Clinical trial NCT02670083
Conditions: Alzheimer's Disease
Sponsor: Hoffmann-La Roche
Start date: 2016-03-22; Completion date: 2019-05-31
Enrollment: 813 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, double-blind, placebo-controlled, parallel group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The final efficacy and safety assessment will be performed 52 weeks after the last crenezumab dose. Participants will then have the option to enter the Open Label Extension (OLE) study if eligible. Participants who do not enter the OLE study will have additional follow-up visits at 16 and 52 weeks after the last dose, primarily for safety and also for limited efficacy assessments.

Detailed description:

Arms: arm 1: Participants received intravenous (IV) infusion of Placebo every 4 weeks (Q4W) for 100 weeks. arm 2: Participants received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W) for 100 weeks.
Interventions: intervention 1: Crenezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Crenezumab was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above. intervention 2: Placebo was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A Phase III, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group, Efficacy and Safety Study of Crenezumab 
in Patients with Prodromal to Mild Alzheimer’s Disease 
NCT Number: 
NCT02670083 
Document Date: 
Protocol Version 5: 10-March-2018  
 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Crenezumab—F. Hoffmann-La Roche Ltd
Protocol BN29552, Version 5 
PROTOCOL
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, EFFICACY AND SAFETY 
STUDY OF CRENEZUMAB IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
BN29552
VERSION NUMBER:
5
EUDRACT NUMBER:
2015-003034-27
IND NUMBER:
100,839
TEST PRODUCT:
Crenezumab (RO5490245)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  25 August 2015
DATES AMENDED:
Version 2:  20 October 2015
Version 3:  5 March 2016
Version 4:  11 November 2016
Version 5:  See electronic date stamp below
 
10-Mar-2018 10:31:17
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Crenezumab—F. Hoffmann-La Roche Ltd
2/Protocol BN29552, Version 5
PROTOCOL AMENDMENT, BN29552, VERSION 5:
RATIONALE
Protocol BN29552 has been amended to clarify the study’s secondary and exploratory 
objectives and planned statistical analysis. Additional minor changes have been made 
to improve clarity.  
The main changes to the protocol, along with a rationale for each change, are 
summarized below:

The secondary efficacy objectives have been restructured for clarity. Exploratory 
efficacy objectives have also been added, and endpoints have been amended 
(Section 2.1.2), specifically:

The secondary endpoint Alzheimer’s Disease Assessment Scale-Cognitive 
(ADAS-Cog 12) has been changed to ADAS-Cog 11 as it affords a more 
differentiated endpoint from ADAS-Cog13.  The Mini Mental State Evaluation
(MMSE) change from baseline to Week 105 has been added to assess severity 
of dementia as this scale is a widely used instrument to approximate stage of 
disease.

The time-to-clinically-evident-decline endpoint has been removed because the 
complex scale-based composite endpoint originally proposed is no longer 
considered to have clinical validity. Instead, a number of exploratory efficacy 
endpoints aiming to enable "time to clinically meaningful event"type analyses 
have been added as they may be clinically useful yet rarer and not well-studied 
event endpoints with which to assess and describe the drug’s potential efficacy. 
These event endpoints will be more clearly defined in the Statistical Analysis 
Plan.

Pharmacokinetic and biomarker objectives and endpoints have been restructured 
and updated for clarity (Sections 2.3 and 2.4).

The protocol statistical considerations and analysis plan have been revised as 
follows:

Sample size re-estimation text has been added to Section 6.1 (Determination of 
Sample Size) as re-estimation is commonly done in pivotal studies. In the event 
the variability of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) endpoint 
is observed to be greater than planned, the proposed sample size increase will 
reduce the risk of an underpowered study, thereby reducing the risk of having 
less than 80% power to reach significance when the true relative reduction in 
CDR-SB equals 30%.

Additional endpoints have been added to the type 1 error control hierarchy to 
reflect their importance for valid hypothesis testing in the secondary efficacy 
endpoints analysis (Section 6.4.2).

The Exploratory Efficacy Analyses (Section 6.4.3) and Interim Analysis 
(Section 6.8) sections have been re-written and updated for greater clarity. In 
order to help guard against higher than planned variability in the primary 
endpoint, the timing of futility has been changed to 18 months following 50% of 


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3/Protocol BN29552, Version 5 
enrollment to provide a slightly higher sample size for the futility analysis.  In 
addition, the interim analysis for positive efficacy has been removed in order to 
ensure 2 years of randomized treatment and follow-up in the full safety 
evaluable patient population.

The Biomarker Analyses section has been updated to reflect the biomarker 
objectives (Section 6.7).
In addition, the following minor changes have been made and are summarized 
below with a rationale for each change:

There has been an update to Background on Alzheimer’s Disease (Section 1.1) to 
reflect recent developments and current thinking in the field of Alzheimer’s disease. 

There has been alignment of the following protocol sections with latest crenezumab 
Investigator’s Brochure (Version 10)

Background on Crenezumab and the Summary of Non-Clinical Studies and 
inclusion of recent nonclinical data related to crenezumab’s nonclinical profile 
and mechanism of action (Sections 1.2 and 1.2.1)

Summary of Clinical Studies (Section 1.2.2)

Safety Overview, Immunogenicity and Pharmacokinetics (Sections 1.2.3–1.2.5)

Study Rationale Background (Section 1.3.1)

Additional information describing the findings of previous studies has been added to 
Biomarkers Section 1.2.6.3. 

The Overall BenefitRisk Summary has been updated for greater clarity 
(Section 1.3.6); the riskbenefit profile remains unchanged.

The Overview of Study Design (Section 3.1.1) has been updated to reflect the 
changes introduced elsewhere in this amendment. The following updates have also 
been made to this section:

Clarification of the primary analysis period from the time of randomization 
through to Week 105 (.

Added guidance regarding Long-Term follow-up of patients who discontinue 
study drug early or complete study treatment but do not enter the OLE has been 
added. 

Permitted Therapy (Section 4.4.1) has been updated to provide additional clarity 
and removal of duplicate text regarding antihistamines.

Text has been added to permit other biomarkers associated with Alzheimer’s 
disease or study treatment to be analyzed in peripheral blood samples as 
pharmacodynamics markers (Section 4.5.7.2).

Text has been added to recognize country variability in designation of 
NonInvestigational Medicinal Properties (NIMP)/IMP status to positron emission 
tomography (PET) tracers (Section 4.3.2.2). Adverse event reporting requirements 
for PET ligands administered in this study and associated substudies were also 
added (Sections 5.3.1 and 5.4.2).


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4/Protocol BN29552, Version 5 

Amyloid-related imaging abnormalities (ARIA) text including management of ARIA 
and required dose adjustments has been updated and restructured for greater 
clarity.  New nonclinical information has also been provided (Sections 5.1.1 and 
5.1.2). Additional information and guidance for the reporting of ARIA adverse 
events have also been included in the Selected Adverse Events section 
(Section 5.2.4).

Medical Monitor contact information has been updated in the Emergency Medical 
Contacts to reflect the change in the secondary Medical Monitor (Section 5.4.1).

The Schedule of Activities (Appendix 1) has been updated to provide additional 
guidance and clarity in the footnotes.

The Diagnostic Verification Form (Appendix 4) has been edited to reflect the correct 
process.
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Crenezumab—F. Hoffmann-La Roche Ltd
5/Protocol BN29552, Version 5
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 28
1.1
Background on Alzheimer’s Disease..................................... 28
1.2
Background on Crenezumab................................................. 30
1.2.1
Summary of Nonclinical Studies............................................ 31
1.2.2
Summary of Clinical Studies.................................................. 33
1.2.2.1
Study ABE4427g ................................................................... 34
1.2.2.2
Study ABE4662g ................................................................ 34
1.2.2.3
Study ABE4869g ................................................................ 34
1.2.2.4
Study ABE4955g ................................................................ 35
1.2.2.5
Study GN28525.................................................................. 35
1.2.2.6
Study GN29632.................................................................. 35
1.2.2.7
Study GP29172 .................................................................. 37
1.2.2.8
Study 
.................................................................. 37
1.2.2.9
Study GN28352.................................................................. 37
1.2.3
Safety Overview .................................................................... 37
1.2.3.1
Overall Adverse Event Profile................................................ 38
1.2.3.2
Deaths ................................................................................... 39
1.2.3.3
Pneumonia ............................................................................ 39
1.2.3.4
Amyloid-Related Imaging Abnormalities of 
Edema/Effusion and Hemosiderin Deposition ....................... 40
1.2.3.5
Summary ............................................................................... 40
1.2.4
Immunogenicity ..................................................................... 41
1.2.5
Pharmacokinetics .................................................................. 42
1.2.6
Biomarkers ............................................................................ 43
1.2.6.1
Summary ............................................................................... 43
1.2.6.2
Brain Imaging Pharmacodynamic Biomarkers....................... 43
1.2.6.3
Plasma and Cerebrospinal Fluid 
Pharmacodynamic Biomarkers.............................................. 44
1.3
Study Rationale and Benefit-Risk Assessment...................... 45


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1.3.1
Background ........................................................................... 45
1.3.2
Efficacy.................................................................................. 46
1.3.3
Dose ...................................................................................... 48
1.3.4
Biomarkers ............................................................................ 50
1.3.5
Risk to Patients without Alzheimer’s Disease 
Pathology............................................................................... 51
1.3.6
Overall Benefit-Risk Summary............................................... 51
2.
OBJECTIVES AND ENDPOINTS ............................................................... 52
2.1
Efficacy Objectives ................................................................ 52
2.1.1
Primary Efficacy Objective..................................................... 52
2.1.2
Secondary Efficacy Objectives .............................................. 52
2.1.3
Exploratory Efficacy Objective Endpoints. ............................. 53
2.2
Safety Objective .................................................................... 53
2.3
Pharmacokinetic Objective .................................................... 54
2.4
Biomarker Objectives............................................................. 54
3.
STUDY DESIGN......................................................................................... 55
3.1
Description of the Study......................................................... 55
3.1.1
Overview of Study Design ..................................................... 55
3.1.2
Substudies............................................................................. 58
3.1.3
Use of Symptomatic Treatments for Alzheimer’s 
Disease.................................................................................. 58
3.1.4
Data Monitoring Committee................................................... 58
3.2
End of Study.......................................................................... 58
3.2.1
Long-Term Follow-Up............................................................ 58
3.3
Rationale for Study Design.................................................... 59
3.3.1
Rationale for Treatment Duration .......................................... 59
3.3.2
Rationale for Long-Term Follow-Up....................................... 59
3.3.3
Rationale for Crenezumab Dosage ....................................... 59
3.3.4
Rationale for Patient Population ............................................ 60
3.3.5
Rationale for Control Group................................................... 62
3.3.6
Rationale for Rescue Strategy............................................... 62
3.3.7
Rationale for Diagnostic Verification...................................... 62
3.3.8
Rationale for Primary Outcome Measure............................... 62


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3.3.8.1
Clinical Dementia Rating-Sum of Boxes................................ 63
3.3.9
Rationale for Key Secondary Outcome Measures................. 63
3.3.9.1
Alzheimer’s Disease Assessment 
Scale-Cognition ..................................................................... 64
3.3.9.2
ADCS-iADL and ADCS-ADL Total Score .............................. 64
3.3.10
Rationale for Pharmacokinetic Sampling............................... 64
3.3.11
Rationale for Biomarker Assessments................................... 65
3.3.11.1
Cerebrospinal Fluid Biomarkers ............................................ 65
3.3.11.2
Positron Emission Tomography Imaging 
Biomarker .............................................................................. 65
3.3.11.3
Brain Volumetry..................................................................... 65
4.
MATERIALS AND METHODS .................................................................... 66
4.1
Patients.................................................................................. 66
4.1.1
Inclusion Criteria.................................................................... 66
4.1.2
Exclusion Criteria................................................................... 68
4.2
Method of Treatment Assignment and Blinding..................... 73
4.3
Study Treatment.................................................................... 74
4.3.1
Formulation, Packaging, and Handling.................................. 74
4.3.1.1
Crenezumab and Placebo ..................................................... 74
4.3.2
Dosage, Administration, and Compliance.............................. 74
4.3.2.1
Crenezumab and Placebo ..................................................... 74
4.3.2.2
Non-Investigational Medicinal Products................................. 75
4.3.3
Investigational Medicinal Product Accountability ................... 75
4.3.4
Post-Trial Access to Crenezumab ......................................... 75
4.4
Concomitant Therapy ............................................................ 76
4.4.1
Permitted Therapy................................................................. 76
4.4.2
Prohibited Therapy ................................................................ 78
4.5
Study Assessments ............................................................... 78
4.5.1
Informed Consent Forms and Screening Log........................ 78
4.5.2
Medical History and Demographic Data ................................ 79
4.5.3
Physical Examinations........................................................... 79
4.5.4
Vital Signs.............................................................................. 80
4.5.5
Cognitive Assessments ......................................................... 80


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4.5.5.1
Clinical Dementia Rating Scale ............................................. 80
4.5.5.2
Alzheimer’s Disease Assessment 
Scale-Cognition ..................................................................... 81
4.5.5.3
Alzheimer’s Disease Cooperative 
Study-Activities of Daily Living Inventory .............................. 81
4.5.5.4
Mini-Mental State Examination.............................................. 81
4.5.5.5
Free and Cued Selective Reminding Test ............................. 81
4.5.5.6
Neuropsychiatric Inventory-Questionnaire............................. 82
4.5.5.7
Columbia−Suicide Severity Rating Scale .............................. 82
4.5.5.8
Zarit Caregiver Interview for Alzheimer’s Disease................. 82
4.5.5.9
Quality of Life–Alzheimer’s Dementia.................................... 82
4.5.5.10
EQ-5D.................................................................................... 83
4.5.6
Electronic Assessment of Rating Scales ............................... 83
4.5.7
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 83
4.5.7.1
Standard Laboratory Samples............................................... 83
4.5.7.2
Biomarker Sampling .............................................................. 84
4.5.7.3
Immunogenicity Sampling...................................................... 86
4.5.7.4
Pharmacokinetic Sampling .................................................... 86
4.5.8
Timing of Study Assessments ............................................... 87
4.5.8.1
Screening and Pretreatment Assessments............................ 87
4.5.8.2
Assessments at Baseline....................................................... 89
4.5.8.3
Assessments during Treatment............................................. 90
4.5.8.4
Assessments at Week 105 (or Early Termination) 
Visit........................................................................................ 91
4.5.9
Confidentiality........................................................................ 91
4.5.10
Brain Magnetic Resonance Imaging...................................... 91
4.5.11
Electrocardiograms................................................................ 92
4.5.12
Samples for Roche Clinical Repository.................................. 93
4.5.12.1
Overview of the Roche Clinical Repository............................ 93
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 93
4.5.12.3
Sample Collection.................................................................. 93
4.5.12.4
Confidentiality........................................................................ 94


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4.5.12.5
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 95
4.5.12.6
Withdrawal from the Roche Clinical Repository..................... 95
4.5.12.7
Monitoring and Oversight....................................................... 95
4.6
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 96
4.6.1
Patient Discontinuation.......................................................... 96
4.6.2
Study Treatment Discontinuation........................................... 96
4.6.2.1
Withdrawal from Study........................................................... 97
4.6.3
Study and Site Discontinuation.............................................. 97
5.
ASSESSMENT OF SAFETY....................................................................... 98
5.1
Safety Plan ............................................................................ 98
5.1.1
Amyloid-Related Imaging 
Abnormalities-Edema/Effusion and Amyloid-
Related Imaging Abnormalities-Hemosiderin 
Deposition.............................................................................. 98
5.1.2
Management of Amyloid-Related Imaging 
Abnormalities including Required Dose 
Adjustments......................................................................... 100
5.1.3
Prevention and Management of Hypersensitivity 
and Infusion Reactions ........................................................ 102
5.1.4
Additional Safety Monitoring................................................ 102
5.2
Safety Parameters and Definitions ...................................... 102
5.2.1
Adverse Events ................................................................... 102
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 103
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 104
5.2.4
Selected Adverse Events..................................................... 104
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 105
5.3.1
Adverse Event Reporting Period ......................................... 105
5.3.2
Eliciting Adverse Event Information..................................... 106
5.3.3
Assessment of Severity of Adverse Events ......................... 106
5.3.4
Assessment of Causality of Adverse Events ....................... 106
5.3.5
Procedures for Recording Adverse Events.......................... 107


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5.3.5.1
Infusion-Related Reactions.................................................. 107
5.3.5.2
Diagnosis versus Signs and Symptoms............................... 107
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................. 107
5.3.5.4
Persistent or Recurrent Adverse Events.............................. 108
5.3.5.5
Abnormal Laboratory Values ............................................... 108
5.3.5.6
Abnormal Vital Sign Values ................................................. 109
5.3.5.7
Abnormal Liver Function Tests............................................ 109
5.3.5.8
Deaths ................................................................................. 110
5.3.5.9
Preexisting Medical Conditions............................................ 110
5.3.5.10
Lack of Efficacy or Worsening of Alzheimer’s 
Disease................................................................................ 110
5.3.5.11
Hospitalization or Prolonged Hospitalization........................ 111
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 111
5.3.5.13
Patient-Reported Outcome Data ......................................... 111
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 111
5.4.1
Emergency Medical Contacts.............................................. 112
5.4.2
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
PET Ligand Adverse Events ................................................... 112
5.4.2.1
Events That Occur prior to Study Drug Initiation.................. 112
5.4.2.2
Events That Occur after Study Drug Initiation...................... 113
5.4.3
Reporting Requirements for Pregnancies............................ 113
5.4.3.1
Pregnancies in Female Patients.......................................... 113
5.4.3.2
Pregnancies in Female Partners of Male Patients............... 114
5.4.3.3
Abortions ............................................................................. 114
5.4.3.4
Congenital Anomalies/Birth Defects .................................... 114
5.5
Follow-Up of Patients after Adverse Events ........................ 114
5.5.1
Investigator Follow-Up......................................................... 114
5.5.2
Sponsor Follow-Up .............................................................. 115
5.6
Post-Study Adverse Events................................................. 115


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5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 115
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 116
6.1
Determination of Sample Size ............................................. 116
6.2
Summaries of Conduct of Study.......................................... 117
6.3
Summaries of Treatment Group Comparability ................... 117
6.4
Efficacy Analyses ................................................................ 117
6.4.1
Primary Efficacy Endpoint.................................................... 117
6.4.2
Secondary Efficacy Endpoints............................................. 118
6.4.3
Exploratory Efficacy Analyses ............................................. 119
6.5
Safety Analyses................................................................... 119
6.6
Pharmacokinetic Analyses................................................... 119
6.7
Biomarker analyses................................................................. 120
6.8
Interim Analysis ................................................................... 120
6.9
China Subpopulation Analysis............................................. 121
7.
DATA COLLECTION AND MANAGEMENT ............................................. 122
7.1
Data Quality Assurance....................................................... 122
7.2
Electronic Case Report Forms............................................. 122
7.3
Source Data Documentation................................................ 123
7.4
Use of Computerized Systems ............................................ 123
7.5
Retention of Records........................................................... 123
8.
ETHICAL CONSIDERATIONS.................................................................. 124
8.1
Compliance with Laws and Regulations .............................. 124
8.2
Informed Consent................................................................ 124
8.3
Institutional Review Board or Ethics Committee.................. 125
8.4
Confidentiality...................................................................... 126
8.5
Financial Disclosure ............................................................ 126
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 126
9.1
Study Documentation .......................................................... 126
9.2
Protocol Deviations.............................................................. 126
9.3
Site Inspections ................................................................... 127


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9.4
Administrative Structure....................................................... 127
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 127
9.6
Protocol Amendments ......................................................... 128
10. REFERENCES ......................................................................................... 129
LIST OF TABLES
Table 1
Adverse Event Severity Grading Scale ..................................... 106
LIST OF FIGURES
Figure 1
Pharmacokinetic Profile Based on Modelling and Simulation 
Data for 60 mg/kg of Crenezumab Administered 
Intravenously Every 4 Weeks Compared with 15 mg/kg 
Crenezumab Administered Intravenously Every 4 Weeks .......... 49
Figure 2
Overall Study Design .................................................................. 57
LIST OF APPENDICES
Appendix 1
Schedule of Assessments........................................................ 136
Appendix 2
National Institute on Aging/Alzheimer’s Association Criteria 
for Dementia due to Alzheimer’s Disease ................................... 144
Appendix 3
National Institute on Aging/Alzheimer’s Association Criteria 
for Prodromal Alzheimer’s Disease (Mild Cognitive 
Impairment due to Alzheimer’s Disease) .................................. 146
Appendix 4
Diagnostic Verification Form .................................................... 147


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PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, EFFICACY AND SAFETY 
STUDY OF CRENEZUMAB IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
BN29552
VERSION NUMBER:
5
EUDRACT NUMBER:
2015-003034-27
IND NUMBER:
100,839
TEST PRODUCT:
Crenezumab (RO5490245)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to your local study monitor. 


