, 271 participants in the 
gantenerumab 105 mg group, and 260 participants in the gantenerumab 225 mg group. 
Participants could enter Part 2 to receive treatment for up to 2 years of extension.  After 
the completion of the double-blind treatment in Part 1 or Part 2, participants had the 
option to enter Part 3, the OLE, after completing a treatment-free follow-up period of 
approximately 1218 months.
Overall,154 participants that had originally enrolled in Study WN25203 continued in Part
3 (OLE). 


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In the OLE, gantenerumab was administered subcutaneously (SC) Q4W with the 
following up-titration regimens to reach the target dose of 1200 mg gantenerumab.:

Up-titration scheme I: dosing in Apolipoprotein E (APOE) 4 carriers (14 and 24 
genotypes) previously on placebo, in any participant previously on 105 mg 
gantenerumab, and in any participant previously on 225 mg gantenerumab meeting 
criteria for dose reduction due to amyloid-related imaging abnormalities (ARIA):
–
Doses 1, 2, and 3: 105 mg SC
–
Doses 4, 5, and 6: 225 mg SC
–
Doses 7 and 8: 450 mg SC
–
Doses 9 and 10: 900 mg SC
–
Dose 11 onwards: 1200 mg SC

Up-titration scheme II: dosing in APOE Ɛ4 non-carriers (0Ɛ4 genotype) and in APOE 
Ɛ4 carriers receiving 225 mg gantenerumab until the end of double-blind treatment 
(1Ɛ4 genotype):
–
Doses 1 and 2: 225 mg SC
–
Doses 3 and 4: 450 mg SC
–
Doses 5 and 6: 900 mg SC
–
Dose 7 onwards: 1200 mg SC
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis and Schedule of Assessments can be found in Appendix 1 and 
Appendix 2 respectively.
2.2
OUTCOME MEASURES
The references for the efficacy assessment and procedures can be found in protocol 
Sections 5.2 and 11.
2.2.1
Efficacy Outcome Measures
Efficacy outcome assessments collected in the OLE include Clinical Dementia Rating 
scale (CDR), Functional Activities Questionnaire (FAQ), Mini Mental State Exam 
(MMSE), Dementia Assessment, Alzheimer Disease Assessment Scale-Cognition 
(ADAS-Cog), and Free and Cued Selective Reminding Test – Immediate Recall 
(FCSRT-IR). Definition and schedules of these measurements can be found in 
WN25203 protocol Section 5.2 and in the Schedule of Assessments in Appendix 2.
Results of these efficacy analyses will be interpreted in a descriptive and exploratory 
fashion.


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2.2.1.1
Clinical Dementia Rating 
The CDR global score is calculated on the basis of Washington University’s CDR 
assignment algorithm (https://biostat.wustl.edu/~adrc/cdrpgm/index.html). Investigators 
enter scores from each of the six categories (“box scores”), and the CDR global score is 
calculated using a calculator available at 
http://www.biostat.wustl.edu/~adrc/cdrpgm/index.html. The global scores are recorded 
on the electronic Case Report Form (eCRF) by investigators and are the basis of 
analyses of CDR global scores in this study.
The global CDR score is derived from the scores in each of the six categories (“box 
scores”) and is determined as follows (Memory [M] is considered the primary category, 
and all others are secondary):

CDR = M if at least three secondary categories are given the same scores as 
memory.

CDR = score of majority of secondary categories with at least three secondary 
categories given a score greater or less than the memory score on one side of M, 
except in the case of CDR= M (see the subsequent point).

CDR = M when three secondary categories are scored on one side of M and two 
secondary categories are scored on the other side of M.

If M = 0.5, then CDR cannot be 0 and it can only be 0.5 or 1; CDR= 1 if at least 
three of the other categories are scored ≥1.

If M = 0, then CDR = 0; if there are impairments (≥0.5) in two or more secondary 
categories, then CDR= 0.5.

When there are ties in the secondary categories on one side of M, the chosen tied 
score for CDR is the closest score to M (e.g., If M and another secondary category 
= 3, two secondary categories = 2, and two secondary categories = 1, then CDR= 
2).

When only one or two secondary categories are given the same score as M, then 
CDR = M as long as no more than two secondary categories are on either side of M.

When M ≥1, then CDR cannot be 0; in such a circumstance, CDR= 0.5 when the 
majority of secondary categories are 0.
2.2.1.2
Functional Activities Questionnaire
The FAQ is an informant-based assessment that presents a forced choice of four levels 
of functioning for ten activities of daily living. Total scores for FAQ will be summarized.
2.2.1.3
Mini Mental State Exam
The MMSE comprises 11 items to assess a participant’s mental status and identifies the 
individual’s general level of impairment in five areas: orientation, short-term memory 
retention, attention, short-term recall, and language. The total score is calculated by 
summing the scores of all 11 items; the maximum total score is 30.