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PROTOCOL SYNOPSIS
TITLE:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND 
SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
BN29552
VERSION NUMBER:
5
EUDRACT NUMBER:
2015-003034-27
IND NUMBER:
100,839
TEST PRODUCT:
Crenezumab (RO5490245)
PHASE:
III
INDICATION:
Prodromal to mild Alzheimer’s disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate crenezumab 60 mg/kg compared with 
placebo when administered by IV infusion every 4 weeks (Q4W) over 100 weeks as measured 
by the following primary endpoint (final outcome assessment at Week 105, 4 weeks after the 
final dose):

Global outcomes, as assessed by the Clinical Dementia Rating-Sum of Boxes (CDR-SB) 
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are to evaluate the benefits of crenezumab 
versus placebo administered to patients by IV infusion Q4W over 100 weeks on the following:
Additional cognitive, functional and behavioral outcomes

Change from baseline to Week 105 on cognition, as assessed by the Alzheimer’s Disease 
Assessment Scale-Cognition (ADAS-Cog) (subscales) 13 (ADAS-Cog-13) and 11 
(ADAS-Cog-11)

Change from baseline to Week 105 on severity of dementia, assessed using the 
CDRGlobal Score (CDR-GS) and Mini Mental State Evaluation (MMSE)

Change from baseline to Week 105 on function as assessed by the Alzheimer’s Disease 
Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL) total score and the 
ADCS-instrumental ADL subscore (ADCS-iADL)

Change from baseline to Week 105 on a measure of dependence derived from the 
ADCS-ADL score

Change from baseline to Week 105 assessed using the Neuropsychiatric Inventory 
Questionnaire (NPI-Q) total score
Caregiver and quality-of-life secondary endpoints

Effect of crenezumab on healthrelated quality of life (QoL), assessed using the Quality of 
LifeAlzheimer’s Disease scale (QOL-AD)

Effect of crenezumab on caregiver burden, assessed using the Zarit Caregiver Interview for 
Alzheimer’s Disease scale (ZCI-AD)


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
Effect of crenezumab on health outcomes in patient and caregiver as measured by EQ-5D
Exploratory Efficacy Endpoints
Events related to disease progression

Effect on cognition, assessed by time to an increase from baseline at any time before or on 
Week 105 (i.e., worsening) on a version of the ADAS-Cog or MMSE

Time to clinically evident decline since baseline as defined by an increment on the CDR 
global score

Time to development of impairment in additional domains or worsening of impairments 
within a domain on the CDR-SB 

Time to increase of dependence level as derived from the ADCS-ADL scale 

Time to decline in ability to perform one or more basic or instrumental ADL present at 
baseline using the ADCS-ADL scale

Composite time-to-event endpoint. Combination of clinical progression events including 
any of the following: worsening disease severity (e.g., CDR Global), increasing care 
needs (e.g., ADCS-ADLderived dependence level), concomitant medications, and other 
events that may be indicative of disease progression.
Safety Objective
The safety objective for this study is to evaluate the safety of crenezumab compared with 
placebo in patients with prodromal to mild Alzheimer’s disease (AD) on the basis of the 
following endpoints:

Nature, frequency, severity, and timing of adverse events and serious adverse events

Physical and neurologic examinations, vital signs, blood tests, ECGs, Columbia-Suicide 
Severity Rating Scale 

Evaluation of ECG parameters (at selected study sites in a separate substudy [BN29552-
ECG])

Adverse events of special interest, specifically pneumonia 

Adverse events as assessed by magnetic resonance imaging (MRI):  amyloidrelated 
imaging abnormalities-edema/effusion (ARIA-E) and amyloidrelated imaging 
abnormalities-hemosiderin deposition (ARIA-H)

The immunogenic potential of crenezumab through measurement of antibodies directed 
against crenezumab and other components of the drug product and assessment of their 
relationship with other outcome measures.
Pharmacokinetic Objective
The pharmacokinetic (PK) objective for this study is to characterize the crenezumab PK profile 
on the basis of the following endpoints:

Serum concentration of crenezumab (administered at a dose of 60 mg/kg IV) at specified 
timepoints

Cerebrospinal fluid (CSF) concentration of crenezumab (administered at a dose of 60 mg/kg 
IV) at specified timepoints in a subset of consenting patients in a substudy (BN29552-CSF 
longitudinal).




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MRIs will be read by a central reader who will exclude patients with other structural causes of 
dementia, significant cerebral vascular pathology, and other relevant exclusion criteria. 
Patients will be eligible for the study whether or not they are receiving standard-of-care 
symptomatic medications for AD (i.e., cholinesterase inhibitors or memantine, or combination, 
or the medical food supplement Souvenaid).  These medications must have been stable 
for 3 months prior to screening, and there must be no planned changes for 6 months 
post-randomization. 
The study will consist of a screening period of up to 8 weeks for each patient who agrees to 
participate signs the informed consent form and is eligible for the study.  Eligible patients will 
then undergo the baseline visit (Week 1), when they will receive the first dose following 
completion of all relevant assessments.  Patients will be enrolled in a doubleblind treatment 
period of 100 weeks (26 doses; 60 mg/kg crenezumab or placebo by IV infusion Q4W), and a 
final efficacy and safety assessment 4 weeks following the patient’s last dose (Week 105).  
Patients will then have the option to enter the open-label extension (OLE) study if eligible.  
Patients who do not enter the OLE will have additional follow-up visits at 16 and 52 weeks after 
the last dose, primarily for safety and also for limited efficacy assessments.  Assessments for 
patients who participate in the OLE will be documented in a specific OLE protocol. 
Patients will undergo brain MRI examinations for monitoring of safety and as a biomarker to 
assess study drug activity.  Patients will also undergo tests to monitor safety (including standard 
safety blood tests, ECG, MRI), as well as tests for cognition, function, and QoL assessments.  
Blood samples for assessment of pharmacokinetics, PD biomarkers, and for the measurement 
of antibodies directed against crenezumab and other components of the drug product will be 
obtained from all patients. 
The incidence and nature of adverse events, serious adverse events, ARIA-E and ARIA-H 
abnormalities, adverse events of special interest, and laboratory abnormalities will be assessed 
on a regular basis by an unblinded independent Data Monitoring Committee (iDMC).
Substudies: 
Substudies associated with Study BN29552 will be described in separate protocols with 
associated Informed Consent Forms.  Substudy protocols may include data analysis plans that 
utilize assessments from the main study, including, but not limited, to demographic and efficacy 
assessments.
Number of Patients
The planned number of patients for this study is approximately 750 (375 randomized to 
crenezumab 60 mg/kg IV and 375 randomized to placebo).  
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able to provide written consent signed by the patient (co-signed by the patient’s legally 
authorized representative, if required by the local regulations, guidelines, and independent 
ethics committee or institutional review board)

Aged between 50 and 85 years at screening, inclusive

Weight between 40 and 120 kg, inclusive

Availability of a person (referred to as the “caregiver” throughout this protocol) who in the 
investigator's judgment:

Has frequent and sufficient contact with the patient to be able to provide accurate 
information regarding the patient’s cognitive and functional abilities, agrees to provide 
information at clinic visits (which require partner input for scale completion), signs the 
necessary consent form, and has sufficient cognitive capacity to accurately report 
upon the patient’s behavior and cognitive and functional abilities.

Is in sufficiently good general health to have a high likelihood of maintaining the same 
level of interaction with the patient and participation in study procedures throughout 
the study duration.


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
Every effort should be made to have same caregiver participate throughout the 
duration of the study. 

Fluency in the language used at the study site

Willingness and ability to complete all aspects of the study (including MRI, lumbar puncture 
[if applicable], clinical genotyping, and PET imaging [if applicable]); the patient should be 
capable of completing assessments either alone or with the help of the caregiver

Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to perform the 
neuropsychological testing (eye glasses and hearing aids are permitted)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of 1% per year during the treatment period and for at least 8 weeks after the last dose of 
study drug.

A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).

Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and 
copper intrauterine devices.

The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures, and agreement to refrain from donating sperm, as defined below:

With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 8 weeks 
after the last dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.

The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception. 

Evidence of the AD pathological process, by a positive amyloid assessment either on CSF 
A142 levels as measured on the Elecsysβ-Amyloid(1-42) Test System OR amyloid PET 
scan by qualitative read by the core/central PET laboratory. 

Demonstrated abnormal memory function at early screening (up to 4 weeks before 
screening begins) or screening [FCSRT cueing index 0.67 AND free recall 27]

Evidence of retrospective decline confirmed by a diagnosis verification form

Mild symptomatology, as defined by a screening MMSE score of 22 points and CDR-GS of 
0.5 or 1.0.  MMSE may be performed at early screening (up to 4 weeks before screening 
begins) or at screening.

Meets NIAAA core clinical criteria for probable AD dementia or prodromal AD (consistent 
with the NIAAA diagnostic criteria and guidelines for MCI) 

If the patient is receiving symptomatic AD medications, the dosing regimen must have been 
stable for 3 months prior to screening.

Inclusion is subject to review of clinical criteria at screening (diagnostic verification form).

Patient must have completed at least 6 years of formal education after the age of 5 years.

For enrollment into the China Extension Phase, patients must have residence in the 
People’s Republic of China.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:


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
Any evidence of a condition other than AD that may affect cognition, including but not 
limited to, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, 
Parkinson’s disease, corticobasal degeneration, Creutzfeldt-Jakob disease, progressive 
supranuclear palsy, frontotemporal degeneration, Huntington’s disease, normal pressure 
hydrocephalus, seizure disorder, or hypoxia.

History or presence of clinically evident vascular disease that could potentially affect the 
brain (e.g., clinically significant carotid, vertebral stenosis or plaque; aortic aneurysm; 
intracranial aneurysm; cerebral hemorrhage; arterio-venous malformation) and that in the 
opinion of the investigator has the potential to affect cognitive function.

History or presence of any stroke with clinical symptoms within the past 2 years, or 
documented history within the last 6 months of an acute event consistent, in the opinion of 
the investigator, with a transient ischemic attack. 

History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) CNS trauma (e.g., cerebral contusion)

History or presence of intracranial tumor (e.g., glioma).  History or presence of meningioma 
that, in the opinion of the investigator, is not clinically significant and is unlikely to result in 
cognitive impairment is not excluded.

Presence of infections that affect brain function or history of infections that resulted in 
neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, viral or bacterial 
meningitis/encephalitis)

History or presence of systemic autoimmune disorders that potentially cause progressive 
neurologic disease with associated cognitive deficits (e.g., multiple sclerosis, lupus 
erythematosus, anti-phospholipid antibody syndrome, Behçet disease)

History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder 

A history of major depression is acceptable if patient has no episode within the past 
year or is considered in remission or depression is controlled by treatment.

At risk of suicide in the opinion of the investigator

Alcohol and/or substance abuse or dependence (according to Diagnostic and Statistical 
Manual of Mental Disorders v5 criteria) within the past 2 years 

Nicotine use is allowed.

Marijuana use is not allowed and must be discontinued 3 months before screening.

According to the MRI central reader, MRI evidence of a) 2 lacunar infarcts, b) any territorial 
infarct1 cm3, or c) any white matter lesion that corresponds to an overall Fazekas score of 
3 that requires at least 1 confluent hyperintense lesion on the FLAIR sequence, which 
is 20 mm in any dimension.

Evidence of more than 4 microbleeds and/or areas of leptomeningeal hemosiderosis 
(ARIA-H) as assessed by central review of T2* GRE MRI (see MRI Charter for further 
details). 

Presence of significant cerebral vascular pathology as assessed by MRI central reader (see 
MRI Charter for further details).

Presence on MRI of any cortical stroke regardless of age.

Inability to tolerate MRI procedures or contraindication to MRI, including, but not limited to, 
presence of pacemakers not compatible with MRI, aneurysm clips, artificial heart valves, 
ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an 
MRI scan; or any other clinical history or examination finding that, in the judgment of the 
investigator, would pose a potential hazard in combination with MRI
The following cardiovascular disorders:

History or presence of atrial fibrillation except if only 1 episode that resolved1 year ago 
and for which treatment is no longer indicated

Within the last 2 years, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction, angina pectoris, or New York Heart Association Class II or 
higher cardiac failure)


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
Uncontrolled hypertension (e.g., blood pressure generally 160 mmHg systolic 
or 95 mmHg diastolic)
The following hepatic/renal disorders:

Chronic kidney disease of Stage4, according to the National Kidney Foundation Kidney 
Disease Outcomes Quality Initiative guidelines for chronic kidney disease

Confirmed and unexplained impaired hepatic function as indicated by screening AST or 
ALT 3 the upper limit of normal (ULN) or total bilirubin2 ULN 
The following infections and immune disorders:

History of or known to currently have hepatitis B or hepatitis C infection that has not been 
adequately treated in the opinion of the investigator

Systemically, clinically significantly immunocompromised patients, owing to continuing 
effects of immune-suppressing medication

Corticosteroids are permitted as long as the dose is 7.5 mg/day prednisolone equivalent 
and the condition being treated is not expected to deteriorate significantly during the study 
period.
The following metabolic/endocrine disorders:

Abnormal thyroid function as indicated by abnormal screening tests that are judged to be 
clinically significant by the Investigator, or abnormal thyroid function that requires a new 
treatment or an adjustment of current treatment

A patient may be rescreened if there is no improvement in cognition in the 
investigator's judgment after 3 months of adequate treatment for thyroid function.

Screening folic acid or vitamin B12 levels that are sufficiently low or remain low on retest 
such that deficiency may be contributing to cognitive impairment.  

A patient may be rescreened if there is no improvement in cognition after 3 months of 
adequate treatment for folic acid or vitamin B12 deficiency.

Screening hemoglobin A1c (HbA1C) 8% (retesting is permitted if slightly elevated) or 
poorly controlled insulin-dependent diabetes (including hypoglycemic episodes).  

A patient may be rescreened after 3 months to allow optimization of diabetic control.

Pregnant or lactating, or intending to become pregnant during the study

Poor peripheral venous access 

Other causes of intellectual disability that may account for cognitive deficits observed at 
screening (e.g., static encephalopathy, closed brain injury, mental retardation).

This may be based on, for example, patient’s sufficient education or work experience.

Sleep apnea that requires treatment (e.g., continuous positive airway pressure) or other 
significant respiratory diseases (e.g., severe chronic obstructive pulmonary disease –
Global initiative for Obstructive Lung Disease criteria Stage IV) likely to result in cognitive 
impairment.

Deformity of the lumbosacral region of the spine that in the opinion of the investigator would 
contraindicate lumbar puncture in those who can only be CSF-eligible due to regional lack 
of availability of PET ligands.

Clinically significantly abnormal screening blood or urine that remain abnormal at retest

Impaired coagulation (screening PT 1.2the ULN that remains abnormal on retest).
History of cancer except:

If considered to be cured

If not being actively treated with anti-cancer therapy or radiotherapy and, in the opinion of 
the investigator, not likely to require treatment in the ensuing 5 years


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
For prostate cancer or basal cell carcinoma, no significant progression over the previous 
2 years 

Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins

Any other severe or unstable medical condition that, in the opinion of the investigator or 
Sponsor, could be expected to progress, recur, or change to such an extent that it could put 
the patient at special risk, bias the assessment of the clinical or mental status of the patient 
to a significant degree, interfere with the patient’s ability to complete the study assessments, 
or would require the equivalent of institutional or hospital care

Residence in a skilled nursing facility such as a convalescent home or long-term care 
facility:  Patients who subsequently require residence in these facilities during the study 
may continue in the study and be followed for efficacy and safety, provided that they have a 
caregiver who meets the minimum requirement.
The following medications are prohibited for a pre-specified duration prior to study start, as 
indicated, and during the entire period of study participation (patients who start these 
medications during the study may be withdrawn from study treatment):

Any previous administration of crenezumab or any other therapeutic that targets A

Any investigational active immunotherapy (vaccine) that is under evaluation to prevent or 
postpone cognitive decline

Any passive immunotherapy (immunoglobulin) or other longacting biologic agent that is 
under evaluation to prevent or postpone cognitive decline within 1 year of screening

Any other investigational treatment within 5 half-lives or 3 months of screening, whichever is 
longer

Any previous treatment with medications specifically intended to treat Parkinsonian 
symptoms or any other neurodegenerative disorder within 1 year of screening 

Certain medications are acceptable if the patient is taking the medicine for a 
non-neurodegenerative disorder, such as restless leg disorder (e.g., pramipexole)

Typical antipsychotic or neuroleptic medication within 6 months of screening except as brief 
treatment for a non-psychiatric indication (e.g., emesis)

Atypical antipsychotics except with intermittent short-term use which is permitted except 
within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive assessment

Anti-coagulation medications within 3 months of screening

Anti-platelet treatments (e.g., aspirin, clopidigrel, dipyridamol) are permitted.

Short-term, peri-operative use of anti-coagulants will not result in discontinuation from 
the study; however, any such use must be discussed with the Sponsor.

Chronic use of opiates or opioids (including long-acting opioid medication) within 3 months 
of screening. 

Intermittent short-term use of shortacting opioid medications for pain is permitted except 
within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive assessment. 

Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) within 
1 month of screening and throughout the study.

Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before screening

Intermittent short term use of benzodiazepines, buspirone, or shortacting hypnotic 
medication for sleep or anxiety is allowed except within 2 days or 5 half-lives (whichever is 
longer) prior to any neurocognitive assessment.  However, intermittent use of barbiturates is 
not permitted.


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End of Study
The end of the study is defined as the date when the last patient last visit occurs.  Last patient 
last visit is expected to occur 153 weeks after the last patient is enrolled (i.e., after the 52week 
follow-up visit).
Patients who discontinue from the study drug or who complete the study treatment and do 
not enter the OLE will be asked to return for the collection of safety and efficacy data 4, 16,
and 52 weeks after administration of the last dose of study treatment.
Additionally, all patients who discontinue from study drug early will be encouraged to return 
for subsequent visits, especially the Week 105 visit (early discontinuation of study treatment 
does not imply study discontinuation).
Length of Study
The study will consist of a screening period of up to 8 weeks in length for each eligible patient 
who signs the informed consent and agrees to participate, followed by a double-blind treatment 
period of 100 (4) weeks, a visit of 4 weeks after the last dose (Week 105) and the first and 
second follow-up visits 16 and 52 weeks after the last dose (Week 117 and Week 153, 
respectively).
Investigational Medicinal Products
Test Product (Investigational Drug)
Crenezumab will be administered via IV infusion to all patients randomized to active arm, at a 
dose of 60 mg/kg Q4W for 26 doses.
Comparator
Placebo of identical physical characteristics and identical volume to crenezumab will be 
administered via IV infusion to all patients randomized to placebo with the same frequency and 
administration.
Non-Investigational Medicinal Products
All patients who are enrolled using PET amyloid evaluation and those in the PET substudies will 
be assessed by PET imaging using an appropriate PET ligand.  Details of the PET substudies 
are described in separate protocols.
Statistical Methods
Primary Analysis
The primary efficacy outcome measure is the change in CDR-SB from baseline (Week 1) to 
Week 105.  For this primary outcome measure, the difference in mean change from baseline to 
Week 105 between crenezumab and placebo treated patients will be estimated.  Mixed model 
repeated measures (MMRMs) adjusting for disease severity, APOE4 status, geographic region, 
and the use or non-use of anti-dementia medications at baseline will be used to estimate the 
mean change from baseline for the primary endpoint.  The analysis will include all randomized 
patients, with patients grouped according to the treatment assigned at randomization.
The MMRM model will be used to estimate the mean change from baseline for the primary 
endpoint.  The model will include the change from baseline in CDR-SB as the dependent 
variable.  The effects in the model will include baseline score, treatment group, visit, treatment-
by-visit interaction and baseline score-by-visit interaction.  Visit week will be treated as the 
repeated variable within a patient.  Patient, treatment, and visit week will be treated as class 
variables. An unstructured variance-covariance structure will be applied to model the within-
patient errors; in case of non-convergence, compound symmetry will be used. 
The difference in the changes from baseline of each dose group from placebo will be estimated 
at each time point.  The 95% CI and p-value for treatment difference will be presented.
All efforts will be made to minimize missing data.  The Sponsor plans to request patients who 
discontinued early from study treatment to return for collection of safety and limited efficacy data 
until Week 105.  To explore the robustness of MMRM results for the primary efficacy 
conclusions, sensitivity analyses (for example, using multiple imputation and pattern mixture 
models) will be performed.  Descriptive summaries of the number of patients with missing data, 
the timing and reasons for discontinuation from study by treatment group will also be provided.
Additional details will be documented in the Statistical Analysis Plan (SAP).




Crenezumab—F. Hoffmann-La Roche Ltd
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the SAP.  The SAP will be submitted to relevant health authorities at least 2 months prior to the 
conduct of the interim analysis. 
As information external to the study (e.g., from other compounds) becomes available during the 
conduct of the study, the Sponsor may implement changes to the protocol to incorporate such 
learnings into the study, if possible.  Such learnings may be concerned with endpoints, 
biomarkers, and sample size reassessment due to the variability and size of treatment effect 
observed in other compounds, for example.  The Sponsor could implement such learnings 
through a protocol amendment while being blinded, but without consultation with the iDMC.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
A
amyloid 
AChE
acetylcholinesterase
AD
Alzheimer’s disease
ADA
anti-drug antibody
ADAS-Cog-11
Alzheimer’s Disease Assessment Scale-Cognition 11
ADAS-Cog-12
Alzheimer’s Disease Assessment Scale-Cognition 12
ADAS-Cog-13
Alzheimer’s Disease Assessment Scale Cognition 13
ADCS-ADL
Alzheimer’s Disease Cooperative StudyActivities of 
Daily Living Inventory
ADCS-iADL
Alzheimer’s Disease Cooperative StudyActivities of 
Daily Living Inventory Instrumental Subscale
ADAD
autosomal dominant Alzheimer’s disease
ADL
activity of daily living
iADL
instrumental activity of daily living
APP
amyloid precursor protein
AUC
area under the concentrationtime curve
AUCss
area under the concentrationtime curve at steady 
state
ARIA
Amyloidrelated imaging abnormalities
ARIA-E
Amyloidrelated imaging abnormalities-edema/effusion
ARIA-H
Amyloidrelated imaging abnormalities-hemosiderin 
deposition
BGTS
Barkhof Grand Total Score
CDR
Clinical Dementia Rating
CDR-GS
Clinical Dementia Rating-Global Score
CDR-SB
Clinical Dementia Rating-Sum of Boxes
ChEI
cholinesterase inhibitors
Cmax
observed maximum serum concentration
COPD
chronic obstructive pulmonary disease
CRO
contract research organization
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
DDI
drug-drug interaction
DLT
Dose Limiting Toxicity
DSMB
Data Safety Monitoring Board
EC
Ethics Committee


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Abbreviation
Definition
eCRF
electronic Case Report Form
EDC
electronic data capture
FACS
fluorescence-activated cell sorting
FcR
Fcreceptor
FCSRT
Free and Cued Selective Reminding Test
FCSRT-IR
Free and Cued Selective Reminding TestImmediate
Recall
FDA
Food and Drug Administration
FDG
18F-fluordeoxyglucose
FLAIR
fluidattenuated inversion recovery
GRE
gradient-recalled echo
hAPP
human amyloid precursor protein
HbA1c
hemoglobin A1c
HIPAA
Health Insurance Portability and Accountability Act
HN
Home Nursing
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)
IRB
Institutional Review Board
IV
intravenous
IxRS
Interactive Voice/Web Response System
LPLV
last patient, last visit
mAb
monoclonal antibody
mAD
mild Alzheimer’s disease
MCI
mild cognitive impairment
mH
microhemorrhage
MMRM
mixed model repeated measure
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NIAAA
National Institute on Aging/Alzheimer’s Association
NMDA
N-methyl-d-aspartate
NPI-Q
Neuropsychiatric Inventory Questionnaire
OLE
open-label extension
pAD
prodromal Alzheimer’s disease


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Abbreviation
Definition
PD
pharmacodynamics
PET
positron emission tomography
PK
pharmacokinetic
PS1
presenilin 1
PS2
presenilin 2
Q2W
every 2 weeks
Q4W
every 4 weeks
QTcF
QT interval corrected using Fridericia’s formula
QoL
quality of life
QOL-AD
Quality of Life-Alzheimer’s Disease scale
RPCP
randomized placebocontrolled period
RCR
Roche Clinical Repository
SAP
Statistical Analysis Plan
SC
subcutaneous
SD
standard deviation
SMC
Safety Monitoring Committee
SUVR
standardized uptake value ratio
Tg
transgenic
TP
therapeutic protein
ULN
upper limit of normal
ZCI-AD
Zarit Caregiver Interview for Alzheimer’s Disease


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1.
BACKGROUND
1.1
BACKGROUND ON ALZHEIMER’S DISEASE 
Alzheimer’s disease (AD) is the most common cause of dementia.  It affects an 
estimated 5.3 million individuals in the United States and 46.8 million worldwide 
(Brookmeyer et al. 2007; Hebert et al. 2013; Prince et al. 2013; Alzheimer’s Disease 
International 2015).  The disease is characterized pathologically by the accumulation of 
extracellular -amyloid (A) plaques and intracellular neurofibrillary tangles in the brain.  
Diagnosis is made through the clinical assessment of the neurologic and 
neuropsychiatric signs and symptoms of AD and the exclusion of other causes of 
dementia.  Approved medical therapies that inhibit acetylcholinesterase (AChE) activity 
or antagonize N-methyl-d-aspartate (NMDA) receptors in the brain may temporarily 
improve the symptoms of AD in some patients, but do not modify progression of the 
disease (Cummings 2004). 
The deposition of extracellular amyloid plaques in the brain is a hallmark pathological 
finding in AD, first reported by Alois Alzheimer in 1906.  These amyloid plaques are 
primarily composed of Apeptides (Haass and Selkoe 2007) generated by the 
sequential cleavage of amyloid precursor protein (APP) via - and -secretase activity. 
A, particularly in its oligomerized forms, is toxic to neurons and is believed to be 
causative in AD.  Human genetic evidence supports this link.  Mutations in the APP or 
presenilin genes (PSN1 and PSN2, 2 members of the -secretase complex) are thought 
to result in early-onset AD (Bateman et al. 2012).  Moreover, expression of these 
mutated forms of human APP in mice results in pathology similar to human AD, including 
amyloid plaque accumulation in the brain and loss of synapse and axon integrity.  These 
observations form the basis of a leading hypothesis in AD research known as the 
amyloid hypothesis (Hardy and Selkoe 2002).
The sequential cleavage of APP by -and -secretase results in 2 primary peptides: 
A1-40 and A1-42.  A1-42 demonstrates enhanced amyloidogenic properties and is 
believed to be the more toxic species.  In animal models, soluble oligomers of A1-42 
directly disrupt synaptic function and cause cognitive deficits (Lesné et al. 2006). 
Therapies that reduce Alevels in the brain have the potential to alleviate cognitive 
dysfunction and to block further synaptic loss, axon degeneration, and neuronal cell 
death.
Acan be transported actively across the blood-brain barrier (Deane et al. 2004). 
In murine models of AD, systemic delivery of anti Aantibodies increased Alevels in 
plasma while reducing levels in the CNS through several proposed mechanisms, 
including dissolution of brain A, phagocytic removal of opsonized A, and finally via 
efflux of Afrom the brain as a result of an equilibrium shift of Adue to circulating 
antibodies (Morgan 2005).  Currently investigated anti-Atherapeutic approaches are 
largely based on these proposed mechanisms.


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AD has until recently been diagnosed at the clinical dementia stage and has commonly 
been classified into stages by a brief cognitive screening examination, the Mini Mental 
State Examination (MMSE; Folstein et al. 1975).  There is great variation in the course of 
the disease. However, a frequently used generic and arbitrary classification scheme is 
anchored on the MMSE, which ranges from a score of 30 (cognitively normal) to 0 (fully 
impaired).  MMSE scores of around 2026 are typically associated with mild AD, 1019 
with moderate AD, and 10 with severe AD (Dash and Villemarete-Pittman 2005).  
Although the progressive deterioration in AD is categorized into these 3 stages:  mild, 
moderate, and severe, it more realistically resembles a continuum (Alzheimer’s 
Association 2015).  
AD is a slowly progressive disorder with no fixed events that define its onset 
(Albert et al. 2011).  Prior to a diagnosis of dementia, an individual may experience 
subjective problems with memory, thinking, judgment, and language, but not to a degree 
sufficient to impact day-to-day life or normal functional activities. Consideration that a 
patient has mild cognitive impairment (MCI) is based on evidence that a patient has 
lower performance in one or more cognitive domains that is greater than would be 
expected for the patient’s age and education background. In addition, a decline in 
performance should be evident over time.  This change can occur in a variety of 
cognitive domains including memory and executive function.  
An impairment in episodic memory is commonly seen in MCI patients who subsequently 
progress to a diagnosis of AD dementia, however this impairment is not sufficient in itself 
to predict AD. According to research criteria that have recently become available (Albert 
et al. 2011), the diagnosis of AD can be made with more certainty at the MCI stage with 
the help of biomarkers, and may then be called "MCI due to AD" or "prodromal AD 
(pAD)". pAD is an early stage of AD and generally recognized as an intermediate stage 
between cognitive normalcy and mild dementia (Gauthier and Touchon 2005; Gauthier 
et al. 2006).  There is greater diagnostic uncertainty earlier in the disease process.  It is, 
nevertheless, important to incorporate this continuum of impairment into clinical and 
research practice as recognition of this early stage of disease may facilitate better 
treatment outcomes (Albert et al. 2011).  Thus, similar to AD dementia, AD 
pathophysiological processes should coexist in an individual who meets the criteria for 
pAD. 
There is also likely to be significant overlap in overt symptomatology between pAD and 
mild AD (mAD), irrespective of the dementia diagnosis.  Biomarker assessments 
(including positron emission tomography [PET] imaging of amyloid and cerebrospinal 
fluid [CSF] assessments) have confirmed that pAD represents a relatively early stage in 
the continuum of AD and is now considered a part of the diagnostic features for pAD 
(Albert et al. 2011).  mAD represents a stage of the disease where patients have not 
only cognitive but also clear functional deficits (McKhann et al. 2011).  The specificity of 
the clinical diagnosis of mAD can also be increased by confirming biomarker changes 
associated with AD.


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For potential patients for this clinical trial, evaluations include a thorough clinical 
assessment as well as measurement of disease relevant biomarkers, i.e., markers of 
amyloid accumulation in CSF or on brain PET scans.  Patients to be enrolled may be at 
the clinical stage of MCI (pAD) or mild dementia and will have positive biomarkers 
indicative of AD (Albert et al. 2011; McKhann et al. 2011).
The rate of AD progression shows great inter-individual variability with survival 
dependent on many factors, including age at onset.  Population studies 
(Brookmeyer et al. 2002; Larson et al. 2004) suggest a lag of approximately 5 years 
between symptom onset and diagnosis (Roberson et al. 2005; Waring et al. 2005).  
Thereafter, the median survival time following a diagnosis of AD depends strongly on the 
patient’s age at diagnosis.  The median survival time ranges from 8.3 years for persons 
diagnosed with AD at age 65 years to 3.4 years for persons diagnosed at age 90 years 
(Brookmeyer et al. 2002).  On average, individuals live 39 years after diagnosis 
(Helzner et al. 2008), and some survive as long as 20 years. 
1.2
BACKGROUND ON CRENEZUMAB 
Crenezumab (RO5490245) is a fully humanized monoclonal antibody (mAb) based on a 
human IgG4 framework that contains heavy chain VHIII and light chain VκII subgroup 
sequences.  In vitro, crenezumab binds to Apeptides A1-40 and A1-42 in multiple 
forms (monomers, oligomers, fibrils and plaques). Recent results suggest higher in 
vitro binding to oligomers over monomers (Ultsch et al. 2016) and in vivo crenezumab 
binding to brain areas postulated to be high in oligomers in AD transgenic (Tg) mice 
and no binding to the dense core of plaques (data on file). 
In vitro studies demonstrated the ability of crenezumab to block Aaggregation, 
promote Adisaggregation, and protect neurons from oligomer-induced cytotoxicity 
(Adolfsson et al. 2012).  Crenezumab’s IgG4 backbone confers reduced activation 
of Fcreceptor (FcRs) in comparison with IgG1 and was shown to minimize 
FcR-mediated activation of microglia and release of inflammatory cytokines upon 
oligomer engagement, which has also been proposed to contribute to neurotoxicity 
(Xing et al. 2011; Heneka et al. 2015), while preserving FcR-mediated microglial 
phagocytosis of oligomers (Adolfsson et al. 2012).  Following in vivo dosing in 
presenilin 2 (PS2) amyloid precursor protein (APP) Tg mice, crenezumab localizes to 
brain areas with putative high concentrations of Aoligomers, i.e., hippocampal mossy 
fibers and the periphery of amyloid plaques (Koffie et al. 2009; Liu et al. 2015) but not 
to the dense core of plaques or vascular amyloid. The neutralization and removal of A
oligomers is a rational approach to modify disease progression in AD.
Amyloid-related imaging abnormalities (ARIAs), indicative of vasogenic edema or 
effusions (ARIA-E) and microhemorrhages (mHs) or leptomeningeal hemosiderosis 
(ARIA-H), have been reported in recent AD trials involving mAbs that bind aggregated 
forms of Aand have IgG1 backbones with fully preserved FcγR-mediated effector 
function (Salloway et al. 2009; Ostrowitzki et al. 2012; Fuller et al. 2014; Sevigny et al. 


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2015). As these molecules demonstrated increases in ARIA-E incidence with 
increasing dose and apolipoprotein E4 (APOE4) allele frequency, the dose levels 
administered in past trials have been constrained to limit these events (Sperling et al. 
2012, Ostrowitzki et al. 2017). Crenezumab was designed with an IgG4 backbone on 
the basis of the hypothesis that reducing effector functionshown to minimize 
FcγR-mediated activation of microglia and release of inflammatory cytokines upon 
oligomer engagementwould lower the risk of inducing ARIA-E and ARIA-H, possibly 
by minimizing inflammation at brain vasculature (Wilcock et al. 2006). A lack of 
binding for crenezumab to vascular amyloid, noted following in vivo dosing in PS2APP 
Tg mice (GNE Study 15-2817B), may additionally reduce the risk of ARIA.  
The safety profile (see Section 1.2.3) to date allows a higher dose of crenezumab than 
those used in the Phase II studies (300 mg SC Q2W or 15 mg/kg IV Q4W) to be used in 
the Phase III program (i.e., 60 mg/kg IV crenezumab). This dose selection is supported 
by the data from the Phase Ib GN29632 study that investigated higher doses than those 
in Phase II, including 60 mg/kg and 120 mg/kg IV Q4W. The aim of the high dose is to 
achieve higher systemic exposure and therefore higher brain concentrations, which are 
predicted to result in greater efficacy than that seen in the completed Phase II studies.
See the Crenezumab (RO5490245) Investigator's Brochure (IB) for details on nonclinical 
and clinical studies.
1.2.1
Summary of Nonclinical Studies
In vivo pharmacology and CNS distribution studies were conducted in human amyloid 
precursor protein (hAPP)-Tg mouse models of AD.  Crenezumab was detected in both 
brain homogenates and CSF following a single IV dose.  Administration of 2 weekly 
doses of 5 mg/kg crenezumab to hAPP-Tg mice decreased total Alevels in soluble 
fractions of brain homogenates and increased plasma total Alevels. An in vivo
pharmacology study in PS2APP Tg mice showed via immunofluorescence microscopy 
that crenezumab localized to brain areas with putatively high concentrations of A
oligomers, i.e., hippocampal mossy fibers and the periphery of amyloid plaques, but not 
to the dense core of plaques or vascular amyloid.
The pharmacokinetics and toxicokinetics of crenezumab were studied in hAPP-Tg mice, 
non-Tg mice, and cynomolgus monkeys. Studies demonstrated biphasic disposition 
characterized by a short distribution phase followed by a long elimination phase of 
crenezumab. Due to presence of anti-drug antibody (ADA) there were less than 
dose-proportional increases in overall crenezumab exposure across the range of doses 
investigated in mice. In monkeys, repeat dosing also resulted in development of ADA 
in a proportion of animals that correlated with a trend toward slightly lower serum 
concentrations of crenezumab, but did not affect dose-proportional increases in 
exposure. In both species, dose-related increases in plasma total Alevels were 
observed and appeared to correlate well with serum crenezumab concentrations. In 


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mice, following a single IV administration, crenezumab was observed in both brain and 
CSF. 
Toxicity studies of crenezumab were conducted in cynomolgus monkeys.  
IV administration of crenezumab to cynomolgus monkeys for 4 weeks at 1 dose/week 
(a total of 5 doses) was well tolerated at doses up to 50 mg/kg.  In a subsequent chronic 
toxicity study, weekly SC administration of crenezumab to cynomolgus monkeys for 
39 weeks (a total of 40 doses) was well tolerated at doses up to 100 mg/kg (the highest 
dose tested).  No observations related to crenezumab administration were seen on 
expanded histopathology evaluation of the brain. Nonclinical safety data provide 2-, 3-, 
and 6-fold safety factors for the 60-mg/kg dose at steady-state on the basis of human 
equivalent dose, exposure (area under the concentration-time curve [AUC]), and 
maximum concentration (Cmax), respectively, relative to the maximum tested dose of 
100 mg/kg via SC administration in cynomolgus monkeys (see the Crenezumab 
Investigator’s Brochure).
A study to further evaluate the pharmacology of crenezumab in hAPP-Tg mice included 
weekly or monthly intraperitoneal administration of crenezumab for 16 weeks (a total of 
17 weekly or 5 monthly doses) at doses up to 50 mg/kg.  When crenezumab was given 
at doses10 mg/kg for2 weekly or monthly doses, unexpected deaths were observed. 
No microscopic findings were identified in the CNS or peripheral tissues to explain the 
mortalities.  A high incidence of anti-crenezumab antibodies was observed (93% of 
animals evaluated), which resulted in attenuation of both serum crenezumab 
concentrations and pharmacodynamic (PD) responses (plasma total A1-40 and 
A1-42).  These data suggest that these unexpected deaths are likely the result of an 
adverse immunogenic response (i.e., anaphylaxis) to the xenogeneic humanized 
crenezumab antibody in mice and are therefore unlikely to be predictive of human safety 
risk.
To address potential safety concerns associated with administration of anti-Aβ
antibodies in the AD population (i.e., ARIA-E and -H), additional studies were 
performed in Tg-mouse models of AD (hAPP or hAPP/PS1) to evaluate for vascular 
injury (e.g., cerebral mHs).  These studies were performed with PRO300491, a 
human/mouse chimeric anti-Aβ mAb that shares a humanized variable domain with 
crenezumab but has the murine IgG2a constant domain with D265A and N297A 
mutations.  This reverse chimera antibody (PRO300491) and crenezumab demonstrate 
comparable binding affinity to human A1-40 and A1-42 peptides.  The murine IgG2a 
Fc was selected to decrease immunogenic potential in mice, as crenezumab appeared 
to be highly immunogenic in hAPP-Tg and non-Tg wild type mice.  Furthermore, the Fc 
mutations D265A and N297A were designed to decrease binding to murine FcR and to 
approximate the reduced effector function of an IgG4 antibody (Shields et al. 2001).
A weekly repeatdose study was conducted in hAPP/PS1-Tg mice with PRO300491 for 
4 weeks (a total of 4 doses).  At IV doses up to 60 mg/kg, PRO300491 was well 


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tolerated and no treatment-related increases in mH were observed.  In a subsequent 
chronic toxicity study, weekly intraperitoneal administration of PRO300491 to hAPP-Tg 
mice for 24 weeks (a total of 25 doses) was well tolerated at doses up to 50 mg/kg.  No 
changes in the cerebral microvasculature (e.g., mH or amyloid deposition) were 
observed despite evidence of sustained antibody exposure and PD activity (plasma total 
A1-40).  These findings support the hypothesis that Aantibodies with reduced effector 
function, such as crenezumab, are well tolerated in hAPP-Tg mice and are not 
associated with the development of adverse effects similar to those described in the 
literature for other Aantibodies.
Overall, the nonclinical studies demonstrated that crenezumab has an acceptable 
pharmacokinetic (PK) and safety profile to support long-term SC or IV dosing in patients.
1.2.2
Summary of Clinical Studies
As of 27 May 2017, crenezumab has been or is being investigated in a total of 
11 completed or ongoing Phase I, Phase II, and Phase III clinical trials.  Approximately 
1051 subjects have been exposed to crenezumab in these studies (exposure in blinded 
studies is estimated using patient enrollment and study randomization scheme).
Four Phase I studies (Studies ABE4427g, AB4662g, GP29172, 
) have 
been completed.  Study ABE4427g studied the safety, tolerability, and pharmacokinetics 
of single- and multiple-ascending doses of IV crenezumab in patients with mild to 
moderate AD who were 5086 years of age.  Study ABE4662g studied the 
pharmacokinetics of IV and SC dosing and the relative bioavailability of crenezumab 
(SC dosing) in healthy volunteers who were 1850 years of age.  Study GP29172 
evaluated the pharmacokinetics of SC dosing and the bioequivalence of two formulations 
of crenezumab (SC dosing) in healthy volunteers who were 1865 years of age. 
 
Two Phase I studies (GN29632 
) are ongoing. Study GN29632 is a 
dose-escalation study designed to assess safety and tolerability of multiple doses of 
crenezumab (30, 45, 60, and 120 mg/kg IV Q4W) in patients with mild to moderate AD
followed by an open-label extension (OLE) phase. 
 