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2.2.1.4
Dementia Assessment
Time to dementia is defined as the time interval between the first treatment date and the 
date that participant is assessed as having Alzheimer-type dementia by investigators.
2.2.1.5
Alzheimer Disease Assessment Scale-Cognition
The ADAS-Cog with an 11-item total score and its modified version with a 13-item total 
score are used in the study. The item scores are derived per description in Appendix 3. 
The 13-item total score is calculated using the sum of all the 13-item scores, whereas 
the 11-item total score is calculated using the sum of all item scores except Item 4 
(delayed word recall task) and Item 13 (number cancellation). If any item score is 
missing or is invalid, the total score will be set to missing. The 13-item ADAS-Cog total 
score has a range of 0−85, whereas the 11-item ADAS-Cog total score has a range of 
0−70. Higher scores indicate greater pathology.
2.2.1.6
Free and Cued Selective Reminding Test – Immediate Recall
The FCSRT-IR uses written words and immediate recall after each card with four words 
completed. The FCSRT-IR is a measure of memory under conditions that control 
attention and cognitive processing in order to obtain an assessment of memory not 
confounded by normal age-related changes in cognition. The performance on the 
FCSRT-IR has been associated with nonclinical and early dementia in several 
longitudinal epidemiologic studies.
2.2.2
Safety Outcome Measures
The following safety outcome measures will be assessed:

Incidence and nature of MRI safety findings: amyloid-related imaging abnormality –
edema (ARIA-E) and amyloid-related imaging abnormality – hemosiderin (ARIA-H)

Incidence, nature, and severity of serious adverse events (SAEs)

Incidence, nature, and severity of adverse events (AEs)

Incidence of treatment discontinuations due to AEs

Mean changes in clinical laboratory tests from baseline over time and incidence of 
abnormal laboratory values and abnormal laboratory values reported as adverse 
events

Mean changes in electrocardiogram (ECG) assessments from baseline over time 
and incidence of abnormal ECG assessments

Incidence of anti-gantenerumab antibodies

Mean change in vital signs assessment from baseline over time and incidence of 
abnormal vital signs measurements

Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent, 
as determined using the Columbia−Suicide Severity Rating Scale (C-SSRS)


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2.2.3
Pharmacokinetic Outcome Measures
The following pharmacokinetic (PK) outcome measures will be assessed:

Plasma concentrations at each PK sample time point
A population PK model previously developed using nonlinear mixed-effects modeling 
(Roche Report No. 1105289) will be used to derive individual measures of exposure at 
steady state such as: 

Maximum plasma concentration (Cmax)

Trough plasma concentration (Cmin)

The area under the plasma concentration-time curve (AUC0-τ)
2.2.4
Biomarker Outcome Measures
Cerebrospinal fluid (CSF) samples for biomarker analysis were not collected in the OLE.
No exploratory biomarker analyses will be reported.
2.3
DETERMINATION OF SAMPLE SIZE
All individuals who had participated in Part 1 or Part 2 prior to the futility analysis and 
had at least one follow-up (FU)/dropout (DO) visit after the double-blind treatment 
(placebo or 105 mg or 225 mg gantenerumab SC Q4W) were offered the opportunity to 
participate in the OLE. A total of 154 participants enrolled in the OLE. The determination 
of sample size for the double-blind section of the study can be found in the protocol 
Section 8.3.
2.4
ANALYSIS TIMING
The analysis covered in this SAP will include all data collected from participants enrolled 
in the OLE. Participants started transitioning from the double blind to the OLE in 
February 2016, receiving gantenerumab based on up-titration scheme I or up-titration 
scheme II up to OLE Week 236. Data from all visits in the OLE until the end of the study
will be reported. In addition, safety data collected between the end of the double-blind 
and the start of OLE will be included.
The start of the OLE is defined as the date when participants received the first dose of 
gantenerumab in the OLE. The end of the study will be considered to be the date of the 
last visit (including the last scheduled follow-up visit according to study protocol) of the 
last participant in the study.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Participants enrolled in the OLE were not randomized. Depending on the APOE 4 
carrier status and/or gantenerumab received previously in Part 1 and Part 2, OLE 
participants were assigned to one of two up-titration dosing schemes. Details can be 
found in Section 2.


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3.2
INDEPENDENT IMAGING REVIEW FACILITY
All MRI scans were read and reported by the central reader in alignment with the 
processes from Parts 1 and 2 of the trial. When the central reader identified a new MRI 
finding, the study center medical staff and the Sponsor were notified, and in the case of 
relevant new MRI findings (as defined in the MRI Review Committee (MRI-C) Charter), 
the Sponsor, in turn, notified the MRI-C concurrently. The MRI-C was actively involved in 
the review and had the remit to make recommendations that might deviate from the 
protocol guidelines, as deemed necessary. During Parts 1 and 2, the MRI-C reviewed 
MRI findings as described in protocol Sections 5.1.3 and 5.1.4.3, respectively. In Part 3, 
the committee reviewed relevant MRI findings as defined in the MRI-C Charter.
3.3
DATA MONITORING
An Internal Monitoring Committee (IMC) was set up in the OLE to review the
accumulating safety and efficacy data in an open-label fashion on a quarterly basis until 
December 2018. Thereafter, the IMC reviewed the accumulating safety and efficacy data 
every 6 months, supplemented by ad-hoc cross-functional review of the data on a per 
need basis.
4.
STATISTICAL METHODS
In the following sections, for all continuous variables for which descriptive statistics are 
indicated, the following statistics will be reported:  the number of observations, the mean, 
median, standard deviation, and minimum and maximum.  The 25th and 75th percentiles 
(Q1 and Q3) will also be reported for selected tables.
Statistical analyses will primarily focus on safety aspects during and after the up-titration 
phase in OLE. The efficacy analyses, including cognitive/functional measures, will be 
analyzed and interpreted in an exploratory fashion.
The start of the OLE is defined as the date when participants received the first dose of 
gantenerumab in the OLE. The OLE baseline is defined as the last available assessment 
up to and including the first day of study drug intake in the open-label extension. Per 
protocol, participants eligible for OLE should be confirmed during the OLE pre-baseline 
and MRI should be performed within 8 weeks, with results available before the first 
dosing visit in the OLE.
4.1
ANALYSIS POPULATIONS
4.1.1
Safety Population
The safety-evaluable (SE) population  includes participants who received any dose of 
gantenerumab during OLE. Analysis using this population will be performed by previous 
randomization. 


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4.1.2
Safety Population with Post OLE Baseline MRI 
The participants in the SE population which had at least one post-OLE baseline MRI.
4.2
ANALYSES OF STUDY CONDUCT
The following will be summarized using descriptive statistics:

Number of participants enrolled, and the number and percentage of participants who 
prematurely withdrew from the study (including the reasons for discontinuation and 
the distribution of these discontinuations by visit) 

Incidence of protocol deviations – overall and by four main categories (inclusion 
criteria, exclusion criteria, medication and procedural)
4.3
ANALYSES OF TREATMENT GROUP
4.3.1
Demographic Data and Baseline Characteristics
Baseline characteristics will be analyzed descriptively for the SE population by previous 
randomization.  The OLE baseline is defined as the last available assessment up to and 
including the first day of study drug intake in OLE.
Treated patients have received at least one dose of study drug.  The patient 
demographic and screening/OLE baseline variables include the following:

Sex

Age at screening and at OLE baseline

Race

Years of education

Weight

Height

Body mass index

Region

APOE 4 carrier status (yes vs no)

APOE genotype (04, 14, or 24)

ARIA-E during double blind period (yes vs no)

Cumulative ARIA-H at OLE baseline

FAQ, total score at OLE baseline

FCSRT-IR, total score at OLE baseline

MMSE, total score at OLE baseline

ADAS-cog (11-item score, 13-items score) at OLE baseline

CDR-SOB at OLE baseline

CDR-Global score at OLE baseline


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4.3.2
Previous and Concomitant Medications and Medical History
The medical history, previous medication and concomitant medication data collected at 
the double blind baseline will be summarized by previous randomization for the 
participants enrolled in the OLE. 
A patient’s medical history is defined as a record of all medical events (for example: 
procedures and diseases) that start prior to the date of the first dose of study treatment
at the start of double blind. Similarly, medications a patient has received with an end 
date prior to the date of the first dose of study treatment will be classified as previous 
medications.
Any medication ongoing on the date of the first dose of study treatment at the start of 
double blind is classified as previous-concomitant, while any medication starting after the 
first dose of study treatment at the start of double blind is classified as concomitant. 
If the medical event (for example: treatment, procedure or disease) does not have 
complete or valid start and end dates, the following rules will be applied. The reference 
date is defined as the date of the first dose of study treatment.
If the medical event start date is (a) completely missing, or (b) only has the year 
specified, and this is the same as the year of the reference date, or (c) only has the 
month/year specified, and these are the same as the month/year of the reference date, 
then the medical event will be assumed to have started before the reference date.
If the medical event end date is (a) completely missing, or (b) only has the year 
specified, and this is the same as the year of the reference date, or (c) only has the 
month/ year specified, and these are the same as the month/ year of the reference date, 
then the medical event will be assumed to have ended after the reference date.
Otherwise, partial medical start and end dates (month/year or year only) will be 
compared with the corresponding part of the reference date to determine whether strictly 
before or strictly after the reference date (no other possibility exists, because this is 
covered by the two previous bullet points).
4.4
EFFICACY ANALYSES
All efficacy analyses will be descriptive and interpreted in a strictly exploratory fashion. 
The baseline visit includes all assessments performed on OLE Day 1 or before, and the 
first post-baseline visit begins on study Day 2.
There may be instances when different questionnaires are performed on different study 
days within the time window of one visit. In such cases, the earlier study day will be used 
for the time to clinically evident decline endpoint.
Descriptive statistics will be summarized by previous randomization.


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4.4.1
Efficacy Endpoint
Efficacy outcomes of CDR, FAQ, MMSE, ADAS-Cog, and FCSRT-IR at OLE baseline, 
Week 24/52/76/104/128/156/FU were assessed and collected. For each of these 
endpoints, the total scores, change from baseline and percentage change from baseline 
will be summarized by visit.
4.5
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
4.5.1
PK and ADA Analysis
A population PK model previously developed using nonlinear mixed-effects modeling 
(Roche Report No. 1105289) will be used to derive individual measures of exposure 
including  Cmax, Cmin, and AUC0-τ at  steady state. These parameters will be descriptively 
summarized including arithmetic mean, median, standard deviation, range, and CV.
Plasma concentration data for gantenerumab will be tabulated and summarized.
Descriptive summary statistics will include the arithmetic mean, median, range, SD, and 
coefficient of variation, as appropriate. 
Data on anti-gantenerumab antibodies will be summarized.  
4.5.2
PD and Exploratory Biomarker Analyses
The positron emission tomography (PET) substudy was initiated in the double-blind
period and only included 112 participants. Florbetapir 18F (Amyvid TM) was used for 
participants in the amyloid-PET substudy of brain amyloid imaging as a 
pharmacodynamic (PD) measurement of potential effects of gantenerumab on amyloid 
load in the brains of subjects with early (prodromal) Alzheimer’s disease. When 
participants continued into the OLE at centers already involved in the PET substudy, 
participants at those centers were offered to take part in the PET substudy. Additional 
centers could be included and could offer OLE participants to enroll in the PET 
substudy. 
A prespecified standard uptake value ratio (SUVR) identical to the method report for SR 
double-blinded analyses will be used. The conversion is a linear transformation which is 
specified using the mean cerebellar gray reference region:
FBPCL = 184.118 x FBPSUVR – 233.718
Changes in cerebellar gray-cortical composite SUVR from OLE baseline in amyloid load 
will be summarized using descriptive statistics. 