 
 
 
The Phase II program (ABE4869g, ABE4955g, GN28525, and GN28352), including an 
OLE study (GN28525), was designed to study safety and tolerability, and to initially 
assess the clinical and biomarker effects of crenezumab in two populations within the 
AD spectrum:  an AD dementia population (5080 years of age) with mild to moderate 
disease severity (MMSE, 1826); and in an at-risk population for AD (3060 years of 


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age) with an autosomal dominant mutation (E280A) in the presenilin (PSEN) 1 gene 
(autosomal dominant AD [ADAD] population).  The open-label extension study 
(GN28525) in patients who previously participated in either Study ABE4869g or 
ABE4955g has been completed.  The Phase II Study GN28352 is ongoing in an ADAD 
population.  
The Phase III studies BN29552 and BN29553, which are evaluating the efficacy, safety, 
and tolerability of crenezumab in pAD to mAD population (MMSE: 2230), are 
ongoing.
Sections 1.2.2.1–1.2.2.9 summarize the crenezumab clinical studies to date.  Refer to 
the Crenezumab Investigator’s Brochure for further information.  
1.2.2.1
Study ABE4427g
Study ABE4427g was a randomized, placebo-controlled, double-blind, Phase I study.  
The study had a single-dose dose-escalation stage, followed by a randomized, 
placebo-controlled, double-blind, parallel, multiple-dose stage in patients 5086 years 
of age who had been diagnosed with mild to moderate AD.  This study assessed four IV 
single dose levels with a range of 0.310 mg/kg and three IV multiple dose levels 
(four weekly doses each) with a range of 0.55 mg/kg.
No patients died, discontinued treatment, or withdrew from the study because of an 
adverse event.  The incidence of adverse events was comparable across cohorts, with no 
evidence of a dose-related effect.  No cases of ARIA-E or infusion-related toxicities were 
reported.  Overall, crenezumab appeared to be well tolerated at the doses investigated.  
The maximum dose administered was 10 mg/kg IV; a maximum-tolerated dose was not 
achieved.  Full details are provided in the Crenezumab Investigator’s Brochure.
1.2.2.2
Study ABE4662g
Study ABE4662g was a Phase I, single-dose, randomized, parallel-group, open-label 
study that evaluated the safety, tolerability, pharmacokinetics, and bioavailability of 
crenezumab following SC and IV administration in healthy volunteers.  Subjects were 
randomized in a 1:1 ratio to receive a single dose of approximately 1.8 mg/kg 
crenezumab by either SC injection or IV infusion.  Subjects were followed for 85 days 
post-dose.  The study has been completed. 
All subjects received a single dose of crenezumab IV (n11) or SC (n11).  Crenezumab 
was well tolerated, and no deaths, discontinuations due to adverse events, or serious 
adverse events were reported.  Full details are provided in the Crenezumab 
Investigator’s Brochure.
1.2.2.3
Study ABE4869g
Study ABE4869g was a Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study designed to evaluate the safety and efficacy of 68 weeks of 


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crenezumab treatment in patients 5080 years of age who had been diagnosed with mild 
to moderate AD (MMSE: 1826).  A total of 444 patients were enrolled and dosed in 
the study:  184 patients in an SC cohort, 247 patients in the IV cohort, and 13 patients 
in a safety run-in cohort.
The study was conducted in two parts.  In Part 1, the SC cohort, 184 patients were 
randomized and dosed in a 2:1 ratio (active: placebo) to receive either crenezumab 
300 mg or matching placebo administered via SC injection Q2W.  In Part 2, the IV 
cohort, 247 patients were randomized and dosed in a 2:1 ratio (active: placebo) to 
receive either crenezumab or matching placebo administered via IV infusion Q4W.  
Since the highest single dose assessed during the Phase I study (10 mg/kg IV) did not 
elicit any dose-limiting toxicities (DLTs), a run-in assessment of the safety and 
tolerability of multiple monthly IV administrations of 15 mg/kg crenezumab was 
conducted in a limited number of patients at selected sites prior to initiating full 
enrollment in the IV cohort in Part 2.  On the basis of the outcome of the safety run-in 
assessment, the dose of crenezumab of 15 mg/kg IV was selected for Part 2.  
Safety information is provided in Section 1.2.3; full details are provided in the 
Crenezumab Investigator’s Brochure.
1.2.2.4
Study ABE4955g
Study ABE4955g, a Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study, was designed to evaluate the effects of crenezumab on brain 
amyloid burden as assessed by florbetapir-PET and other biomarkers in patients 
5080 years of age who had been diagnosed with mild to moderate AD (MMSE: 1826).  
This was a companion study to Study ABE4869g (see Section 1.2.2.3).  The 15-mg/kg 
dose was selected on the basis of the outcome of the safety run-in assessment during 
Study ABE4869g.  Thirty-nine patients were enrolled and dosed in Part 1 (SC cohort) 
of the study; 52 patients were enrolled and dosed in Part 2 (IV cohort).  Patients were 
randomized to receive crenezumab or placebo in a 2:1 ratio.  Safety information is 
provided in Section 1.2.3; full details are provided in the Crenezumab Investigator’s 
Brochure. 
1.2.2.5
Study GN28525
Study GN28525 was an OLE study to the Phase II Studies ABE4869g and ABE4955g.  
The primary objective of Study GN28525 was to further evaluate the long-term safety 
and tolerability of crenezumab administered via IV or SC doses in patients with AD for 
up to 144 weeks. Safety information is provided in Section 1.2.3; full details are 
provided in the Crenezumab Investigator’s Brochure.
1.2.2.6
Study GN29632
Study GN29632 is an ongoing, randomized, double-blind, placebo-controlled Phase Ib 
study to evaluate crenezumab in patients with mild to moderate AD (see the 
Crenezumab Investigator’s Brochure for further details).  The primary objective is to 
evaluate the safety and tolerability of doses higher than that used in the Phase II studies 


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(15 mg/kg IV Q4W), including 60 mg/kg IV Q4W (the dose selected for Phase III) and 
higher. 
Study GN29632 is designed to assess increasing doses of crenezumab in separate 
cohorts.  Dose escalation in new cohorts is governed by dose-limiting criteria and 
reviewed by an unblinded internal safety monitoring committee (SMC).  The purpose of 
the study is to identify early onset and high frequency adverse events, such as ARIA-E. 
If a patient experiences a dose-limiting event (defined below), he or she will not receive 
additional study drug.  If 2 patients on active treatment in a dose cohort experience a 
dose-limiting event as assessed by the SMC, then an evaluation of all available safety 
data will be performed to determine whether further dosing may continue at that dose 
or the dose reduced to a dose level not associated with DLT.
The dose-limiting definitions are as follows:

DLT:  One National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.0 (NCI CTCAE v4.0) Grade3 adverse event; or 
Grade 2 adverse event falling in specific neurological categories or any 
infusion-related toxicity that occurs within 24 hours after study drug 
administration that is severe or serious or does not resolve promptly with 
a reduced infusion rate and/or supportive care.

Dose-limiting criteria related to ARIA-E:  A patient who exhibits 
ARIA-E will not receive any additional study drug until the ARIA-E has 
resolved.  Upon resolution, the patient may resume study drug 
administration at the same dose level; however, upon the first recurrence 
of ARIA-E, the patient will be discontinued from the study.

Dose-limiting criteria relating to ARIA-H:  A patient who exhibits 
ARIA-H that meets the criteria for superficial siderosis of the CNS; 
exhibits one new cerebral macrohemorrhage; has an increase of 1 in the 
number of symptomatic cerebral mH compared with screening; or has an 
increase of 6 in the number of asymptomatic cerebral mH compared with 
screening will be discontinued from treatment.
Patients received double-blind treatment for 13 weeks followed by an OLE.  The initial 
cohort received placebo or crenezumab 30 or 45 mg/kg IV Q4W.  There was a specified 
SMC meeting after all patients on the 30- and 45-mg/kg doses reached 13 weeks of 
treatment.  No stopping criteria were met (including no ARIA-E), and no serious 
adverse events related to study drug were observed; no DLTs have been reported.  
A second cohort included 26 patients on a crenezumab dose of 60 mg/kg IV Q4W or 
placebo (randomized in a 5:1 ratio).  There was a specified SMC meeting after all 
patients on the 60-mg/kg dose reached 13 weeks of treatment.  No stopping criteria were 
met (including no ARIA-E), and no serious adverse events related to study drug were 
observed.  


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A third cohort included 23 patients on a crenezumab dose of 120 mg/kg IV Q4W or 
placebo (randomized in a 5:1 ratio), with a specified SMC meeting after all patients 
reached 13 weeks of treatment.  No stopping criteria were met (including no ARIA-E), 
and no serious adverse events related to study drug were observed.
The majority of patients entered the OLE phase, which is ongoing. Patients in the OLE 
continued on the same dose as per cohort assignment, except for those in the third 
cohort, who by design received a dose of 60 mg/kg IV Q4W. Additionally, the protocol 
was subsequently amended so that patients in the first cohort are given the option to 
increase to 60 mg/kg IV Q4W.  
Safety data review for all dose groups is regularly conducted. Safety information is 
provided in Section 1.2.3; full details are provided in the Crenezumab Investigator’s 
Brochure.
1.2.2.7
Study GP29172
Study GP29172 was a Phase I, single-dose, randomized, open-label, parallel-group 
study to assess the relative bioavailability of two formulations of crenezumab in healthy 
subjects following SC administration of a single 720-mg dose.  This study has been 
completed.
1.2.2.9
Study GN28352
Study GN28352 is an ongoing Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study designed to evaluate the safety and efficacy of crenezumab in 
patients 3060 years of age who are carriers of the PSEN 1 E280A mutation and who 
do not meet criteria for MCI or dementia because of AD.  Safety data are reviewed 
approximately every 6 months by an independent Data Safety Monitoring Board 
(DSMB).
1.2.3
Safety Overview
Nonclinical characterization of crenezumab did not show relevant safety findings. 
The clinical safety of crenezumab has been evaluated using all available clinical data 
from the four completed Phase I studies (ABE4427, ABE4662g, GP29172, and 
 three completed Phase II studies (ABE4869g, ABE4955g, and GN28525), 
one ongoing Phase II study (GN28352), and two ongoing Phase I studies (
and 
GN29632). 
The safety and tolerability profile of crenezumab to date supports its continued 
development in both sporadic (idiopathic) AD and ADAD.


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In the Phase II studies in mild to moderate AD, more fatal events and events of 
pneumonia were reported in crenezumab-treated patients versus placebo-treated 
patients.  However, the rates of death and pneumonia in the crenezumab arms were 
within the expected rates for the enrolled population.  Please refer to Sections 1.2.3.2
and 1.2.3.3, respectively, for more information.
ARIA-E and ARIA-H remain potential risks for crenezumab, even if they were not 
identified as a safety concern in crenezumab studies:  ARIA-E and ARIA-H have been 
observed with other mAbs that target Aspecifically, ARIA-E events have been dose 
limiting for several anti-Aantibodies (see Section 1.2.3.4).  
Injection and infusion site reactions have been reported at similar rates in patients 
receiving crenezumab SC or IV and placebo in the Phase II studies.
No clinically relevant changes have been observed in laboratory parameters, physical 
and neurologic examinations, vital signs, and ECG parameters. 
A Phase Ib study (GN29632) to evaluate doses higher than those used in the 
Phase II studies, including 60 mg/kg IV Q4W and 120 mg/kg IV Q4W, is ongoing.  As 
of the date of protocol release, no new or unexpected safety findings have been 
documented. Specifically, no DLTs, drug-related serious adverse events, and ARIA-E 
events have been reported (see Section 1.2.2.6).  
Detailed safety data from all studies are reported in the Crenezumab Investigator’s 
Brochure.  
The Sponsor performs regular review of blinded data from the ongoing studies and, to 
date, has not identified unexpected safety findings. Furthermore, Study GN29632 is 
overseen by an internal SMC, while an iDMC regularly reviews unblinded data from 
Study BN29552 (and study BN29553) and a DSMB from study GN28352.
1.2.3.1
Overall Adverse Event Profile
The Phase II program in mild to moderate AD (Studies ABE4869g and ABE4955g) 
comprises the largest completed studies conducted to date with crenezumab.
The RPCP of the Phase II program in mild to moderate AD was defined as the 
protocol-specified reporting period of the 2:1 randomization IV and SC dose arms of 
Studies ABE4869g and ABE4955g.  The RPCP excluded the safety run-in arm of 
Study ABE4869g. 
In the RPCP, patients were treated over a 68-week period and monitored for safety for 
4 additional weeks if they rolled over into Study GN28525 or for 16 weeks if they did 
not enter Study GN28525 or they discontinued treatment prematurely.  The 
observation period included the 68-week treatment period and the safety follow-up 
period. 


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The safety evaluable database for the Phase II program included 535 patients with mild 
to moderate AD who received at least one dose of study drug.  Of these, 522 patients 
had been randomized to receive crenezumab at either 300 mg Q2W SC (n148) or 
15 mg/kg Q4W IV (n198) or to receive placebo (n176).  During the RPCP of the 
Phase II program, 9 patients (2.6%) who received crenezumab and 9 patients (5.1%) 
who received placebo withdrew on account of adverse events.  There were no imbalances 
in the overall rates of adverse events between patients who received crenezumab and 
patients who receive placebo (91.1% [n318] vs. 90.8% [n157], respectively).  Serious 
adverse events were reported in 57 patients (16.3%) who received SC or IV crenezumab 
and in 21 patients (12.1%) who received SC or IV placebo.  The imbalance in the rate of 
serious adverse events was mainly due to reports of pneumonia (see Section 1.2.3.3).
In the completed OLE study of the Phase II studies (Study GN28525), a total of 93.2% 
of patients from the original SC cohort and 87.7% of patients from the original IV 
cohort experienced at least one adverse event.  Reported adverse events were as expected 
in an elderly population with AD, with fall and urinary tract infection being the most 
frequently recorded adverse events.  
1.2.3.2
Deaths
During the RPCP of the Phase II program, there were 5 deaths.  All 5 deaths occurred 
in patients treated with crenezumab; none was assessed as related to study drug by the 
investigator.  This represents 1.4% of patients who received crenezumab compared with 
0% of patients who received placebo.  The rate of death in the crenezumab arms was 
within the expected rates of death in the AD clinical trial population treated with 
placebo (0%1.9%) or with A-directed passive immunotherapy (2.1%2.4%; 
Salloway et al. 2009, 2014; Doody et al. 2014).  
During the OLE part of the Phase II program, 15 patients died.  Ten of the 15 patients 
had received active crenezumab and 5 had received placebo during RPCP of the Phase II 
study. All deaths were assessed as not related to study drug by the investigator.  
1.2.3.3
Pneumonia
An imbalance in the rates of serious adverse events of pneumonia was observed in the 
RPCP of the Phase II program, with 6 cases (1.7%) in the crenezumab arms and 1 case 
(0.6%) in the placebo arms.  All serious pneumonia cases occurred 713 months after 
the first study dose.  Individual cases were confounded by age, smoking history, 
diabetes, obesity, some by previous pneumonia events, and tuberculosis, which are 
known risk factors for developing pneumonia.  An imbalance in non-serious adverse 
events of total lower respiratory tract infection, also driven by pneumonia, was 
observed in the RPCP of the Phase II program, with 5 cases versus 0 cases (1.4% vs. 
0%) of non-serious pneumonia observed in the crenezumab and placebo arms, 
respectively.


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The diagnosis of pneumonia was confirmed by chest radiology in 5 of the 11 cases 
reported in crenezumab-treated patients.  The vast majority of cases resolved upon 
standard treatment with antibiotics and in the absence of modification of the study 
drug regimen. 
Overall, the pneumonia rates observed in the RPCP of Studies ABE4869g and 
ABE4955g (3.2% total and 1.7% serious) were slightly higher than those observed 
among Phase III AD clinical trial populations (Henley et al. 2012; Doody et al. 2014; 
Henley et al. 2014; Salloway et al. 2014).  The pneumonia rates in the placebo-treated
population were slightly lower (0.6%; Henley et al. 2012; Doody et al. 2014; Henley et 
al. 2014; Salloway et al. 2014).  However, the precision of these estimates is limited by 
the relatively smaller sample size in crenezumab Phase II data compared to Phase III 
safety populations in bapineuzumab, solanezumab, and semagacestat studies.  The rate 
of pneumonia in crenezumab-treated patients (3.2%) is within the reported incidence of 
pneumonia in the elderly population (2.5%4.4%; Vila-Corcoles et al. 2009).
The rate observed during the OLE part of the Phase II program was similar to that 
observed in the RPCP.
1.2.3.4
AmyloidRelated Imaging Abnormalities of Edema/Effusion 
and Hemosiderin Deposition
In the RPCP of the Phase II program in mild to moderate AD, a single case of 
asymptomatic ARIA-E was reported in a patient who received crenezumab. This patient 
experienced asymptomatic recurrences during the OLE phase.  The proportion of 
patients with ARIA-H was similar in the crenezumab and placebo arms:  new (incident) 
mHs were documented in 11.5% (N40) of crenezumab-treated patients versus 12.7% 
(N22) of placebo-treated patients.  
1.2.3.5
Summary
Crenezumab has demonstrated an acceptable safety and tolerability profile at the 
highest dose tested (15 mg/kg Q4W IV) in the Phase II studies and up to 120 mg/kg in 
the ongoing Phase Ib study GN29632.  Imbalances in rates of fatal events and 
pneumonia, including serious cases, have been observed during the RPCP of the Phase 
II program.  There was no pattern seen in the causes of death, and no obvious 
mechanism linking crenezumab treatment with pneumonia (e.g., no evidence of 
immunosuppression).  Importantly, there was no relationship between steady-state 
exposure (AUC or Cmax) and safety events. In addition, rates of deaths and pneumonia 
in crenezumab-treated patients were within the expected ranges for the elderly AD 
population. Therefore, the safety profile of crenezumab supports the exploration of 
60 mg/kg of crenezumab in patients with prodromal to mild AD in Study BN29552.  
Further details are presented in the Crenezumab Investigator’s Brochure.


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1.2.4
Immunogenicity
The immunogenicity of crenezumab was assessed in the completed Phase I and 
Phase II Studies ABE4427g, ABE4662g, ABE4869g, and ABE4955g.  It is being further 
assessed in the ongoing Phase I and II trials.
A positive anti-drug antibody (ADA) sample was defined as one in which the presence 
of detectable ADAs could be confirmed by competitive binding with crenezumab.  The 
prevalence of ADAs at baseline was calculated from the total number of patients who 
tested positive for ADAs at baseline divided by total number of patients with sample 
available at the baseline timepoint.  The incidence of ADAs post-dose with crenezumab, 
or treatment-emergent ADAs, was calculated from the total number of patients who 
tested positive for ADAs post-dose divided by the total number of crenezumab-treated 
patients who had post baseline samples available for ADA analysis:

In Study ABE4427g, a positive ADA response (post-baseline) was detected in 
1 of 36 patients (2.8%) given crenezumab.

In Study ABE4662g, no ADAs were detected.

In Study ABE4662g, no incidence of the formation of ADAs was detected.

In Study ABE4869g, 444 patients were enrolled (including the safety run-in 
cohort).  Of these, 300 patients were treated with crenezumab and 144 with 
placebo.  The prevalence of ADAs at baseline was calculated as 2 in 441 (0.5%).  
The incidence of ADAs post-baseline was 2.7% (8 of 300) in patients treated with 
crenezumab.  Among these 8 patients, 7 of 122 (5.7%) were from the SC 
treatment arm, and 1 of 165 (0.6%) was from the IV treatment arm.  There was 
no effect observed on PK and/or safety readout in ADA-positive patients.

In Study ABE4955g, there were a total of 91 evaluable patients for 
immunogenicity, including 29 placebo- and 62 crenezumab-treated patients.  
The prevalence of ADAs at baseline was 1.1% (1 of 89 patients).  A single 
patient tested positive at baseline only and did not have any subsequent 
timepoints collected.  Post-baseline, there were 88 immunogenicity-evaluable 
patients.  There was no observed incidence of ADAs in either placebo- or 
crenezumab-treated patients.

In the ongoing Phase I study GN29632, the baseline prevalence of ADA-positive 
patients was 17.6% (13/74). All baseline positive samples had borderline 
positive signals. ADAs were not detected post-baseline in any of the dose 
cohorts. Nevertheless, the presence of circulating crenezumab could interfere 
with the ADA detection, and negative results cannot rule out the presence of 
ADAs.




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Study ABE4869g, the mean (SD) CSF: serum ratio was 0.26% (0.16%) and 0.28% 
(0.17%) for IV and SC dosing, respectively.  
 
 
 
In the Phase Ib study (GN29632) a preliminary PK analysis based on data from the 
13-week double-blind treatment period at doses of 30, 45, 60, and 120 mg/kg IV Q4W
has been performed.  Crenezumab pharmacokinetics increased proportionally to dose at 
doses up to 120 mg/kg and was consistent with the PK findings in prior studies of 
crenezumab.
 
 
Additional PK information for Studies ABE4427g, ABE4662g, ABE4869g, GP29172, 
GN29632, and 
 is provided in the Crenezumab Investigator’s Brochure. 
Data from Phase II studies suggest that there are no clinically significant drugdrug 
interactions (DDIs) with crenezumab.  Therapeutic proteins (TPs) typically do not 
undergo metabolism or transport as their clearance pathway; therefore, the potential is 
limited for small molecule drugs to affect TPs through metabolism or transport pathways.  
Patients enrolled in the studies mentioned above were permitted to continue on 
approved stable doses of AchE inhibitors or memantine.  Stable doses of other 
maintenance medications were also permitted.  Doses of concomitant medications were 
considered stable if the dose level and frequency had not been adjusted for3 months. 
In Studies ABE4869g and ABE4955g, no impact on crenezumab steady state exposure 
metrics (AUCss and Cmax at steady state) by concomitantly administered medications 
(statins, non-steroidal anti-inflammatory drugs, NMDA antagonists, or cholinesterase 
inhibitors [ChEIs]) was seen in patients who received crenezumab via IV administration 
(N193) or via SC administration (N147).  This suggests that there is no PK DDI 
between these compounds and crenezumab.  
1.2.6
Biomarkers
1.2.6.1
Summary
Plasma, CSF, florbetapir amyloid PET, 18F-fluordeoxyglucose (FDG)-PET and volumetric 
MRI measurements were evaluated as PD biomarkers in the Phase II studies in mild to 
moderate AD. 
1.2.6.2
Brain Imaging Pharmacodynamic Biomarkers
Florbetapir PET, FDG-PET, and volumetric MRI measurements were evaluated in 
Study ABE4955g.  Volumetric MRI measures from Studies ABE4869g and ABE4955g 
are currently under evaluation.


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Florbetapir-Positron Emission Tomography 
An evaluation of the effect of crenezumab on amyloid accumulation was conducted in 
Study ABE4955g.  Overall, there was no evidence of a treatment effect in either the SC 
or IV cohorts on changes from baseline to Week 69 in fibrillary brain amyloid using 
pre-specified imaging normalization via cerebellar gray matter reference region. 
A further analysis using a subcortical white matter reference was conducted for the 
overall population and in the mild AD subpopulation (MMSE, 2026).  There was no 
evidence of a treatment effect in the SC cohort.  In the IV cohort, an overall increase in 
the mean change in Florbetapir-PET standardized uptake value ratio (SUVR) was 
observed for patients in both the placebo and crenezumab treatment arms.  
The estimated mean change in Florbetapir-PET SUVR from baseline was less for the 
crenezumab arm than the placebo arm at Weeks 47 and 69.  The treatment difference at 
Week 69 was 0.015 (95% CI, -0.005, 0.035; p0.131).  This difference represents a 
58.8% reduction in the rate of amyloid accumulation relative to placebo at Week 69.
In the mild AD subpopulation, the difference in SUVR increased to 
0.018 (95% CI, -0.006, 0.041; p0.135).  This difference represents a 60.4% reduction 
in the rate of amyloid accumulation relative to placebo at Week 69.
18F-fluordeoxyglucose Positron Emission Tomography
There was no evidence of a treatment difference between crenezumab and placebo 
mean changes from baseline for either the SC or IV cohorts.
1.2.6.3
Plasma and Cerebrospinal Fluid Pharmacodynamic 
Biomarkers
Plasma and CSF biomarker measurements were evaluated in Study ABE4955g.  
Concentrations of Aβ42, total tau, and p-tau in CSF were assessed in 55 patients with 
mild to moderate AD (MMSE, 1826) and who had both a baseline and Week 69 CSF 
sample analyzed.  The treatment effects (expressed as placebo mean change from 
baseline – crenezumab mean change from baseline) 
were -127.01 pg/mL (95% CI, -197.94, -56.07; p0.001) and -94.51 pg/mL 
(95% CI, -173.80, -15.22; p0.022) for the SC and IV cohorts, respectively, which 
indicated an overall increase in CSF Aβ42 concentrations in patients given crenezumab.
There was no evidence of a treatment difference between crenezumab and placebo
mean changes from baseline for either the SC or IV cohorts on either CSF total tau or on 
P-tau.
Preliminary data from Phase I Study ABE4427g (Adolfsson et al. 2012), Phase II 
Studies ABE4869g and ABE4955g, and Phase I study GN29632 show that total plasma 
A42 and A40 significantly increased following administration of crenezumab 
demonstrating peripheral target engagement. The increase in plasma 
pharmacodynamics is expected based on the fact that when the A42 and A40 binds to 


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crenezumab it takes on the slow half-life of the antibody and therefore stays in the 
circulation longer. Please refer to the Investigator Brochure for further information.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
1.3.1
Background
Current therapies for AD focus on symptomatic approaches that target synaptic function 
and cognitive enhancement (Cummings 2004). Genetic evidence (e.g., Hardy and 
Selkoe 2002; Jonsson et al. 2012) has linked the accumulation of Apeptides to AD 
progression (i.e., the amyloid hypothesis).  This hypothesis suggests that overproduction 
of Aor failure to effectively clear this peptide leads to AD.  Thus, the targeting of A
and subsequent displacement of Afrom the brain is a rational approach to modify AD 
progression.
After nearly a decade of research on immunologic approaches to treating AD, including 
both active and passive immunization programs, much has been learned about selection 
criteria for antibodies that may maximize efficacy and minimize safety concerns.  
Consequently, the key efficacy considerations for the selection of an appropriate 
molecule to target Aincluded the selection of a mAb that 1) binds potentially toxic 
forms of A, 2) reduces CNS Alevels and/or amyloid plaque load, and 3) alleviates 
behavioral deficits in nonclinical animal models.
These criteria led to the selection of crenezumab, a fully humanized IgG4 mAb to Athat 
binds to Apeptides in multiple forms (monomers, oligomers, fibers, and plaques). 
Recent results suggest higher in vitro binding to oligomers over monomers (Ultsch et al. 
2016) and in vivo crenezumab binding to brain areas postulated to be high in oligomers 
in AD Tg mice and no binding to the dense core of plaques (data on file).
Crenezumab’s IgG4 backbone confers reduced activation of FcRs in comparison to
IgG1 and was shown to minimize FcR-mediated activation of microglia and release of 
inflammatory cytokines upon oligomer engagement, which has also been proposed to 
contribute to neurotoxicity (Xing et al. 2011; Heneka et al. 2015)while preserving 
FcR-mediated microglial phagocytosis of oligomers (Adolfsson et al. 2012).  
Crenezumab was also designed as an IgG4 on the hypothesis that reducing effector 
function would lower the risk of inducing ARIA-E and ARIA-H, possibly by 
minimizing inflammation at brain vasculature (Wilcock et al. 2006).  A lack of binding 
to vascular amyloid, noted following in vivo dosing in PS2APP Tg mice 
(Study 15-2817B), may similarly reduce crenezumab’s risk of inducing ARIA. Thus, 
crenezumab was chosen with the expectation that it might combine anti-Aactivity with 
a more favorable safety profile. 
The Phase II results showed a lack of consistent treatment effect at the lower dose 
(300 mg SC Q2W), and a possible treatment effect at the higher dose (15 mg/kg IV Q4W) 
that increased in patients with an MMSE in the milder range of 2226. Taken together 
with the safety profile observed in the Phase II program (see Section 1.2.3) and 


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subsequent Phase I dose-escalation study (see Section 1.2.2.6) these data suggest that 
the therapeutic window had not been explored fully.  Therefore use of a higher dose 
(60 mg/kg IV Q4W) is proposed for the Phase III studies, to obtain greater efficacy while 
maintaining a favorable benefit-risk profile (see Section 1.3.3 for further details).
Furthermore, recent advances in the fieldnotably data from the mAb against A
aducanumab (Sevigny et al. 2015) are supportive of the notion that higher doses than 
perhaps originally postulated (Ostrowitzki et al. 2017) may be needed in this field of 
anti-amyloid antibodies. Thus, in this study, 60 mg/kg will be used to potentially enable 
better efficacy to be demonstrated (see Section 1.3.3 for further information on dose). 
1.3.2
Efficacy
The results of Phase II studies showed that consistent but modest treatment effects 
were observed on the co-primary or key secondary endpoints with the higher dose of 
crenezumab (15 mg/kg Q4W IV) in Study ABE4869g with a 16.8% treatment effect in the 
Alzheimer’s Disease Assessment Scale-Cognition, 12 questions (ADAS-Cog-12) change 
score was seen in the mild to moderate AD population (defined as an MMSE score of 
1826) at Week 73 relative to placebo (1.78 point difference; 95% CI, 0.89,4.44; 
p0.190) (Cummings et al. 2014; Mackey et al. 2016). 
The observed treatment effect increased to 23.8% in the mild AD population 
(MMSE score of 2026; 2.24-point difference; 95% CI, -0.66, 5.15; p0.128) and 
35.4% in patients with an MMSE of 2226 (3.44-point difference; 95% CI, 0.24, 6.64; 
p0.036). 
No treatment effect was observed in the Clinical Dementia Rating-Sum of Boxes 
(CDR-SB) in either the mild to moderate (3.1%; 0.08-point difference; 95% CI, -0.77, 
0.92; p0.853) or mild AD (1.0%; 0.02-point difference; 95% CI, -1.0, 0.96; p0.964) 
population.  In an exploratory analysis of a subset with milder AD (MMSE, 2226), the 
treatment effects for CDR-SB change from baseline to Week 73 scores relative to 
placebo increased to 19.6% (1.8-point difference favoring crenezumab; 95% CI, -0.65, 
1.52; p0.423).  No consistent treatment effect was observed on the co-primary 
(ADAS-Cog-12 or CDR-SB) or secondary ADCS-ADL endpoints at the lower dose of 
300 mg Q2W SC. 
When taken together, these data show a treatment effect only when a 2.5-fold higher 
exposure of crenezumab was attained (see Section 1.2.5 for further information).  
Data from the Phase II program also showed that patients with milder disease (i.e., 
MMSE 2226) received greater treatment benefit.  Similar findings were observed in the 
biomarker Study ABE4955g.  In the more recent 18-month Phase III global program with 
anti-amyloid antibodies in mild to moderate AD, solanezumab failed to meet primary 
endpoints on cognition and function.  However, treatment effects were observed in a 
prespecified secondary analysis of pooled data from patients with mild AD data from the 


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EXPEDITION1 and EXPEDITION 2 studies (Doody et al. 2014), which showed a 
statistically significant effect on cognition (ADAS-Cog subscales 11 and 14) and a trend 
on function (ADCS-ADL).  No clinical benefit was observed in patients with moderate AD 
on any clinical scale, which supported the hypothesis that intervention is needed early in 
the course of disease. 
AD is a slow, progressive disorder with no fixed events that define its onset 
(Albert et al. 2011).  As AD is symptomatic long before dementia is diagnosed, 
prodromal AD is recognized as an intermediate stage between normalcy and dementia.  
According to this approach, Dubois et al. (2014) proposed the diagnosis of early AD on 
the objective evidence of significantly impaired memory and the presence of 
hippocampal atrophy on MRI, an abnormal pattern of CSF biomarkers, or a specific 
pattern on PET neuroimaging.  This approach includes prodromal and mild AD, 
irrespective of the dementia diagnosis.  Because the accumulation of brain amyloid 
begins before the onset of AD dementia, it is reasonable to postulate that the benefit of 
anti-amyloid therapy may be greater if initiated at this earlier stage of the disease whilst 
neuronal damage is more limited.  This supports enrollment of patients who have 
detectable but subtler cognitive deficits but have confirmed pathophysiology.  
The use of a single endpoint across both subpopulations of prodromal and mild AD is 
consistent with the current understanding of AD. Use of the CDR-SB as the primary 
outcome measure for studies of prodromal to mild AD enables simultaneous 
demonstration of benefit on primary symptoms (e.g., cognition, function) and clinical 
relevance (Aisen 2009; Aisen et al. 2011), whilst also ensuring use of a clinical outcome 
assessment with adequate measurement properties (U.S. Food and Drug Administration 
[FDA] 2013).
The approach to population and appropriate primary endpoint is used by others and 
many clinical programs now target the prodromal to mild AD continuum and use the 
CDR-SB to measure treatment benefit (see AMARANTH [NCT02245737] and PRIME 
[NCT02477800]).
Collectively, the data support the rationale and strategy for conducting Phase III efficacy 
and safety studies with crenezumab in patients with prodromal to mild AD who have 
biomarker (CSF or PET) evidence of amyloid pathology.
The purpose of this study is to establish efficacy and safety of crenezumab in patients 
with prodromal to mild AD who may or may not be treated concurrently with approved 
treatments for AD.
As anti-amyloid therapy is not expected to provide acute improvement of symptoms, a 
minimum of a 100-week, 26-dose treatment period was selected to demonstrate 
enduring clinical benefit on the basis of the mechanism of action of crenezumab that is 
expected to delay disease progression rather than provide symptomatic improvement 


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over baseline.  The proposed trial duration is supported by data from Study ABE4869g 
which demonstrated that the difference in decline between placebo- and 
crenezumab-treated patients’ increased over time.  Placebo decline is expected to be 
greater at 24 months relative to 18 months; this greater decline allows greater potential 
to demonstrate treatment effect.
The use of the OLE enables a longer assessment of benefit-risk in the target population 
among a large proportion of patients who enter the study and enables those who 
received placebo in the double-blind portion of the trial to obtain the potential benefit of 
active treatment.
1.3.3
Dose
Given the very limited brain penetration observed for IgGs in general (0.2%0.3% of 
levels in serum; Reiber and Felgenhauer 1987), high-serum drug concentrations will be 
required to increase exposure to the site of action.  
 
  
 
 
The Phase II studies demonstrated consistent treatment effects in the high-dose 
(15 mg/kg q4w IV) arm without eliciting dose-limiting events.  The therapeutic window for 
crenezumab has not been fully explored; increasing the dose in this study has the 
potential to increase efficacy while maintaining a favorable safety profile.
Higher doses of crenezumab are predicted to increase concentrations in the brain 
compared with 15 mg/kg IV and therefore maintain drug concentrations above the EC50
in the brain throughout the treatment period. In vitro, the EC50 for crenezumab was 
0.2 g/mL (1.42 nM) and higher target engagement of soluble Awas observed with 
higher crenezumab concentrations (Adolfsson et al. 2012).  Crenezumab binds both A
1-40 and A1-42 with high affinity (7.30.6 nM and 11.11.2 nM, respectively), inhibits 
Aaggregation, and promotes Adisaggregation.  The dose of 60 mg/kg is predicted to 
result in a 4-fold increase in average exposure (AUC) compared with 15 mg/kg (see 
Figure 1).
The increase in concentration of crenezumab, at 60 mg/kg Q4W IV, compared with that 
provided by 15 mg/kg IV is predicted to result in higher target engagement.  This 
increase is predicted to improve efficacy over that previously observed in the 
Phase II program (ABE4869g, ABE4955g). 
 
 


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Higher doses are also under evaluation in the Phase Ib study (GN29632) to provide 
additional safety and tolerability data above the dose used in this Phase III study 
(BN29552).
Figure 1
Pharmacokinetic Profile Based on Modelling and Simulation Data 
for 60 mg/kg of Crenezumab Administered Intravenously Every 
4 Weeks Compared with 15 mg/kg Crenezumab Administered 
Intravenously Every 4 Weeks
Conc concentration; Q4wevery 4 weeks; Dotted red lineEC50


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The evaluation of the 60-mg/kg Q4W IV dose levels is supported by nonclinical safety 
data and results from Phase II and the ongoing GN29632 studies, where consistent 
treatment effects were observed in the 15 mg/kg Q4W cohort without evidence of a 
relationship between the overall adverse event rate and dose and without evidence of a 
relationship between exposure and adverse events of Grade3, serious adverse events, 
or adverse events of special interest.  This suggests that the therapeutic window for 
crenezumab has not been fully explored. 
Nonclinical safety data provide 2-, 6-, and 3-fold safety factors for the 60-mg/kg dose at 
steady state on the basis of human equivalent dose, exposure (AUC), and Cmax, 
respectively, relative to the maximum tested dose of 100 mg/kg via SC administration in 
cynomolgus monkeys (see the Crenezumab Investigator’s Brochure).
The dose used in this study, 60 mg/kg IV Q4W, along with higher doses, is being 
evaluated in the ongoing Phase Ib Study GN29632 (see Section 1.2.2.8).  This study 
was designed to provide evidence of early safety signals for higher doses of 
crenezumab than had been used in the completed Phase II program.  All patients in this 
study are able to continue into an OLE.  Up to the date of this protocol no serious 
adverse events or ARIA-E have been reported within the randomized, placebo-controlled 
portion of the phase IB protocol.  All patients who reached 13 weeks of treatment 
transitioned to an OLE at the same dose.
In this Phase III study, use of a higher dose (60 mg/kg) Q4W than previously used in the 
Phase II program has been selected as it provides the opportunity to determine the 
optimal benefit-risk for patients.
Based on the analysis of safety from the Phase I and Phase II studies, crenezumab
appears to have an acceptable safety and tolerability profile (see Section 1.2.3 and the 
Crenezumab Investigator’s Brochure).  Risk minimization activities, including appropriate 
inclusion/exclusion criteria, monitoring and stopping rules, are in place to ensure patient 
safety during the study.
1.3.4
Biomarkers
In AD, core biomarkers that have been developed that reflect amyloid and neurofibrillary 
tangle pathology, and neuronal degeneration.  Additional biomarkers that reflect other 
aspects of Alzheimer’s pathology are also being developed.
Two imaging modalities are mainly used as secondary or exploratory endpoints in 
clinical trials on AD:  structural MRI and amyloid PET.  The change in volumes of 
specific brain regions as measured by structural MRI is thought to reflect neuronal loss 
and atrophy.  PET tracers that bind to fibrillar Ain the brain (e.g., florbetapir, approved 
for use by the FDA in 2011) are thought to represent accumulation of the Aplaques 
(Joshi et al. 2012).  


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The CSF is in direct contact with the extracellular space of the brain and biomarkers 
measured in CSF can reflect biochemical changes in the brain.  Low CSF Aβ42 is well 
established as a biomarker of Alzheimer’s pathology (Shaw et al. 2009; 
Le Bastard et al. 2013).  Thus, CSF Alevels may provide information on diagnosis and 
disease progression and act as a biomarker for target engagement and for the impact of 
crenezumab on Aretention and aggregation.  Changes in CSF total tau and 
phospho-tau-181 levels over time may provide information on the impact of crenezumab
on tau pathology.  Other exploratory biomarkers in CSF may provide additional 
understanding of the impact of crenezumab on disease progression. 
1.3.5
Risk to Patients without Alzheimer’s Disease Pathology
Due to rigorous screening procedures in this study, including the measurement of CSF 
A1-42 and amyloid-PET scan, it is expected that only patients with AD pathology will be 
enrolled.  In the event that a patient without amyloid pathology is enrolled, no additional 
risk is expected.  However, such a patient may experience other side effects related to 
the product (e.g., infusion reactions, development of ADAs).
1.3.6
Overall Benefit-Risk Summary
The benefit-risk profile of investigation of crenezumab at a dose of 60 mg/kg IV Q4W in 
a population of prodromal to mild AD patients is favorable.
Overall, the benefit-risk assessment of crenezumab is based on the following.

In Phase II studies in patients with AD:
In prespecified subanalyses, a consistent effect on ADAS-Cog-12 was 
observed in the subset of patients with mild AD (MMSE, 2226) who were 
treated with crenezumab 15 mg IV q4w versus placebo. 
Treatment with crenezumab was associated with an increase in CSF-A42
relative to placebo, which was suggestive of target engagement in the CNS.
ARIA events were within the range of background events in this population.  
A single patient experienced three events of asymptomatic ARIA-E, all of 
which were Grade 1 in severity. 
ARIA appears to be manageable with MRI monitoring and dose-intervention 
algorithms and do not appear to lead to significant adverse outcomes (e.g., 
Sperling et al. 2012a).
While more deaths and pneumonia cases were observed with crenezumab 
versus placebo, there was no pattern seen in the causes of death, and no 
obvious common mechanism observed for pneumonia 
(e.g., immunosuppression).  In addition, death rates are in line with 
background rates for the placebo-treated or untreated AD population (Henley 
et al. 2014) and in the variability range reported in clinical trials for 
compounds of this class with similar patient populations and durations of 
treatment (Doody et al. 2014; Salloway et al. 2014).  The rate of pneumonia in 


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crenezumab-treated patients (3.2%) is within the reported incidence of 
pneumonia in the elderly population (2.5%4.4%; Chong and Street 2008), 
and slightly higher than the rate of pneumonia cases reported in the active and 
placebo arms of the solanezumab Phase III trials (2.0% and 2.1%, respectively; 
Doody et al. 2014).  This may be attributable to the small patient numbers in 
the Phase II studies.

Until January 2018, two additional ARIA-E [one symptomatic] have been 
observed in the ongoing clinical development program. The benefitrisk 
profile remains unchanged by the adverse events.

Patients will undergo regular brain MRI monitoring, and discontinuation 
rules in case of ARIA are in place.

Patients will be asked about prior respiratory history and any risk factors for 
pneumonia at screening.  Those with significant respiratory disease (such 
as severe chronic obstructive pulmonary disease [COPD]) will be excluded.  
Pneumonia cases, other serious respiratory infections, and deaths will be 
closely monitored in the study, through the requirement to report these 
cases to the Sponsor within 24 hours with a full description of the case (see 
Section 5.2.3). 