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4.5.3
Magnetic Resonance Imaging Volumetric Measures
The volumetric data for particiants in the OLE were measured by the Learning 
Embeddings for Atlas Propagation (LEAP) technology, which computed the cortical 
thickness. The data received were the percentage change from double-blind screening. 
The percentage changes from screening in hippocampal volume, whole brain volume, 
ventricular volume, and cortical thickness will be summarized by previous randomization 
using descriptive statistics. Available time points include OLE baseline, OLE Week 48, 
OLE Week 100, and OLE Week 152/FU/DO.
4.6
SAFETY ANALYSES
Descriptive statistics will be used to analyze all safety data. The outputs defined in this 
section will be produced using the SE population, unless otherwise specified.
For all safety analyses, Day 1 is defined as the start date of gantenerumab treatment in 
the OLE (Part 3). All analyses, except those for ARIA, will be summarized by previous 
randomization. For ARIA analyses, outputs will be summarized by up-titration scheme 
and/or carrier status.
4.6.1
Exposure to Study Medication
Exposure to study drug will be summarized using the following descriptive statistics:

Treatment duration (years)

Total number of administrations

Total cumulative gantenerumab dose (mg)

Duration on 105mg / 225mg / 450mg / 900mg / 1200mg gantenerumab dosing steps

Total patient years on gantenerumab: time from first dose in OLE until CCOD or 
withdrawal from treatment/study (whichever occurs first)
4.6.2
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version that is current at the time of the analysis (Version 22.1). For each treatment 
group, the frequency of each AE preferred term (PT) will be defined as the number of 
participants experiencing at least one occurrence of the event. As participants will have 
had different amounts of time in the study, the incidence rate will be calculated as the
occurrences divided by the total number of patient-years exposure for the participants in 
the population and treatment group specified. Each table will also present the overall 
number of participants experiencing at least one AE and the total number of AEs
reported. Participant listings will contain PTs and comments for each event. In summary 
tables, AEs will be sorted by system organ class (SOC) (in decreasing order of overall 
incidence), then by PT (in decreasing order of overall incidence). 


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The following safety information will be summarized:  

AEs

SAEs

Study drug-related AEs

Study drug-related SAEs

AEs leading to discontinuation of study treatment 

AEs leading to dose reduction

AEs events leading to no further up-titration 

AEs leading to dose interruption

AEs of special interest (AESIs)
For scientific interpretation, it is important to separate ARIA-H and ARIA-E events in 
listings and tables.Using MedDRA standards, ARIA-E is mapped to the following PTs:
“AMYLOID RELATED IMAGING ABNORMALITY-OEDEMA/EFFUSION” or 
“VASOGENIC CEREBRAL OEDEMA”. ARIA-H is mapped to “CEREBELLAR 
MICROHAEMORRHAGE" or  "CEREBRAL HAEMOSIDERIN DEPOSITION" or 
"CEREBRAL MICROHAEMORRHAGE" or "AMYLOID RELATED IMAGING 
ABNORMALITY-MICROHAEMORRHAGES AND HAEMOSIDERIN DEPOSITS”
AESIs for this study are as follows:

An elevated ALT or AST in combination with either an elevated bilirubin or clinical 
jaundice

Suspected transmission of an infectious agent by the study drug
AESIs are discussed in more detail in protocol Section 7.1.1.4. AESIs in this study will 
be captured by recording all case details on the AE eCRF. 
In the summary table of AEs by relationship to study drug, if a participant has more than 
one occurrence of an event, the most closely related event will be counted. If the 
relationship 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 relationship.
4.6.3
MRI Safety Findings and Injection-Site Reactions
 
 
 
 
 


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Injection-site reactions will be listed and summarized by previous randomization and by 
up-titration scheme. 
4.6.4
Laboratory Data
Laboratory data will be summarized for each assessment using descriptive statistics of 
absolute values, change from baseline values, and percent change from baseline. The 
proportion of participants who develop marked abnormalities during study treatment, on 
the basis of the National Cancer Institute Common Terminology Criteria for Adverse 
Events (NCI CTCAE v4.0) and the International Standard for Handling and Reporting of 
Laboratory Data (COG 2.2), will be summarized.
4.6.5
Vital Signs and Electrocardiograms
Vital signs assessments include systolic blood pressure, diastolic blood pressure, and 
pulse measured throughout the study. Summaries of vital sign measurements at each 
assessment visit using descriptive statistics will be generated for the actual values, the 
change from baseline, and the percent change from baseline.
ECGs are collected throughout the study. Descriptive statistics will be generated for the 
actual values, the change from baseline and the percent change from baseline for the 
following parameters:

Heart rate

PQ (PR) interval

QRS interval

QT interval

RR interval

QT corrected using Bazett’s formula (QTcB) and QT corrected using Fridericia’s 
formula (QTcF)


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18/Statistical Analysis Plan WN25203: Part 3
Duration of the QT interval is inversely correlated with the corresponding heart rate, so it 
should be corrected relative to heart rate to allow a reliable interpretation of changes in 
the QTc interval, independent of the changes in the heart rate. The QT intervals will be 
corrected for the heart rate using Bazett’s and Fridericia’s as follows: 

The QTcB value will be calculated as the QT interval (in milliseconds) divided by the 
squared root of the RR interval (in seconds). 

The QTcF value will be calculated as the QT interval (in milliseconds) divided by the 
cube root of the RR interval (in seconds). 
In some cases, multiple ECGs were performed in error. In these cases, the mean values 
across the ECGs should be used.
Abnormal ECG measurements will be summarized.
4.6.6
Deaths
Deaths will be listed.
4.6.7
Subgroup Analyses
Selected safety analyses will be performed for participants with post-OLE baseline MRI.
4.7
INTERIM ANALYSES
No efficacy interim analyses were planned in the OLE.
4.8
ANALYSES RELATED TO COVID-19 
Listings of AEs associated with COVID-19 and major protocol deviations related to 
COVID-19 will be prepared.


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Appendix 1
Protocol Synopsis
SYNOPSIS OF PROTOCOL NUMBER WN25203H
TITLE
Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group Two Year Study to Evaluate the 
Effect of Subcutaneous RO4909832 on Cognition and 
Function in Prodromal Alzheimer's Disease with Option for 
up to an Additional Two Years of Treatment and an Open-
Label Extension with Active Study Treatment
SPONSOR
Roche
Clinical Phase
3
INDICATION
Prodromal Alzheimer’s Disease
OBJECTIVES OF DOUBLE-
BLIND PART OF THE STUDY
Primary
Secondary
Cognition, global, and functioning
Safety
MRI volumetry
    
   
CSF Biomarkers
Pharmacokinetics/
Anti-Drug Antibodies
To evaluate the effect of gantenerumab versus placebo on 
the change in the Clinical Dementia Rating scale Sum of 
Boxes (CDR-SOB), a global measure of cognition and 
functional ability.
To evaluate the effect of gantenerumab versus placebo on 
cognition (assessed with the Alzheimer Disease 
Assessment Scale-Cognition [ADAS-Cog], Mini Mental 
State Exam [MMSE], Cambridge Neuropsychological Test 
Automated Battery [CANTAB], and the Free and Cued 
Selective Reminding Test-Immediate Recall [FCSRT-IR]) 
on global measures (based on the CDR global score), and 
on functioning (assessed with the Functional Activities 
Questionnaire [FAQ]), on  neuropsychiatric functioning 
(assessed with  the Neuropsychiatric Inventory 
Questionnaire [NPI-Q]) and on time to onset of dementia.
To assess the safety and tolerability of gantenerumab 
assessed by magnetic resonance imaging (MRI), physical 
and neurological examinations, vital signs, blood and urine 
safety tests, ECGs, Columbia-Suicide Severity Rating 
Scale (C-SSRS), Geriatric Depression Scale (GDS), and 
adverse event monitoring.
To evaluate the effect of gantenerumab versus placebo on 
hippocampal volume, whole brain volume, ventricular 
enlargement, and possibly other volumetric measures of 
the brain.
To evaluate the effect of gantenerumab versus placebo on 
levels of cerebrospinal fluid (CSF) biomarkers of 
Alzheimer’s disease (AD) pathology (i.e., total tau [T-tau], 
phospho-tau [p-tau], and amyloid-beta (A1-42]). 
To determine the relationship of plasma and CSF 
concentrations of gantenerumab on other responses. To 
assess incidence of anti-gantenerumab antibodies, and if 
relevant, evaluate its effect on the pharmacokinetic (PK), 
pharmacodynamic (PD), efficacy. and safety parameters. 


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Exploratory
Plasma Biomarkers
Clinical Genotyping
To evaluate the effect of treatment on peripheral 
biomarkers of amyloid deposition and/or clearance, 
neurodegeneration, inflammation, and other markers 
known to be involved in the pathogenesis of AD.
To evaluate the effect of gene encoding apoliprotein E 
(ApoE) 4 genotype and fragment crystalizable gamma 
receptor (FcR) genotype on PK/PD, efficacy, and safety 
parameters
OBJECTIVES OF THE 
OPEN-LABEL EXTENSION -
PART 3
Primary:
Safety:
Secondary:
Brain MRI Volumetry
Brain Amyloid Load by Positron 
Emission Tomography (PET) 
Imaging
Pharmacokinetics
Anti-Drug Antibodies
Cognition, Global, Functioning, 
and Dementia Assessment
To assess short-term and long-term safety and tolerability 
of gantenerumab (RO4909832) given at doses up to 1200 
mg subcutaneous (SC) every 4 weeks (Q4W) by MRI, 
physical and neurological examinations, vital signs, blood 
safety tests, ECGs, C-SSRS, and adverse event 
monitoring.
To evaluate the effect of gantenerumab over time on 
hippocampal volume, whole brain volume, ventricular 
enlargement, and possibly other volumetric measures of 
the brain compared to baseline and to the start of Part 3
To assess changes in amyloid load over time using 
Florbetapir 8F (AV-45; Amyvid) compared to screening 
(if applicable) and to the start of Part 3.  PET scans 
performed within 12 months prior to the first study drug 
administration in Part 3 will be used for the baseline of 
Part 3.  This objective will be evaluated in a subset of 
consenting subjects participating in the PET substudy.
To determine the relationship of plasma concentrations of 
gantenerumab on other responses
To assess the development of anti-gantenerumab 
antibodies and, if detected, explore their association with 
the PK, PD, efficacy, and safety parameters of 
gantenerumab. 
To evaluate the effect of gantenerumab over time as 
assessed with the CDR-SOB, the ADAS-Cog, the MMSE, 
the FCSRT-IR, the CDR global score, the FAQ compared 
to baseline and to the start of Part 3, and to determine the 
presence of and time to onset of dementia.
TRIAL DESIGN
Multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study, followed by open-label extension with 
active study drug treatment