An unblinded independent Data Monitoring Committee (iDMC) is in place to 
review adverse events, serious adverse events, ARIA-E and ARIA-H 
findings, adverse events of special interest (including pneumonia) as well 
as laboratory and ECG data.  Review will occur regularly (e.g., quarterly).  
Details of the iDMC will be provided in the iDMC Charter (available on 
request).
2.
OBJECTIVES AND ENDPOINTS
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate crenezumab 60 mg/kg 
compared with placebo when administered by IV infusion q4w over 100 weeks as 
measured by the following primary endpoint (final outcome assessment at Week 105, 
4 weeks after the final dose):

Global outcomes, as assessed by the CDR-SB 
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study are to evaluate the benefits of 
crenezumab versus placebo administered to patients by IV infusion Q4W over 
100 weeks on the following:
Additional cognitive, functional, and behavioral outcomes

Change from baseline to Week 105 on cognition, as assessed by the 
ADAS-Cog (subscale) 13 (ADAS-Cog-13) and 11 (ADAS-Cog-11)


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
Change from baseline to Week 105 on severity of dementia, assessed using 
the CDR Global Score (CDR-GS) and MMSE

Change from baseline to Week 105 on function as assessed by the 
ADCS-ADL total score and the ADCS-instrumental ADL subscore 

Change from baseline to Week 105 on a measure of dependence derived 
from the ADCS-ADL score

Change from baseline to Week 105 assessed using the Neuropsychiatric 
Inventory Questionnaire (NPI-Q)
Caregiver and quality-of-life secondary endpoints

Effect of crenezumab on healthrelated quality of life (QoL), assessed 
using the Quality of LifeAlzheimer’s Disease (QoL-AD) scale

Effect of crenezumab on caregiver burden, assessed using the Zarit 
Caregiver Interview for Alzheimer’s Disease (ZCI-AD) scale

Effect of crenezumab on health outcomes in patient and caregiver as 
measured by EQ-5D
2.1.3
Exploratory Efficacy Objective Endpoints:
Events related to disease progression

Effect on cognition, assessed by time to an increase from baseline at any 
time before or on Week 105 (i.e., worsening) on a version of the 
ADAS-Cog or the MMSE

Time to clinically evident decline since baseline as defined by an 
increment on the CDR global score

Time to development of impairment in additional domains or worsening of 
impairment within a domain on the CDR-SB 

Time to increase of dependence level as derived from the ADCS-ADL scale 

Time to decline in ability to perform one or more basic or instrumental 
ADL present at baseline using the ADCS-ADL scale

Composite time-to-event endpoint. Combination of clinical progression 
events including any of the following: worsening disease severity (e.g.,
CDR Global), increasing care needs (e.g., ADCS-ADLderived 
dependence level), concomitant medications, and other events that may be 
indicative of disease progression
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety of crenezumab compared 
with placebo in patients with prodromal to mild AD on the basis of the following 
endpoints:

Nature, frequency, severity, and timing of adverse events and serious 
adverse events


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
Physical and neurologic examinations, vital signs, blood tests, ECGs, 
Columbia-Suicide Severity Rating Scale (C-SSRS) 

Evaluation of ECG parameters (at selected study sites in a separate 
substudy [BN29552-ECG]) 

Adverse events of special interest, specifically pneumonia 

Adverse events as assessed by MRI:  ARIA-E and ARIA-H

The immunogenic potential of crenezumab through measurement of 
antibodies directed against crenezumab and other components of the drug 
product and assessment of their relationship with other outcome measures.
2.3
PHARMACOKINETIC OBJECTIVE
The PK objective for this study is to characterize the crenezumab PK profile on the basis 
of the following endpoints:

Serum concentration of crenezumab (administered at a dose of 60 mg/kg 
IV) at specified timepoints

CSF concentration of crenezumab (administered at a dose of 60 mg/kg IV) 
at specified timepoints in a subset of consenting patients in a substudy 
(BN29552-CSF longitudinal).
2.4
BIOMARKER OBJECTIVES
The PD biomarker objectives for this study are as follows.
To evaluate the effect of crenezumab compared with placebo in patients with prodromal 
to mild AD based on the following endpoints: 

Brain amyloid load over time measured by amyloid-PET in a substudy 
(BN29552/BN29553-Amyloid PET longitudinal)

Brain tau load over time measured by tau-PET in a substudy 
(BN29552/BN29553-tau PET longitudinal)

CSF markers of disease over time in a substudy (BN29552-CSF longitudinal)

MRI-derived measurements over time such as volumetric changes in whole 
brain, ventricles, hippocampus, or other structures

Plasma Aconcentrations
To explore possible exposureresponse relationships in patients with prodromal to mild 
AD based on the following endpoints:

CSF biomarkers

Plasma PD biomarkers

Imaging biomarkers

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To conduct exploratory genetic analysis on disease progression and response to 
crenezumab based on the following:


APOE genotype 
To evaluate the concordance of amyloid detection methods (CSF vs. PET) in a substudy 
(BN29552-concordance)
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the safety and efficacy of crenezumab in patients with 
prodromal to mild AD. 
The planned number of patients in the Global Enrollment Phase for this study is 
approximately 750 (375 randomized to crenezumab 60 mg/kg IV and 375 randomized to 
placebo).  
 
 
 
 This China subpopulation may include patients enrolled at sites in 
China during both the Global Enrollment Phase and the China Extension Phase.
To maintain a balanced number of patients enrolled in each treatment arm, 
randomization will be stratified by dementia status (pAD vs. mAD), APOE (presence or 
absence of ε4 allele), anti-dementia medications (present of absent) at baseline, and 
geographic region.  Approximately 250 centers in approximately 30 countries worldwide 
will participate in this study. 
Patients will be selected on the basis of clinical diagnosis of probable AD (according to 
the National Institute on Aging/Alzheimer’s Association [NIAAA] Diagnostic Criteria and 
Guidelines for AD; see Appendix 2; McKhann et al. 2011) OR prodromal AD (according 
to the NIAAA Diagnostic Criteria and Guidelines for AD; see Appendix 3; 
Albert et al. 2011). 
Eligible patients will be 5085 years old and must have increased brain amyloid as 
indicated by reduced CSF A1-42 concentration (i.e., CSF-enrolled patients) or positive 
amyloid PET scan by qualitative read (i.e., PET-enrolled patients). 


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At the time of screening, patients must have a MMSE score of22 points and a 
CDR-GS of 0.5 or 1.0.  To confirm objective memory impairment, patients must have a 
Free and Cued Selective Reminding TestImmediate Recall (FCSRT-IR) Cueing Index * 
of 0.67 and a total free recall score of27.
* FCSRT cueing index is calculated as follows: 
[Free recall scoretotal score achieved] / [Free recall score– 48]
Neuroradiologic evaluation will use a standard MRI protocol (including T2*-weighted 
gradientrecalled echo [GRE] and fluidattenuated inversion recovery [FLAIR]).  
Screening MRIs will be read by a central reader who will exclude patients with other 
structural causes of dementia, significant cerebral vascular pathology, and other relevant 
exclusion criteria (see Section 4.1.2). 
Patients will be eligible for the study whether or not they are receiving standard-of-care 
symptomatic medications for AD (i.e., ChEIs or memantine, or combination, or the 
medical food supplement Souvenaid).  These medications must have been stable 
for3 months prior to screening, and there must be no planned changes for 6 months 
post-randomization. 
The study will consist of a screening period of up to 8 weeks for each patient who agrees 
to participate signs the informed consent form and is eligible for the study.  Eligible 
patients will then undergo the baseline visit (Week 1), when they will receive the first 
dose following completion of all relevant assessments.  Patients will be enrolled in a 
doubleblind treatment period of 100 weeks (26 doses; 60 mg/kg crenezumab or placebo 
by IV infusion Q4W), and a final efficacy and safety assessment 4 weeks following the 
patient’s last dose (Week 105).  Patients will then have the option to enter the OLE study 
if eligible.  Patients who do not enter the OLE will have additional follow-up visits at 16 
and 52 weeks after the last dose, primarily for safety and also for limited efficacy 
assessments.  Assessments for patients who participate in the OLE will be documented 
in a specific OLE protocol.
Patients who discontinue treatment before Week 105 should be encouraged to return for 
subsequent visits and noninfusion-related assessments, especially the Week 105 visit.
Patients will undergo brain MRI examinations for monitoring of safety and as a 
biomarker to assess study drug activity.  Patients will also undergo tests to monitor 
safety (including standard safety blood tests, ECG, MRI), as well as tests for cognition, 
function, and QoL assessments.  Blood samples for assessment of pharmacokinetics, 
PD biomarkers, and for the measurement of antibodies directed against crenezumab 
and other components of the drug product will be obtained from all patients. 


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The incidence and nature of adverse events, serious adverse events, ARIA-E and 
ARIA-H abnormalities, adverse events of special interest, and laboratory abnormalities 
will be assessed on a regular basis by an unblinded iDMC. 
An overview of the study design is provided in Figure 2.  A schedule of assessments is 
provided in Appendix 1.
Figure 2
Overall Study Design
Q4W every 4 weeks; W week.
Note:  Patients who discontinue treatment early will be encouraged to return for subsequent visits and
non-infusion related assessments, especially the Week 105 visit.
The study consists of 4 distinct periods:

Screening:  Up to 8 weeks in length for each eligible patient

Double-Blind Treatment:  Double-blind treatment period of 100 weeks.  
After screening, patients who meet all eligibility criteria will be randomly 
assigned to 1 of 2 arms (crenezumab 60 mg/kg or placebo) in a 1:1 ratio. 
Starting on week 1, after baseline assessments, each patient will receive 
26 total IV infusions Q4W. 

Primary Analyses Period:  Randomization through Week 105

Long-Term Treatment Follow-up:  Patients who discontinue from the 
study drug or who complete the study treatment and do not enter the OLE 
will be asked to return for the collection of safety and efficacy data 4, 16, 
and 52 weeks after administration of the last dose of study treatment. 
Additionally, all patients who discontinue from study drug early will be 


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encouraged to return for subsequent visits, especially the Week 105 visit 
(early discontinuation of study treatment does not imply study 
discontinuation). 

Open-Label Extension:  All eligible patients will have the opportunity to 
enter an OLE (documented in a separate protocol).
For the schedule of assessments at each visit, see Appendix 1.
3.1.2
Substudies
Substudies associated with Study BN29552 will be described in separate protocols with 
associated Informed Consent Forms.  Substudy protocols may include data analysis 
plans that utilize assessments from the main study, including, but not limited to, 
demographic and efficacy assessments. 
3.1.3
Use of Symptomatic Treatments for Alzheimer’s Disease
Patients will be eligible for the study whether or not they are receiving symptomatic 
medications for AD (i.e., ChEIs or memantine, or combination, or the medical food 
supplement Souvenaid®).  These medications must have been stable for3 months prior
to screening with no expected change for at least 6 months post-randomization. 
3.1.4
Data Monitoring Committee
The incidence and nature of adverse events, serious adverse events, adverse events of 
special interest, ARIA-E and ARIA-H abnormalities, ECG findings, vital signs, laboratory 
abnormalities, and limited efficacy data will be assessed on a regular basis by an 
iDMC.  It is anticipated that these assessments will occur approximately every 3 months.
The details of iDMC will be provided in the iDMC Charter.
The iDMC will also undertake evaluation of any planned interim analyses for efficacy or 
futility (see Section 6.8).
3.2
END OF STUDY
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for safety analyses or safety follow-up is 
received for the last patient, whichever occurs later.  LPLV for the double-blind treatment 
period is expected to occur 153 weeks after the last patient is enrolled (i.e., 52 weeks 
after the last dosing visit at week 101) for those patients who do not enter the OLE.
3.2.1
Long-Term Follow-Up
Patients who discontinue from the study drug or who complete the study treatment and do not 
enter the OLE will be asked to return for the collection of safety and efficacy data 4, 16, and 
52 weeks after administration of the last dose of study treatment. 


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Additionally, all patients who discontinue from study drug early will be encouraged to return for 
subsequent visits, especially the Week 105 visit (early discontinuation of study treatment does 
not imply study discontinuation).
3.3
RATIONALE FOR STUDY DESIGN
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study of the efficacy and safety of crenezumab in patients with a diagnosis 
of prodromal to mild AD, as defined by clinically evident symptoms (consistent with the 
NIAAA updated diagnostic research criteria for AD dementia; Appendix 2), increased 
amyloid burden (defined by CSF or PET criteria), and clinical symptoms. 
3.3.1
Rationale for Treatment Duration
The treatment duration of 100 weeks (26 doses) for assessment of the primary endpoint 
has been selected on the basis of the mechanism of action of crenezumab that is 
expected to delay disease progression rather than provide symptomatic improvement 
over baseline.  Any difference between treatment and control will be on the basis of a
reduction in the progression of AD over time.  Ongoing trials in the AD area have used 
durations of at least 18 months. 
The proposed trial duration is supported by data from Study ABE4869g which 
demonstrated that the difference in decline between placebo- and crenezumab-treated 
patients’ increases over time until 18 months.  Placebo decline is expected to be greater 
at 24 months relative to 18 months; this greater decline allows greater potential to 
demonstrate a treatment effect.
To ensure that evidence relating to early efficacy is captured, assessments relevant to the 
study objectives will be obtained at 6, 12, and 18 months.
3.3.2
Rationale for Long-Term Follow-Up
The primary objective of the long term follow-up is to estimate the long-term safety of 
crenezumab.  Assessments performed 16 and 52 weeks after the last dose of treatment 
will evaluate the effects of treatment on both efficacy and safety parameters over an 
extended period when no study drug is administered.  These assessments will be 
conducted in all patients who discontinue treatment early or who complete the study but 
do not enter the OLE.  These assessments will allow for the exploration of the long-term 
effects of exposure to study drug given that continued cognitive decline is expected in 
this patient population. 
3.3.3
Rationale for Crenezumab Dosage
The goal of dose selection in this Phase III study is to select a safe treatment regimen 
that also efficiently removes amyloid species from the brains of patients with AD.  In the 
Phase II studies, 198 patients (163 in Study ABE4869g and 35 in Study ABE4955g) 
received the IV crenezumab dose of 15 mg/kg Q4W and demonstrated consistent 


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treatment effects in prespecified subgroups without eliciting dose-limiting events.  
This suggested that the therapeutic window for crenezumab had not been fully explored 
A higher dose than that used in the Phase II program will result in increased brain 
exposure and thus result in increased target engagement and the potential for better 
efficacy (see Section 1.3.3 for further details). 
3.3.4
Rationale for Patient Population
The patient selection approach is consistent with the NIAAA research diagnostic criteria 
and guidelines for AD as well as with the Qualification Opinion from the European 
Medicines Agency’s Committee for Medicinal Products for Human Use on the use of 
CSF biomarkers for enrichment of trials in mild to moderate AD dementia (2012), and 
FDA draft guidance for early AD (2013).  Although the FDA guidance refers to the early 
stage of AD in which individuals present with MCI, there is consensus in the field that
biomarkers of amyloid pathology are expected to also add value to patient selection in 
mild AD studies.
To adequately determine the safety and tolerability of crenezumab, an antibody that 
targets Aβ, the study population should have documented evidence of amyloid pathology.  
Therefore, the study will enroll patients with prodromal to mild AD with evidence of an 
abnormal brain amyloid load.  The rationale for selecting amyloid-positive patients in this 
study is to ensure that patients are enrolled with the pathology targeted by crenezumab. 
The crenezumab Phase III prodromal to mild AD study will enroll patients who have 
biomarker evidence for -amyloid deposition.  Biomarker enrichment may be important 
for anti-amyloid therapy clinical trials because recent results have demonstrated that 
approximately 20% patients who are enrolled in trials based on a clinical diagnosis of AD 
may not have underlying amyloid pathology as assessed by amyloid-PET 
(Doody et al. 2014; Sperling et al. 2012b).  These results are consistent with screening 
results in Study ABE4995g, in which 16.5% (18/109) of screened patients with a clinical 
diagnosis of AD subsequently screen-failed due to a negative florbetapir amyloid-PET 
scan (visual read).  Lastly, biomarker evidence of amyloid pathology is consistent with 
recently proposed revised diagnostic criteria for AD (McKhann et al. 2011; 
Dubois et al. 2014).
For enrollment, biomarker evidence of -amyloid deposition will be assessed either by 
decreased CSF A142 levels (using a pre-specified cutpoint and the Roche Diagnostics 
Elecsysamyloid [142] immunoassay) or a centralized visual assessment of PET 
brain amyloid imaging.  The Sponsor is proposing to enroll patients on the basis of a 
positive CSF test or PET scan because both approaches have been shown to correlate 
with the “gold standard” of -amyloid pathology at autopsy (Shaw et al. 2009; 
Clark et al. 2011; Le Bastard et al. 2013). Both methods have been widely used in the 
research community, and patients or physicians in the trial and in clinical practice 
generally may not have access to both methods. 


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This approach is in line with emerging evidence that indicates consistency between 
PET-amyloid imaging and CSF biomarkers.  Low CSF A142 shows an inverse 
relationship with in vivo amyloid cortical load as measured with Pittsburgh 
Compound B amyloid PET imaging (Fagan et al. 2006; Forsberg et al. 2008; 
Tolboom et al. 2009).  There is concordance on the information obtained via PET 
amyloid imaging and low CSF A142 in broad populations across a range of severity of 
AD (pre-dementia through mild to moderate AD; Jagust et al. 2009; Fagan et al. 2011; 
Landau et al. 2013; Zwan et al. 2014). 
As the accumulation of Abrain amyloid begins before the onset of AD dementia, it is 
reasonable to postulate that the benefit of anti-amyloid therapy may be greater if initiated 
at an early stage of the disease.  This hypothesis is supported by the Phase II data from 
crenezumab and Phase III data from solanezumab in mild to moderate AD, where the 
treatment effects were observed in patients with mild AD, but not in patients with 
moderate AD (Doody et al. 2014).  For this reason, Roche has focused clinical 
development of crenezumab on the prodromal to mild segment of AD. 
Patients in this study are required to meet standard research criteria for AD (according to 
the NIAAA research criteria and guidelines for AD dementia; Appendix 2) in the mild 
dementia stage or pAD (according to the NIAAA research criteria and guidelines for MCI; 
Appendix 3).  Patients with pAD will present with documented objective evidence of 
deficit in 1 cognitive domain.  Patients with mAD will present with documented deficits in 
at least 2 cognitive domains and functional decline.  Overall, the population will have an 
MMSE of22 points and a CDR-GS of between 0.5 and 1.0.  The MMSE score provides 
evidence of mild disease severity and the CDR-GS score indicates that the patients 
have noticeable amnestic (pAD) or cognitive and functional deficits (mAD). 
To ensure that the patients selected are likely to decline over the 2-year trial, 
2 approaches have been included.  The first is that all patients have to demonstrate 
amnestic deficits as measured by the cueing index of the FCSRT 
(e.g., Sarazin et al. 2007) and the total free recall score.  The FCSRT cueing index 
of 0.67 AND a free recall score of27 have been selected.  The cueing-index 
measures the ability of the patient to benefit from being reminded by the use of specific 
cue words in order to recall the target word.  To prevent patients who have a high free 
recall who don’t appear to further benefit from reminding from being included simply due 
to an apparent low cueing-index, a free recall score of27 has also been included.  
The cueing index cut-off has been generated from internal data sets (prior to the start of 
this study), in which patients with cueing index of0.67 had a greater likelihood of decline 
over the proposed time frame.  The FCSRT index is consistent with those published by 
Sarazin et al. (2007) and Auriacombe et al. (2010).
The second approach to ensure decline is to verify that there is evidence of prior decline
through observations made by clinician or caregiver and recorded on the diagnostic 
verification form (see Appendix 4).  A caregiver is defined as a person who in the 


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investigator’s judgment has frequent and sufficient contact with the patient so as to be 
able to provide accurate information as to the patient’s cognitive and functional abilities, 
who agrees to provide information at clinic visits that require partner input for scale 
completion, and who signs the necessary consent form.  This person should not be a 
caregiver in a paid position (e.g., a healthcare professional).
To minimize the effects of confounding the cognitive assessments, anyone with a current 
untreated depressive episode (i.e., presence of depressive symptoms) will be excluded 
from the study.  Current treatment for depression will be documented in the electronic 
Case Report Form (eCRF).
3.3.5
Rationale for Control Group
This is placebo-controlled trial in which patients will be eligible for study participation 
whether or not they are receiving standard of care medications for AD (i.e., ChEIs, 
memantine, and/or the medical supplement Souvenaid®).  Given that there are currently 
no approved disease-modifying compounds that could serve as an active control, 
patients will be randomized to crenezumab or placebo. 
3.3.6
Rationale for Rescue Strategy
A rescue strategy may be recommended by the iDMC based on their unblinded 
assessment of the benefit-risk profile (see Section 3.1.4).  In the event that this strategy 
is recommended, all ongoing patients will be switched to a lower dose of IV crenezumab.  
In the event that this occurs, the sample size will be adjusted so that all existing patients 
are replaced by new patients at the revised study dose (see Section 6.1).
3.3.7
Rationale for Diagnostic Verification
Enrollment into this trial is subject to adjudication by the Medical Monitor or designated 
staff.  The objective of the adjudication process is to ensure that patients are enrolled on 
the basis of objectively ascertained and well-documented diagnosis of AD 
(McKhann et al. 2011) or prodromal AD symptomatology sufficient to meet the 
appropriate criteria specified in Albert et al. (2011).  The Medical Monitor or assignee may 
review anonymized source documents and may solicit advice from other qualified 
Sponsor staff or external, independent experts to support this adjudication process. The 
scope and detailed procedures for the diagnostic verification process will be described in 
the study documents and documented for review on the diagnostic verification form (see 
Appendix 4).
3.3.8
Rationale for Primary Outcome Measure
AD is considered a continuous disease that passes through consecutive stages without 
discrete transition points.  Thus, the use of a single endpoint across both subpopulations 
of prodromal and mild AD is consistent with the current understanding of AD.
Demonstrating the benefit of new therapies for patients in the early stages of AD is 
challenging due to the lack of sensitive assessment tools.  Use of the CDR-SB as the 


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primary outcome measure for studies of prodromal to mild AD enables simultaneous 
demonstration of benefit on primary symptoms (e.g., cognition, function) and clinical 
relevance (Aisen 2009; Aisen et al. 2011), whilst also ensuring use of a clinical outcome 
assessment with adequate measurement properties (FDA 2013).
Assessments in clinical trials for AD should be obtained across several domains of 
neurologic function, including cognitionmeasured directly by objective tests (cognitive 
endpoints)and functioning.  Improved clinical outcomes in both cognitive and 
functional domains should translate to an overall benefit measured by global 
improvement score, which would demonstrate that a proportion of patients achieved a 
clinically meaningful benefit from this therapy. 
3.3.8.1
Clinical Dementia Rating-Sum of Boxes
The Washington University CDR is a global assessment instrument that yields Global 
(GS) and Sum of Boxes (SB) scores.  The CDR is derived from a semi-structured
interview with the patient and an appropriate informant, and it rates impairment in 
6 categories (memory, orientation, judgment and problem solving, community affairs, 
home and hobbies, and personal care) on a 5-point scale in which no impairment0, 
questionable impairment0.5, and mild, moderate, and severe impairment1, 2, and 3, 
respectively.  From the 6 individual category ratings, or box scores the CDR-GS is 
established by clinical scoring rules where CDR 0no dementia and CDR 0.5, 1, 2, or 
3questionable, mild, moderate, or severe dementia, respectively (Morris 1993).  
The CDR-SB score is a detailed quantitative general index that provides more 
information than the CDR-GS in patients with prodromal to mild dementia 
(O'Bryant et al. 2010).  In particular, the CDR-SB has been proposed for use in 
longitudinal assessment of dementia and is widely used in AD studies as a global 
measure of disease progression (Lynch et al. 2006). Furthermore, as proposed in the 
FDA’s draft guidance for developing drugs for the early stages of disease, the use of a 
composite scale, validated in early stage patients to assess both cognition and function 
as a single primary efficacy outcome measure, is appropriate.  The CDR-SB score fulfills 
these criteria (FDA 2013) and is now being utilized as the sole primary endpoint in 
studies of patient populations that encompass prodromal to mild AD including 
AMARANTH (https://clinicaltrials.gov/ct2/show/NCT02245737) and PRIME 
(https://clinicaltrials.gov/ct2/show/NCT02477800)
The proposal for the Phase III program is to employ the CDR-SB as a primary endpoint 
for an integrated functional/global assessment, and the ADAS-Cog, ADCS-iADL, and 
ADCS-ADL as key secondary endpoints to additionally support assessment of cognition as a 
core symptom of this disease (ADAS-Cog-13 and ADAS-Cog-11) and function (ADCS-ADL
instrumental function subscore and total score) (see Section 3.3.9).
3.3.9
Rationale for Key Secondary Outcome Measures
The key secondary endpoints for studies in prodromal to mild AD have been chosen to 
reflect the treatment benefit on cognitive and functional endpoints.  The rationale for 