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NUMBER OF SUBJECTS
Approximately a total of 770 subjects; 514 on 
gantenerumab and 256 on placebo.  The sample size was 
confirmed following a planned blinded evaluation of the 
variance in the change in the CDR-SOB at Week 76. The 
study enrolled 799 subjects, and 797 subjects were dosed 
with double-blind treatment:  266 subjects in the placebo 
group, 271 subjects in the gantenerumab 105 mg group, 
and 260 subjects in the gantenerumab 225 mg group. 
The number of subjects enrolled in Part 3 is 154.
TARGET POPULATION
Subjects who meet memory and biomarker criteria which 
indicate a strong likelihood that they are in the prodromal 
phase of Alzheimer’s Disease
LENGTH OF STUDY 
Double-blind treatment period:
Part 1:  Approximately 2 years and 2 months which 
includes 8 weeks for screening and 2 years (104 weeks) of 
treatment.
Part 2:  Up to additional 2 years of treatment.
Dosing was suspended on 19 December 2014. As a result 
duration of the double-blind treatment period varied 
depending on the number of study weeks that subjects 
completed.
Treatment-free follow-up period:  
Twelve weeks of follow up after completion of the double-
blind treatment in Part 1 or Part 2, with an optional follow-
up visit approximately 1 year (52 weeks) after the end of 
the double-blind treatment.  
Approximate duration of the study for subjects completing 
both Part 1 and Part 2 with the maximum 52-week follow-
up and not continuing in Part 3 will be 5 years and 2 
months.  For the last subjects enrolled, approximate 
duration of the study will be 2 years and 2 months (year 1 
of Part 1 and 1 year of treatment-free follow-up).
Open-label extension
Part 3:  Up to 3 years of active study drug treatment (with a 
4-week follow-up visit) after treatment-free follow-up 
period. For subjects continuing in Part 3, treatment-free 
follow-up period will last approximately between 12 and 18 
months (depending on the approval of study protocol 
WN25203G by local Competent Authorities).  All subjects 
who complete 3 years of open-label treatment will be 
given the option of extending open-label treatment 
until July 2020 and may receive up to 21 additional 
administrations every 4 weeks during Years 4 and 5.  
END OF STUDY
The end of the study will be considered to be the date of 
the last visit (including the last scheduled follow-up visit 
according to study protocol) of the last subject in the study.




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PROCEDURES (summary):
Screening and baseline:  After written informed consent is obtained, screening 
assessments, which include general health and cognitive testing, brain MRI, and 
lumbar puncture for cerebrospinal fluid (CSF) collection, and must be completed 
within 8 weeks followed by up to 1 week for baseline assessments. (See schedule 
of assessments in protocol)
Treatment (Part 1):  In this study, all subjects will receive 26 treatments (drug 
administrations) with a 4-week interval between each dose.  On each dosing day, 
gantenerumab or matching placebo will be administered as 
 SC injections in 
the abdominal area.  Safety and efficacy evaluations will be performed according 
to the schedule of assessments. 
Treatment Extension (Part 2):  Subjects who complete the entire 2 years of 
treatment and the Week 104 follow-up visit may continue to receive the same 
treatment that they were receiving at the Week 100 visit.  The double-blind 
treatment can resume at the Week 104 visit after all assessments have been 
completed for that visit.  
Follow-up:  Subjects will be followed for 12 weeks, with an optional follow-up visit 
approximately 1 year (52 weeks) after the last dose of study treatment in Part 1 or 
Part 2 (double-blind treatment phase). The Week 52 visit is not required for 
subjects entering Part 3.
Futility Analysis:  A futility interim analysis was performed when approximately 50% 
of the sample size completed the Week 104 visit.  As the study was declared futile, 
with a low likelihood of meeting the prespecified primary outcome measure with 
the doses studied (105 and 225 mg), dosing was suspended on 
19 December 2014.  This analysis did not reveal any new safety signal.
Open-Label Extension (Part 3):  Additional analyses of efficacy and PD results 
(CSF biomarkers of neurodegeneration and amyloid PET standardized uptake 
value ratio [SUVR]) indicated that higher doses of gantenerumab may have 
clinically relevant effect on cognition and function.  Doses were modeled based on 
the results of the PET substudy (brain amyloid PET SUVR) and on the supportive 
results of the Phase 1b (PRIME) study, investigating the effects of aducanumab 
on a total of 165 patients with prodromal or mild AD.  Aducanumab is a monoclonal 
antibody with similar properties and mode of action as gantenerumab.  The results 
showed a dose- and time-dependent reduction of amyloid plaques in the brain that 
was associated with dose-dependent clinical effect, which reached statistical 
significant clinical effect with the highest aducanumab dose tested.  Extrapolation 
of the data indicated that approximately 20% reduction in brain amyloid detected 
by PET may be needed to achieve clinical effect, compared to overall 
approximately 5% achieved with 225 mg gantenerumab over 2 years.
All subjects who were eligible for and enrolled into protocol WN25203 and had at 
least one follow-up/dropout visit after the double-blind treatment will be offered the 




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25/Statistical Analysis Plan WN25203: Part 3
Appendix 2
Schedule of Assessments
Table 1
Schedule of Assessments – Open-Label Extension Year 1 - for ApoE 4 carriers previously on:  1) 
Placebo, 2) 105 mg Gantenerumab and 3) 225 mg Gantenerumab meeting Criteria for Dose Reduction 
due to ARIAs
Visit by week #
OLE Pre-baseline 
(8 weeks)
Day 1 (OLE 
Baseline)
4
8
12
16
20
24
28
32
33
36
40
44
48
52
Dose Number
1 
2
3
4
5
6
7
8
9
10
11
12
13
14
Dose (mg)
105
105
105
225
225
225
450
450
900
900
1200 1200 1200 1200
Physical Exam
P
P
P
Neurological Exam
P
P
P
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
P
ECG 
P
P
Blood Labs
P
X
Urine Pregnancy 
Test4
P
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
P
X
P
P
ADA samples
P
P
P
CDR
P-1wk
P
P
FAQ
P-1wk
P
P
MMSE
P-1wk
P
P
Dementia 
Assessment
P-1wk
P
P
ADAS-Cog
P-1wk
P
P
FCSRT-IR
P-1wk
P
P
C-SSRS
P-1wk
X
X
MRI
X
X2
*
X2
*
X2
*
X2
*
X2
*
Refer to Table 4 footnotes.


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Table 2
Schedule of Assessments – Open-Label Extension Year 1- for:  1) ApoE 4 non-carriers and 2) ApoE 4 
Carriers receiving 225 mg Gantenerumab until the End of Double-blind Treatment
Visit by week #
OLE Pre-
baseline 
(8 weeks)
Day 1 
(OLE 
Baseline) 
4
8
12
16
17
20
24
28
32
36
40
44
48
52
Dose Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Dose (mg)
225
225
450
450
900
900
1200
1200
1200
1200
1200
1200
1200
1200
Physical Exam
P
P
P
Neurological Exam
P
P
P
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
P
ECG 
P
P
Blood Labs
P
X
Urine Pregnancy 
Test4
P
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
P
X
P
P
ADA samples
P
P
P
CDR
P-1wk
P
P
FAQ
P-1wk
P
P
MMSE
P-1wk
P
P
Dementia 
Assessment
P-1wk
P
P
ADAS-Cog
P-1wk
P
P
FCSRT-IR
P-1wk
P
P
C-SSRS
P-1wk
X
X
MRI
X
X2
*
X2
*
X2
*
X2
*
X2
*
Refer to Table 4 footnotes.


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27/Statistical Analysis Plan WN25203: Part 3
Table 3
Schedule of Assessments – Open-Label Extension Year 2 for all Participants
Visit by week #
56
60
64
68
72
76
80
84
88
92
96
100
101
104
Dose Number
15
16
17
18
19
20
21
22
23
24
25
26
27
Physical Exam
P
Neurological Exam
P
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
P
ECG 
P
Blood  Labs
X
Urine Pregnancy Test4
P
P
P
P
P
P
P
P
P
P
P
P
P
PK  plasma
P
P
X
P
ADA samples
P
P
CDR
P
P
FAQ
P
P
MMSE
P
P
Dementia Assessment
P
P
ADAS-Cog
P
P
FCSRT-IR
P
P
C-SSRS
X
X
MRI
X2
*
X2
*
Refer to Table 4 footnotes.


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Table 4
Schedule of Assessments – Open-Label Extension Year 3 for all Participants
Visit by week #
108
112
116
120
124
128
132
136
140
144
148
152
OLE156/
FU/DO 5
Unsch.1
Dose Number
28
29
30
31
32
33
34
35
36
37
38
39
Physical Exam
X
X
Neurological Exam
X
X
Vital Signs
P
P
P
P
P
P
P
P
P
P
P
P
X
X
ECG
X
X
Blood  Labs
X
X
Urine Pregnancy 
Test4
P
P
P
P
P
P
P
P
P
P
P
P
X
X
PK  plasma
P
X
X
ADA samples
P
X
X
CDR
P
X
X
FAQ
P
X
X
MMSE
P
X
X
Dementia 
Assessment
P
X
X
ADAS-Cog
P
X
X
FCSRT-IR
P
X
X
C-SSRS
X
X
X
MRI
X2
*
X2,3
*
X


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29/Statistical Analysis Plan WN25203: Part 3
Table 4
Schedule of Assessments – Open-Label Extension Year 3 for all Participants (cont.)
Note: Visit window:   +/- 7 days for dosing days; +/- 3 days for visits that are 1 week post-dose.
OLE Open-Label Extension; P prior to study drug administration: P-1 wk is within 1 week prior the first dose.
Eligibility for Part 3 should be confirmed during OLE pre-baseline, and MRI should be performed within 8 weeks and the results available before 
the first dosing visit in the OLE.  Additional assessments can be performed as per the investigator’s judgment.
MRI scans must be performed within a maximum of 20 days (ideally 1020 days) after dose administration and results made available and 
reviewed before the next scheduled dose. 
* The MRI result as determined by the central reader must be known before a subsequent dose can be given.
1 Any procedure or assessment may be performed at an unscheduled visit as required. 
2 Subjects will be asked if they experience CNS adverse events up to 1 week before each MRI is performed.
3 The results of the final MRI should be available before the final follow-up visit to allow review before the final visit (after the last dose for patients 
not continuing in Part 3 extension after 3 years).
4 Women who are of childbearing potential must have a urine pregnancy test done at the site prior to each dose.
5 Follow-up/drop-out visit to be performed 4 weeks after the last dose during the initial 152 weeks of treatment.