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selection of key secondary endpoints is provided in Sections 3.3.9.1 (ADAS-Cog) and 
3.3.9.2 (ADCS-iADL and ADCS-ADL total score).
3.3.9.1
Alzheimer’s Disease Assessment Scale-Cognition
The ADAS-Cog is an examiner-administered battery that assesses multiple cognitive 
domains, including memory, comprehension, praxis, orientation, and spontaneous 
speech (Rosen et al. 1984; Mohs et al. 1997).  The ADAS-Cog is considered the 
standard primary endpoint in AD treatment studies (Mani 2004) and is generally 
considered the gold standard for assessing cognitive function in AD clinical studies 
(Cano et al. 2010; Sevigny et al. 2010).  The 11-item version of the scale does not 
include adequate assessment of executive function, attention, and working memory, 
particularly for patients in the early stages of AD.  In the crenezumab Phase II program, 
the 12-item version (ADAS-Cog-12) was used in patients with mild to moderate AD 
(defined as screening MMSE score of 1826), and a treatment effect was detected in a 
subpopulation of patients with mild AD (MMSE, 2226).  Because of the expected 
increased sensitivity to detect a treatment effect in patients on the milder part of the AD 
continuum, the Sponsor proposes to use the 13-item version (ADAS-Cog-13), which is 
supplemented with executive measures sensitive to change in patients at the milder end 
of the disease spectrum (Mohs et al. 1997) as the key secondary endpoints. 
3.3.9.2
ADCS-iADL and ADCS-ADL Total Score
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional outcome 
in patients with AD (Vellas et al. 2008).  The ADCS-ADL covers both basic ADL (e.g., eating 
and toileting) and more complex "instrumental" ADL or iADL (e.g., using the telephone, 
managing finances, preparing a meal). The ADCS-ADL scale is considered a standard (co-
)primary endpoint in treatment trials in patients in the mild to moderate dementia stage of 
Alzheimer disease. Because of the expected increased sensitivity to detect a treatment effect in 
patients on the milder part of the AD continuum, the Sponsor will use the ADCS-ADL total 
score and the ADCS-iADL subscore as a key secondary endpoint in order to capture meaningful 
clinically evident decline on functional abilities.
In addition, loss of ADL, as defined above, must be accompanied by a confirmed decline 
of 2 points on the MMSE, which is considered an indicator of overall general disease 
deterioration. 
3.3.10
Rationale for Pharmacokinetic Sampling
A sparse sampling schedule is being utilized to minimize patient burden and yet provide 
an adequate characterization of the population PK profile of crenezumab.  The PK data 
may be compared with available data from other crenezumab studies and may be used 
to assess exposure-response relationships for relevant imaging, CSF, plasma PD 
biomarkers, ECG, and efficacy and safety outcomes in patients with prodromal to mild 
AD, as appropriate.


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3.3.11
Rationale for Biomarker Assessments
The following biomarker assessments described in Section 3.3.11.1 (CSF), 
Section 3.3.11.2 (PET imaging), and Section 3.3.11.3 (brain volumetry) will be used to 
investigate the effect of crenezumab on the underlying pathology of AD in the clinical 
trial population.
3.3.11.1
Cerebrospinal Fluid Biomarkers
Amyloid plaque deposition, neurofibrillary tangle formation, and neuronal degeneration 
are known pathologic features of AD.  Decreased CSF A1−42 and elevated CSF t-tau 
and p-tau are considered a biochemical signature of AD.  Accumulating evidence 
suggests that low CSF A1−42 reflects underlying amyloid plaque pathology, whereas 
increased t-tau and p-tau levels may be reflective of neurodegeneration and/or tau 
pathology.  In Phase II studies, treatment with crenezumab was associated with 
increased levels of CSF A1−42, which suggested target engagement in the CNS. 
Similarly, increases in CSF A1−42 have been observed following treatment with 
solanezumab (Doody et al. 2014).  However, a precise mechanistic basis for these 
increases in A1−42 has not yet been demonstrated.  No treatment effect on CSF tau or 
p-tau was observed in the crenezumab Phase II studies, although this analysis was 
limited by the small number of patients with longitudinal CSF collection.  Consequently, 
CSF tau and p-tau will continue to be evaluated.
3.3.11.2
Positron Emission Tomography Imaging Biomarker
The definitive postmortem diagnosis of AD requires the presence of progressive 
dementia during life and the presence of neuropathological lesions (i.e., neuritic plaques 
composed of -amyloid aggregates and neurofibrillary tangles formed from 
hyperphosphorylated tau protein).  However, imaging approaches using ligands that 
demonstrate high affinity for aggregated amyloid and tau are able to provide an 
assessment of deposition in vivo, which can be evaluated over time (Clark et al. 2011).
3.3.11.3
Brain Volumetry
A characteristic feature of AD is neuronal destruction.  Such neuronal loss is 
demonstrated at a macroscopic level by progressive cerebral atrophy, which can be 
tracked on MRI (Fox and Kennedy 2009).  Multiple changes in brain anatomy beyond 
those associated with normal aging have been reported in patients with AD 
(e.g., enlarged ventricles, decreased cortical thickness, decreased total brain volume, 
and hippocampal atrophy), and there is evidence for strong correlations between these 
imaging biomarkers and functional cognitive measures  (Li and Wahlund 2011).  Based 
on volumetric MRI measurements, the 2 most established markers of disease 
progression through longitudinal observational studies are hippocampal and whole brain 
atrophy (Fox et al. 2000, 2005; Jack et al. 2010), with ventricular expansion a third and 
related quantitative marker.
Therefore, to quantify the effects of crenezumab on neurodegeneration, whole brain 
volume, ventricular enlargement, and regional brain volume changes will be assessed at 


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screening and following treatment with crenezumab.  All MRI reads and volume 
measures will be conducted by the central reader.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study will include approximately 750 male and female patients with increased 
amyloid burden (defined by CSF or PET criteria), objective memory impairment indicated 
by cognitive assessment, and a diagnosis of probable AD or prodromal AD based on 
diagnostic verification (and relevant NIAAA criteria) enrolled during the Global 
Enrollment Phase.  Additional criteria are defined in Section 4.1.1.  
 
 
 
If the patient is currently receiving medications for AD, doses must have been stable for 
at least 3 months prior to screening and the dose regimen must be anticipated to be 
stable for at least 6 months after randomization.
Patients who discontinue from this study are not permitted to be enrolled and 
re-randomized for a second course of treatment.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Able to provide written consent signed by the patient (co-signed by the 
patient’s legally authorized representative, if required by the local 
regulations, guidelines, and independent ethics committee or institutional 
review board [IRB])

Aged between 50 and 85 years at screening, inclusive

Weight between 40 and 120 kg, inclusive

Availability of a person (referred to as the “caregiver” throughout this 
protocol) who in the investigator's judgment:
Has frequent and sufficient contact with the patient to be able to provide 
accurate information regarding the patient’s cognitive and functional abilities, 
agrees to provide information at clinic visits (which require partner input for 
scale completion), signs the necessary consent form, and has sufficient 
cognitive capacity to accurately report upon the patient’s behavior and cognitive 
and functional abilities.
Is in sufficiently good general health to have a high likelihood of maintaining the 
same level of interaction with the patient and participation in study procedures 
throughout the study duration.
Every effort should be made to have same caregiver participate throughout the 
duration of the study. 


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
Fluency in the language used at the study site

Willingness and ability to complete all aspects of the study (including MRI, 
lumbar puncture [if applicable], clinical genotyping, and PET imaging [if 
applicable]); the patient should be capable of completing assessments 
either alone or with the help of the caregiver

Adequate visual and auditory acuity, in the investigator’s judgment, 
sufficient to perform the neuropsychological testing (eye glasses and 
hearing aids are permitted)

For women of childbearing potential:  agreement to remain abstinent 
(refrain from heterosexual intercourse) or use contraceptive methods that 
result in a failure rate of1% per year during the treatment period and for 
at least 8 weeks after the last dose of study drug.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures, and agreement to refrain from 
donating sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for at least 8 weeks 
after the last dose of study drug to avoid exposing the embryo.  Men must refrain from 
donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. 

Evidence of the AD pathological process, by a positive amyloid 
assessment either on CSF A142 levels as measured on the Elecsys β-
Amyloid(1-42) Test System OR amyloid PET scan by qualitative read by 
the core/central PET laboratory. 

Demonstrated abnormal memory function at early screening (up to 4 weeks 
before screening begins) or screening (FCSRT cueing index0.67 AND 
free recall27)


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
Evidence of retrospective decline confirmed by a diagnosis verification form 
(see Appendix 4)

Mild symptomatology, as defined by a screening MMSE score of22 points 
and CDR-GS of 0.5 or 1.0.  MMSE may be performed at early screening 
(up to 4 weeks before screening begins) or at screening.

Meets NIAAA core clinical criteria for probable AD dementia (see 
Appendix 2; McKhann et al. 2011) or prodromal AD (consistent with the 
NIAAA diagnostic criteria and guidelines for MCI; Appendix 3; Albert et al. 
2011) 

If the patient is receiving symptomatic AD medications, the dosing regimen 
must have been stable for 3 months prior to screening.

Inclusion is subject to review of clinical criteria at screening (diagnostic 
verification form – see Appendix 4).

Patient must have completed at least 6 years of formal education after the 
age of 5 years.

For enrollment into the China Extension Phase, patients must have 
residence in the People’s Republic of China.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Any evidence of a condition other than AD that may affect cognition, 
including but not limited to, frontotemporal dementia, dementia with Lewy 
bodies, vascular dementia, Parkinson’s disease, corticobasal degeneration, 
Creutzfeldt-Jakob disease, progressive supranuclear palsy, frontotemporal 
degeneration, Huntington’s disease, normal pressure hydrocephalus, 
seizure disorder, or hypoxia.

History or presence of clinically evident vascular disease that could 
potentially affect the brain (e.g., clinically significant carotid, vertebral 
stenosis or plaque; aortic aneurysm; intracranial aneurysm; cerebral 
hemorrhage; arterio-venous malformation) and that in the opinion of the 
investigator has the potential to affect cognitive function.

History or presence of any stroke with clinical symptoms within the past 2 
years, or documented history within the last 6 months of an acute event 
consistent, in the opinion of the investigator, with a transient ischemic 
attack. 

History of severe, clinically significant (persistent neurologic deficit or 
structural brain damage) CNS trauma (e.g., cerebral contusion)

History or presence of intracranial tumor (e.g., glioma). History or 
presence of meningioma that, in the opinion of the investigator, is not 
clinically significant and is unlikely to result in cognitive impairment is not 
excluded.


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
Presence of infections that affect brain function or history of infections that 
resulted in neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, viral 
or bacterial meningitis/encephalitis)

History or presence of systemic autoimmune disorders that potentially 
cause progressive neurologic disease with associated cognitive deficits 
(e.g., multiple sclerosis, lupus erythematosus, anti-phospholipid antibody 
syndrome, Behçet disease)

History of schizophrenia, schizoaffective disorder, major depression, or 
bipolar disorder 
A history of major depression is acceptable if patient had no episode within the past year 
or is considered in remission or depression is controlled by treatment.

At risk of suicide in the opinion of the investigator

Alcohol and/or substance abuse or dependence (according to Diagnostic 
and Statistical Manual of Mental Disorders v5 criteria) within the past 2 
years 
Nicotine use is allowed.
Marijuana use is not allowed and must be discontinued 3 months before screening.

According to the MRI central reader, MRI evidence of a)2 lacunar infarcts, 
b) any territorial infarct1 cm3, or c) any white matter lesion that 
corresponds to an overall Fazekas score of 3 that requires at least 1 
confluent hyperintense lesion on the FLAIR sequence, which is≥20 mm in 
any dimension.

Evidence of more than 4 microbleeds and/or areas of leptomeningeal 
hemosiderosis (ARIA-H) as assessed by central review of T2* GRE MRI 
(see MRI Charter for further details). 

Presence of significant cerebral vascular pathology as assessed by MRI 
central reader (see MRI Charter for further details).

Presence on MRI of any cortical stroke regardless of age.

Inability to tolerate MRI procedures or contraindication to MRI, including, 
but not limited to, presence of pacemakers not compatible with MRI, 
aneurysm clips, artificial heart valves, ear implants, or foreign metal objects 
in the eyes, skin, or body that would contraindicate an MRI scan; or any 
other clinical history or examination finding that, in the judgment of the 
investigator, would pose a potential hazard in combination with MRI
The following cardiovascular disorders:

History or presence of atrial fibrillation except if only 1 episode that 
resolved1 year ago and for which treatment is no longer indicated

Within the last 2 years, unstable or clinically significant cardiovascular 
disease (e.g., myocardial infarction, angina pectoris, or New York Heart 
Association Class II or higher cardiac failure)


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
Uncontrolled hypertension (e.g., blood pressure generally160 mmHg 
systolic or95 mmHg diastolic)
The following hepatic/renal disorders:

Chronic kidney disease of Stage4, according to the National Kidney 
Foundation Kidney Disease Outcomes Quality Initiative guidelines for 
chronic kidney disease

Confirmed and unexplained impaired hepatic function as indicated by 
screening AST or ALT3 the upper limit of normal (ULN) or total 
bilirubin2ULN 
The following infections and immune disorders:

History of or known to currently have hepatitis B or hepatitis C infection that 
has not been adequately treated in the opinion of the investigator

Systemically, clinically significantly immunocompromised patients, owing to 
continuing effects of immune-suppressing medication

Corticosteroids are permitted as long as the dose is7.5 mg/day 
prednisolone equivalent and the condition being treated is not expected to 
deteriorate significantly during the study period.
The following metabolic/endocrine disorders:

Abnormal thyroid function as indicated by abnormal screening tests that 
are judged to be clinically significant by the Investigator, or abnormal 
thyroid function that requires a new treatment or an adjustment of current 
treatment
A patient may be rescreened if there is no improvement in cognition in the investigator's 
judgment after 3 months of adequate treatment for thyroid function.

Screening folic acid or vitamin B12 levels that are sufficiently low or remain
low on retest such that deficiency may be contributing to cognitive 
impairment
A patient may be rescreened if there is no improvement in cognition after 3 months of 
adequate treatment for folic acid or vitamin B12 deficiency.

Screening hemoglobin A1c (HbA1C)8% (retesting is permitted if slightly 
elevated) or poorly controlled insulin-dependent diabetes (including 
hypoglycemic episodes).
A patient may be rescreened after 3 months to allow optimization of diabetic control.

Pregnant or lactating, or intending to become pregnant during the study 

Poor peripheral venous access 

Other causes of intellectual disability that may account for cognitive deficits 
observed at screening (e.g., static encephalopathy, closed brain injury, 
mental retardation).


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o
This may be based on, for example, patient’s sufficient education or work 
experience.

Sleep apnea that requires treatment (e.g., continuous positive airway 
pressure) or other significant respiratory diseases (e.g., severe COPD –
Global initiative for Obstructive Lung Disease criteria Stage IV) likely to 
result in cognitive impairment.

Deformity of the lumbosacral region of the spine that in the opinion of the 
investigator would contraindicate lumbar puncture in those who can only be 
CSF-eligible due to regional lack of availability of PET ligands.

Clinically significantly abnormal screening blood or urine that remain 
abnormal at retest

Impaired coagulation (screening PT1.2the ULN that remains abnormal 
on retest).
History of cancer except:

If considered to be cured

If not being actively treated with anti-cancer therapy or radiotherapy and, in 
the opinion of the investigator, not likely to require treatment in the ensuing 
5 years

For prostate cancer or basal cell carcinoma, no significant progression over 
the previous 2 years 

Known history of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric, human, or humanized antibodies or fusion proteins

Any other severe or unstable medical condition that, in the opinion of the 
investigator or Sponsor, could be expected to progress, recur, or change to 
such an extent that it could put the patient at special risk, bias the 
assessment of the clinical or mental status of the patient to a significant 
degree, interfere with the patient’s ability to complete the study 
assessments, or would require the equivalent of institutional or hospital 
care

Residence in a skilled nursing facility such as a convalescent home or 
long-term care facility:  Patients who subsequently require residence in 
these facilities during the study may continue in the study and be followed 
for efficacy and safety, provided that they have a caregiver who meets the 
minimum requirement (refer to Section 4.1.1).
The following medications are prohibited for a pre-specified duration prior to study start, 
as indicated, and during the entire period of study participation (patients who start these 
medications during the study may be withdrawn from study treatment):

Any previous administration of crenezumab or any other therapeutic that 
targets A


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
Any investigational active immunotherapy (vaccine) that is under evaluation 
to prevent or postpone cognitive decline

Any passive immunotherapy (immunoglobulin) or other longacting biologic 
agent that is under evaluation to prevent or postpone cognitive decline 
within 1 year of screening

Any other investigational treatment within 5 half-lives or 3 months of 
screening, whichever is longer

Any previous treatment with medications specifically intended to treat 
Parkinsonian symptoms or any other neurodegenerative disorder within 1 
year of screening 

Certain medications are acceptable if the patient is taking the medicine for 
a non-neurodegenerative disorder, such as restless leg disorder 
(e.g., pramipexole)

Typical antipsychotic or neuroleptic medication within 6 months of 
screening except as brief treatment for a non-psychiatric indication (e.g., 
emesis)

Atypical antipsychotics except with intermittent short-term use which is 
permitted except within 2 days or 5 half-lives (whichever is longer) prior to 
any neurocognitive assessment

Anti-coagulation medications within 3 months of screening
Anti-platelet treatments (e.g., aspirin, clopidigrel, dipyridamol) are permitted.
Short-term, peri-operative use of anti-coagulants will not result in discontinuation from
the study; however, any such use must be discussed with the Sponsor.

Chronic use of opiates or opioids (including long-acting opioid medication) 
within 3 months of screening. 

Intermittent short-term use of shortacting opioid medications for pain is 
permitted except within 2 days or 5 half-lives (whichever is longer) prior to 
any neurocognitive assessment. 

Stimulant medications (amphetamine, methylphenidate preparations, or 
modafinil) within 1 month of screening and throughout the study.

Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months 
before screening

Intermittent short term use of benzodiazepines, buspirone, or short-acting 
hypnotic medication for sleep or anxiety is allowed except within 2 days or 
5 half-lives (whichever is longer) prior to any neurocognitive assessment.  
However, intermittent use of barbiturates is not permitted.

Permitted medications are described in Section 4.4.1


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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Randomization will be performed centrally using an interactive voice/Web response 
system (IxRS) that uses stratified block randomization.  After screening, patients who 
meet all eligibility criteria will be randomly assigned to 1 of 2 treatment groups 
(crenezumab or placebo).  Patients will be randomized in a drug to placebo ratio of 1:1. 
Randomization to treatment allocation will also be stratified by dementia status (pAD vs. 
mAD), patient APOE4 status (presence or absence of 4 allele), background 
medication at baseline (present, absent) and geographic region.  Stratification factors 
will ensure balance of these strong prognostic factors across treatment arms and 
facilitate unbiased estimate of treatment effect in subgroups based on disease severity 
and geographic regions. 
Except in circumstances in which a health authority, Ethics Committee (EC), or IRB 
requires the patient be told of his or her APOE status, patients, investigators, central 
MRI reader and the cognitive test rater as well as the Sponsor will be blinded to individual 
patient APOE genotype results.  APOE status information will be supplied directly to the 
IxRS vendor by the central testing laboratory so that the information can be incorporated 
at the time of randomization. In cases where APOE status is already known, these prior 
results will be blinded to the Sponsor and as much as possible to the site and central 
MRI reader. 
The study is to be conducted in a double-blind manner to minimize potential bias from 
investigators and patients.  The Sponsor will be blinded to study treatment.  The Master 
Randomization or Master Medication List will not be available at the study center, to 
Roche monitors, project statisticians, or to the project team at Roche with the exception 
of those responsible for performing PK, PD, and ADA assessments. Personnel responsible 
for performing PK assays will be unblinded to patients’ treatment assignments to identify 
appropriate PK samples to be analyzed. Samples from patients assigned to the placebo 
group will not be analyzed except by request (e.g., to evaluate a possible error in dosing).  
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient care might be affected by knowledge of treatment assignment), 
the investigator will be able to break the treatment code by contacting the IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study treatment for any other reason, he 
or she should contact the Medical Monitor directly.  The investigator should document 
and provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event).
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions that are considered by the investigator or Sponsor to be related to study drug.