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30/Statistical Analysis Plan WN25203: Part 3
Table 5
Schedule of Assessments – Open-Label Extension Years 4 and 5 for Participants Continuing Part 3 until 
July 2020
Visit by week #
156
160176
180
184204
208
212Onwards 
(Up to 236)
OLE/FU/DO 
5
Unsch. 1
Dose Number
40
4145
46
4752
53
54Onwards 
(Up to 60)
Physical Exam
P
P
X
X
Neurological Exam
P
P
X
X
Vital Signs
P
P
P
P
P
P
X
X
ECG
P
P
X
X
Blood  Labs
P
P
X
X
Urine Pregnancy Test4
P
P
P
P
P
P
X
X
PK  plasma
P
P
X
X
ADA samples
P
P
X
X
CDR
P
FAQ
P
MMSE
P
P
P
X
X
Dementia Assessment
P
ADAS-Cog
P
FCSRT-IR
P
C-SSRS
P
P
P
X
X
MRI
*
L2, 3
*
L2, 3
*
L2, 3
*
X


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Table 5
Schedule of Assessments – Open-Label Extension Years 4 and 5 for Participants Continuing Part 3 until 
July 2020 (cont.)
Note: Visit window:   +/- 7 days for dosing days.
L an MRI after the Last dose within the indicated interval;  OLEOpen-Label Extension; P prior to study drug administration and prior to 
the injections on the day of dosing.
The schedule of assessment outlines the maximum number of week visits and doses until July 2020 and serves as guidance.  The duration of 
Part 3 extension will vary for each subject dependent on when the subject begins the OLE.
MRI scans are scheduled at approximately 6-month intervals and is mandatory after the last study drug administration.  The time between the 
previous scan and the final study scan should not exceed 8 months.
An MRI must be performed within 20 days (ideally 1020 days) after dose administration and results made available and reviewed before the 
next scheduled dose.
* The MRI result as determined by the central reader must be known before a subsequent dosing visit and should be available before the OLE 
follow-up/drop-out visit to allow review before the final visit.
1 Any procedure or assessment may be performed at an unscheduled visit as required. 
2 Subjects will be asked if they experience CNS adverse events up to 1 week before each MRI is performed.
3 The results of the final MRI (after the last dose) should be available before the final follow-up visit to allow review before the final visit.
4.Women who are of childbearing potential must have a urine pregnancy test done at the site prior to each dose.
5 OLE follow-up/drop-out visit to be performed 4 weeks after the last dose in Years 4or 5 of Part 3.


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32/Statistical Analysis Plan WN25203: Part 3
Appendix 3
Alzheimer’s Disease Assessment Scale - Cognition
The Alzheimer’s Disease Assessment Scale (ADAS)-cognition, also referred to as 
ADAS-Cog, with 11-item total score and its modified version with 13-item total score are 
used in the study.  The 13-item total score is calculated using the sum of all the 13-item 
scores shown below, whereas the 11-item total score is calculated using the sum of 
all-item scores except Item 4 (delayed word recall task) and Item 13 (number 
cancellation).
The item scores are derived from the following:

Item 1: word recall
Three trials of reading and recall are given. The item score is calculated using 
the mean number of “total not recalled” recorded on the electronic Case Report 
Form (eCRF) for the three trials. The item score has a range of 010. If the 
“total not recalled” in any of the three trials is missing, then the item score will be 
set to missing.

Item 2:  following commands
The item score is the number of incorrect responses on commands (i.e., no) for
Questions 2ae on the eCRF. The score has a range of 05.

Item 3:  constructional praxis
The item score is available from Question 3e on the eCRF. The score has a 
range of 05.

Item 4:  delayed word-recall task
The item score is “total not recalled” on the eCRF. The score has a range of
010.

Item 5:  naming objects and fingers
The item score is derived on the basis of “total incorrect” recorded on the eCRF 
and determined as follows:
002 incorrect
135 incorrect
268 incorrect
3911 incorrect
41214 incorrect
51517 incorrect

Item 6:  ideational praxis
The item score is equal to the “total incorrect” recorded on the eCRF for this item.  
The score has a range of 05.


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
Item 7:  orientation
The item score is equal to the “total incorrect” recorded on eCRF for this item. 
The score has a range of 08.

Item 8:  word recognition
The item score is equal to the “total incorrect” recorded on eCRF if “total 
incorrect” is 12. If the “total incorrect” is 12, the item score is 12. The item 
score has a range of 012.

Item 9:  remembering test instructions
The item score is derived on the basis of replies recorded on the eCRF and
determined as follows: 0none, 1very mild, 2mild, 3moderate, 
4moderately severe, and 5severe.

Item 10: comprehension
The item score is derived on the basis of replies recorded on the eCRF and
determined as follows: 0none, 1very mild, 2mild, 3moderate, 
4moderately severe, and 5severe.

Item 11:  word-finding difficulty
The item score is derived on the basis of replies recorded on the eCRF and
determined as follows: 0none, 1very mild, 2mild, 3moderate, 
4moderately severe, and 5severe.

Item 12:  spoken language ability
The item score is derived on the basis of replies recorded on the eCRF and
determined as follows: 0none, 1very mild, 2mild, 3moderate, 
4moderately severe, and 5severe.

Item 13:  number cancellation
The item score has a range of 05 with a maximum score of 5, given if the item is 
not performed for cognitive reasons.  The item score is derived from the
cancellation score, which is equal to the number of target hits (minus) the 
number of errors (minus) the number of times reminded of task, and is 
determined as shown below:
0cancellation score is 23
1cancellation score is 1822
2cancellation score is 1317
3cancellation score is 912
4cancellation score is 58
5cancellation score is 04
This 45-second version of scoring rule is the scoring rule that Alzheimer Disease 
Neuroimaging Initiative is using and is based on the proposal of the ADAS 
Instrument Committee.