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4.3
STUDY TREATMENT 
The investigational medicinal product (IMP) for this study is crenezumab.
4.3.1
Formulation, Packaging, and Handling
4.3.1.1
Crenezumab and Placebo
Crenezumab and placebo will be supplied by the Sponsor as a solution buffered at pH 
5.5 (using arginine succinate solution that contains polysorbate 20 and water for 
injection) in 6.0 mL glass vials.  For information on formulation and handling of 
crenezumab, see the pharmacy manual and crenezumab IB.
4.3.2
Dosage, Administration, and Compliance
4.3.2.1
Crenezumab and Placebo
Crenezumab or placebo will be administered via IV infusion to all patients.  Those 
randomized to the active arm will receive crenezumab at a dose of 60 mg/kg q4w for 
26 doses. 
The IV drug will be prepared and infused from the IV bag by infusion pump.  The bag 
size, drug preparation and infusion rates are all described in the pharmacy manual 
guidance.  IV infusions will be administered by appropriately trained staff in the clinic or 
other agreed environment (e.g., the patient’s home); the first 4 infusions of study drug 
must be administered at the clinic.  All patients will be monitored for a minimum of 1 hour 
after dosing, and vital signs will be measured immediately following completion of the 
infusion and60 minutes after the end of the infusion as described in the pharmacy 
manual.
For the IV dose calculation, the patient’s screening weight (reference weight) should be 
used.  If the current weight changes by10%, the current weight should become the 
new reference weight for subsequent dosing.  If the patient’s weight changes again 
by10% from the reference weight, the IV dose should again be recalculated.  See the 
pharmacy manual for further information.
Crenezumab will be administered to patients under close medical supervision in a 
setting with access to emergency equipment and staff who are trained to monitor and 
respond to medical emergencies.  In the event that a patient experiences a mild 
infusion-related reaction, the infusion will be halted.  Once the reaction has resolved, the 
infusion rate will be resumed at half of the most recently used rate (e.g.,
 
).  Patients who experience a moderate infusion-related reaction (e.g., fever 
or chills) should have the infusion stopped immediately and should receive aggressive 
symptomatic treatment.  The infusion should not be restarted before all symptoms have 
disappeared, and then it should be restarted at half the initial rate.  Patients who 
experience serious or severe hypersensitivity reactions (e.g., hypotension, mucosal 
involvement) should not receive additional study drug. In any patient developing 
anaphylaxis, anaphylactoid, or serious hypersensitivity reactions, a blood sample will be 
collected for analyses of antibodies to crenezumab and/or other components of the drug 


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product.  In addition, for any patient suspected of developing anaphylaxis, anaphylactoid, 
or serious hypersensitivity reactions warranting discontinuation of dosing, a washout 
ADA sample (16 weeks post-dose) and a concurrent PK sample must be collected.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF.
At applicable sites, following the first 4 infusions, study drug may be administered by a 
trained home nursing (HN) professional at the patient's home or another suitable location, 
if the patient has given written informed consent to participate in HN visits (please refer 
to Section 4.5 for details).
4.3.2.2
Non-Investigational Medicinal Products
All patients that are enrolled using PET amyloid evaluation and those in the relevant
substudies, which include PET imaging, will be assessed using appropriate PET ligands.  
Details of the PET substudies are described in separate protocols.
According to EU guidance, the PET ligands used in the context of this study (and associated sub-
studies) have been designated as Non-IMP.  In some regions, according to local regulations, these 
PET tracers may be considered as Investigational Medicinal Products.
Regarding the safety profile of and reporting requirements for the PET ligands 
administered in this study (and associated substudies) please refer to Section 5.7.  
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (crenezumab or placebo) will be provided 
by the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs, using the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced.
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Post-Trial Access to Crenezumab
The Sponsor will offer post-trial access to the study drug (crenezumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.


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A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 

There are no appropriate alternative treatments available to the patient

The patient and his or her doctor comply with and satisfy any legal or 
regulatory requirements that apply to them
A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met:

The study drug is commercially marketed in the patient's country and is 
reasonably accessible to the patient (e.g., is covered by the patient's 
insurance or would not otherwise create a financial hardship for the patient)

The Sponsor has discontinued development of the study drug or data 
suggest that the study drug is not effective for AD

The Sponsor has reasonable safety concerns regarding the study drug as 
treatment for AD

Provision of study drug is not permitted under the laws and regulations of 
the patient's country
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient 
3 months prior to screening through the study completion/early termination visit.  
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF page.
4.4.1
Permitted Therapy 
Dosing status of AD medications at entry (i.e., receiving or not receiving background AD 
medication, dose, and dose regimen) should remain stable for at least 6 months after 
randomization. 
Adding a new medication or changing the dose of a medication after randomization 
should occur only for the treatment of an adverse event or as medically indicated.  


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The following medications are permitted if the dose and dose regimen have been stable 
for 3 months prior to screening and are expected to remain stable after screening or if 
required for treatment of an adverse event after randomization: 

Prescription medications that might affect cognitive function (e.g., 
antidepressants, anticonvulsants)

Over-the-counter and/or herbal medications, food additive or any other 
agent or supplement intended to improve cognition or reduce cognitive 
decline

Medications used to treat a mood or anxiety disorder given as maintenance 
treatment

Medications with anticholinergic activity that may impair cognition or 
attention (e.g., centrally acting antihistamines, including brompheiramine, 
chlorpheniramine, dimenhydrinate, diphenhydramine, and doxylamine, or 
anti spasmodic medicines)

Intermittent use of centrally acting antihistamines is permitted, but no use 
within 2 days or 5 half-lives (whichever is longer) of cognitive assessment

Intermittent use of shortacting (non-extended release) opioid medications 
for pain is permitted except within 2 days or 5 half-lives (whichever is the 
longer) of any neurocognitive assessment (up to a maximum of 3 
consecutive days per month) 

Intermittent use of benzodiazepines including alprazolam, lorazepam, 
oxazepam, triazolam, or temazepam, or a 1-time dose of diazepam or a 
shortacting hypnotic medication (e.g., zolpidem) if use is intermittent for 
sleep or anxiety, except in the 2 days or 5 half-lives (whichever is the 
longer) prior to any cognitive assessment.

Dose of benzodiazepine for pre-surgical and pre-imaging sedation at 
appropriate visits if allowed by EC or IRB

Anti-platelet therapies are permitted during study conduct
Under certain circumstances, anticoagulation therapy (e.g., temporary usage during 
surgery, or for treatment of deep vein thrombosis) is permitted.  In these circumstances, 
appropriate safety assessments should be made, if occurring prior to a lumbar puncture.  
The investigator should discuss with the Sponsor all individual patient cases that require 
anticoagulant therapy.
Concomitant and excluded therapies for determination of patient eligibility are described 
in Section 4.1.2.
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use.


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4.4.2
Prohibited Therapy
Any medication that is prohibited before screening is also prohibited during conduct of 
the study (see Section 4.1.2).  If a patient receives any prohibited treatment during the 
study, the patient may be withdrawn from study treatment.
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of assessments to be performed during the 
study.
Patient-centered outcome instruments are to be adequately translated and adapted for 
the local language and culture, and where feasible, according to the International 
Society of Pharmacoeconomics and Outcomes good principles (Wild et al. 2005), 
distributed by the investigative staff, and completed in their entirety by the designated 
responder. 
Adverse event reports will not be derived patientcentered outcome data.  For further 
details see Section 5.3.5.13.
In this study, patient-centered outcomes instruments will be completed in the 
recommended order specified in Sections 4.5.8 and as specified in the schedule of 
assessments (see Appendix 1). 
At applicable sites, certain study assessments may be performed by an HN professional 
at the patient's home or nursing center to improve access and convenience for patients 
who participate in the study.  The Sponsor will select a healthcare company that will be 
responsible for providing HN services for participating sites (the HN vendor).  The HN 
vendor is responsible for ensuring that all HN professionals are licensed, qualified, and 
in good standing, as per applicable regulations, and that appropriate background checks 
have been performed.  If the investigator at a participating site determines that HN 
services are appropriate for a patient and the patient gives written informed consent to 
participate in HN visits, the HN network will communicate with the patient and the 
patient’s site.  HN visits will be scheduled on specified visit days, to allow for relevant 
assessments to be performed by the HN professional.  The schedule of assessments 
(see Appendix 1) specifies the assessments and visits that may be performed by an HN 
professional.
Rescue medications and equipment to treat anaphylactic and anaphylactoid reactions 
must be available for home nursing visits.  Patients and their caregivers 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.
4.5.1
Informed Consent Forms and Screening Log
All patients and caregivers must review, sign and date the most current IRB-EC 
approved written informed consent for participation in the study before any 


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studyspecific screening tests or evaluations are performed.  Informed Consent Forms 
for enrolled patients and their caregivers, and for those who are not subsequently 
enrolled, will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that a patient 
meets all eligibility criteria before randomization.  The investigator will maintain a 
screening log to record details of all patients screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
4.5.2
Medical History and Demographic Data
Medical history status includes clinically significant diseases, respiratory diseases and 
risk factors, surgeries, cancer history (including prior cancer therapies and procedures), 
smoking history, use of alcohol and drugs of abuse, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements) used by the patient within 3 months prior to the screening visit.  
Demographic data will include age, sex, and self-reported race/ethnicity.  Medical history 
and demographic data will be collected at the screening visit only.
As this study is being conducted in multiple geographic regions, it is likely that patients of 
different ethnic origins will be enrolled in the study.  Although there is currently no 
indication that crenezumab (RO5490245) is metabolized or eliminated differently or that 
the treatment effect would be different in patients with different ethnic origins, collecting 
this information is essential to adequately evaluate the results of this study (e.g., 
possible differences in PK exposure [concentration of the drug in the blood] or treatment 
effect).
4.5.3
Physical Examinations
A physical examination should be performed and should include an evaluation of the 
head, eyes, ears, nose, and throat, and of the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems, 
as clinically indicated.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.  At Week 105, this examination 
is repeated.
At intervening visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF.
The schedule of assessments indicates when height and weight should be recorded.


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4.5.4
Vital Signs
Blood pressure and heart rate should be taken when the patient is at rest and should not 
be measured unless at least 15 minutes have elapsed since the last blood draw.  
The same arm should be used for all blood pressure measurements. 
Body temperature should be taken at each visit.
Respiratory rate and oxygen saturation will be taken at each visit.
Heart rate will be determined by radial pulse and will be recorded as beats per minute. 
The pulse should be counted for a minimum of 20 seconds at each assessment.
The schedule of assessments indicates when vital signs (blood pressure, heart rate, 
respiratory rate, oxygen saturation, and body temperature) are to be recorded (see 
Appendix 1).
4.5.5
Cognitive Assessments
Cognition will be assessed using the ADAS-Cog, FCSRT, CDR, and MMSE. 
The cognitive assessments described in this section is recommended to be performed per the 
order specified in Section 4.5.8 and the schedule of assessments (see Appendix 1). 
The scales and assessments for this study will be provided unless otherwise specified.  
Whenever possible, the same rater and caregiver should complete the scales for a given
patient throughout the study.  Potential raters will receive training and be approved by 
the rating scale contract research organization (CRO) prior to being allowed to 
administer any cognitive assessments/rating scales in the study. 
Raters who are rating secondary scales do not need approval but do need to have 
completed appropriate training.  In addition, given that the primary outcome measure in 
this trial involves subjective judgment, the adequacy of patient interviews and ratings will 
be monitored by an endpoint reliability program administered by the rating scale CRO; 
this is considered to be an essential part of good research methodology.  Prior studies 
have clearly demonstrated that the failure to adequately monitor such ratings can 
substantially increase the risks of failed trials (Becker and Greig 2008; Kobak 2010). 
4.5.5.1
Clinical Dementia Rating Scale
Washington University’s CDR is a global assessment instrument that yields global 
scores (i.e., CDR-GS).  The sum of boxes (i.e., CDR-SB) score is a detailed quantitative 
general index that provides more information than the CDR-GS in patients with mild 
dementia (O'Bryant et al. 2010).  The CDR characterizes 6 domains of cognitive and 
functional performance applicable to AD and related dementias:  memory, orientation, 
judgment and problem solving, community affairs, home and hobbies, and personal care.  
The necessary information to make each rating is obtained through a semi-structured 


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interview of the patient and a reliable informant or collateral source (e.g., a caregiver).  
Details of the CDR can be found at the website: 
http://knightadrc.wustl.edu/cdr/aboutcdr.htm. 
As much as feasible, the CDR should be administered to an individual patient by the 
same assessor throughout the study and that assessor should not perform the MMSE, 
ADAS-Cog, or ADCS-ADL.  However, if in exceptional circumstances only this assessor 
is available to perform these other scales, then the CDR patient interview must be 
completed after the caregiver interview but before ADAS-COG, MMSE and other 
cognitive scales are completed. 
Raters who assess the CDR should not be involved in any other aspects of patient care 
for the person that they are rating, including assessment of adverse events and 
preparation or infusion of study drug.
4.5.5.2
Alzheimer’s Disease Assessment Scale-Cognition 
The ADAS-Cog is the most frequently used scale to assess cognition in clinical trials for 
mild to moderate AD (Rozzini et al. 2007; Connor and Sabbagh 2008; Ihl et al. 2012).  
The modified version will be used; it has 13 items and includes the addition of 1) delayed 
word recall, and 2) number cancellation, as well as use of only 1 trial for word 
recognition.  This is the version used in the Alzheimer’s Disease Neuroimaging Initiative 
protocol (http://www.adni-info.org/Scientists/ADNIStudyProcedures.aspx).  Equivalent 
alternate forms of the word recall, word recognition, and number cancellation subtests 
will be used in successive test administrations. 
The 11-item version of ADAS-COG will be also be analyzed.
4.5.5.3
Alzheimer’s Disease Cooperative StudyActivities of Daily 
Living Inventory
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in patients with AD (Vellas et al. 2008).  The ADCS-ADL covers both basic ADL 
(e.g., eating and toileting) and more complex ADL or instrumental ADL (e.g., using the 
telephone, managing finances, preparing a meal). 
4.5.5.4
Mini-Mental State Examination 
The MMSE (v9.8 including serial 7s) is a set of standardized questions used to evaluate 
possible cognitive impairment and help stage the severity level of this impairment.  
The questions target 6 areas: orientation, registration, attention, short-term recall, 
language, and constructional praxis/visuospatial abilities. 
4.5.5.5
Free and Cued Selective Reminding Test 
The version of the FCSRT-IR is a measure of memory under conditions that control 
attention and cognitive processing in order to obtain an assessment of memory.  
Impairments in FCSRT-IR performance have been associated with preclinical and early 


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dementia in several longitudinal epidemiological studies (Grober and Buschke 1987;
Sarazin et al. 2007).
4.5.5.6
Neuropsychiatric Inventory-Questionnaire 
The NPI-Q (Cummings et al. 1994; Cummings 2009) was developed to assess a range 
of behaviors encountered in dementia patients, to provide a means of distinguishing 
severity of behavioral changes, and to facilitate rapid behavioral assessment through the 
use of screening questions.  It is an informant-based instrument that evaluates 
12 neuropsychiatric disturbances common in dementia:  delusions, hallucinations, 
agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor 
behavior, night-time behavioral disturbances, and appetite and eating abnormalities.  
The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, 
moderate, and marked) while the distress is rated on a 6-point scale (no distress, 
minimal, mild, moderate, severe, extreme or very severe). 
4.5.5.7
Columbia−Suicide Severity Rating Scale 
The C-SSRS (http://www.cssrs.columbia.edu) is an assessment tool used to assess the 
lifetime suicidality of a patient (C-SSRS at baseline) as well as any new instances of 
suicidality (C-SSRS since last visit).  The structured interview prompts recollection of 
suicidal ideation, including the intensity of the ideation, behavior, and attempts with 
actual/potential lethality.  The C-SSRS baseline will be collected at baseline and the 
C-SSRS since last visit will be collected at subsequent visits as indicated in the schedule 
of assessments (Appendix 1).  The assessment will be completed by a certified C-SSRS 
rater after he or she interviews the patient and if necessary, the patient’s caregiver during 
the study visit. 
4.5.5.8
Zarit Caregiver Interview for Alzheimer’s Disease 
The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally 
designed to reflect the stresses experienced by caregivers of people with dementia 
(Zarit and Zarit 1990).  The modified version includes slight modifications in item and title 
wording (e.g., removal of “your relative” to refer directly to the patient, removal of 
“burden” from title) and the use of 11-point numerical rating scales.  The ZCI-AD scale 
consists of a total of 30 items and is completed by the caregiver without involvement 
from the site staff.  Total and domain scores will be calculated (higher scores indicate 
higher levels of distress).  Documentation of the questionnaire’s psychometric properties 
will be performed as exploratory analyses. 
If a patient’s caregiver is replaced during the study, the ZCI-AD will not be completed by 
his or her new caregiver. 
4.5.5.9
Quality of Life–Alzheimer’s Dementia 
The QoL-AD was developed to assess QoL in patients who have dementia 
(Logsdon et al. 1999, 2002).  The QoL-AD consists of 13 items covering aspects of 


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patients’ relationships with friends and family, physical condition, mood, concerns about 
finances, and overall assessment of QoL.  Items are rated on 4point Likert-type scales. 
In this study, the QoL-AD will be administered in a standardized, structured interview 
format to the patient by investigative staff in order to gather patient responses on QoL.  
The caregiver will also complete the caregiver version of the questionnaire to enable 
proxy responses from the caregiver.  A global score will be generated, with a higher 
score indicating better QoL.  Documentation of the questionnaire’s psychometric 
properties in the study population will be performed as exploratory analyses. 
4.5.5.10
EQ-5D
The EQ-5D is a standardized measure of health status designed to provide a simple 
generic measure of health for clinical and economic appraisal.  It is broadly applicable 
across a wide range of health conditions and treatment.
The EQ-5D assesses five domains to provide a health state index.  These are 
anxiety/depression, pain/discomfort, usual activities, mobility, and self-care.
Two versions are used in this study:  EQ-5D-5L proxy v1, reported on behalf of the 
patient and the EQ-5D-5L patient version provided to caregivers to assess caregiver 
health status. 
4.5.6
Electronic Assessment of Rating Scales
The following rating scales will be captured electronically and transferred to the 
database directly from the core laboratory:  ADAS-Cog, ADCS-ADL, CDR, MMSE, 
FCSRT, and CSSR-S.  The diagnostic verification will also be included on the device 
used for scales and submitted electronically.
4.5.7
Laboratory, Biomarker, and Other Biological Samples
4.5.7.1
Standard Laboratory Samples
Samples for the following laboratory tests will be sent to a central laboratory for analysis. 
Instruction manuals and supply kits will be provided for all central laboratory 
assessments. 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual. 

Serum chemistry:  AST, ALT, alkaline phosphatase, total protein, total 
bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, 
calcium, BUN/UREA, and serum creatinine (and creatinine clearance 
calculated by the central laboratory) 

HbA1c, folic acid, and vitamin B12, T4, free T4, and thyroid-stimulating 
hormone levels will also be assessed as per the schedule of assessments 


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
Hematology:  hemoglobin, hematocrit, RBC (with morphology), WBC, 
platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and 
WBC–other total counts 

Screening serologies:  HIV, hepatitis B, hepatitis C

Coagulation:  PT 

Immunophenotyping: including CD4, CD8, CD3, CD19, CD1656.  

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 patient eligibility pertaining to drugs of abuse. 
Inconclusive results may be repeated once during the screening period.  
Investigators should use their best clinical judgment in cases where results may be 
erroneous (e.g., permitted use of opiates or ingestion of food/food supplements). 

Urinalysis:  At screening only, urinalysis will be performed at the site by 
dipstick for blood, protein, glucose, and pH.  Microscopic examination will 
be performed by the central laboratory if blood and/or protein results are 
positive or strongly positive. 

Urine for pregnancy:  Urine pregnancy testing will be performed at each 
dosing visit for women of childbearing potential (including those who have 
had a tubal ligation), and at the site for any other female participants if 
required by local regulations.  If a urine pregnancy test is positive, it must 
be confirmed by a serum pregnancy test at the central laboratory. 
4.5.7.2
Biomarker Sampling
Samples will be collected from all patients and will be used for research purposes to 
identify dynamic biomarkers that may be predictive of response to treatment with 
crenezumab (in terms of dose, safety, and tolerability) and will help to better understand 
the pathogenesis, course, and outcome of AD and related diseases. 
For patients who consent to the optional Roche Clinical Repository (RCR), residual 
biomarker samples will be kept for future biomarker research (see Section 4.5.12).
The procedures for the collection, handling, and shipping of biomarker samples are 
specified in the Sample Handling and Logistics Manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biomarker samples will be destroyed 
no later than 5 years after the final clinical study report has been completed.  However, 
the storage period will be in accordance with the IRB/EC-approved Informed Consent 
Form and applicable laws (e.g., health authority requirements).


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Cerebrospinal Fluid Sampling 
CSF samples will be collected in those patients who chose this approach for 
confirmation of Alevels for eligibility purposes (CSF-enrolled patients) and in those 
patients who enroll in the following substudies:  BN29552-CSF longitudinal or BN29552-
concordance.
Samples will be collected according to the schedule of assessments (Appendix 1).  
Lumbar puncture will be performed by an individual who meets all local requirements 
and is proficient in the procedure.  Lumbar puncture procedures and post−lumbar 
puncture care will be performed in accordance with local practice.  CSF sampling should 
be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal 
variation of CSF parameters.  
Approximately 12 mL of CSF will be collected at screening from patients who are 
enrolled using CSF A(see Appendix 1).  The sample will be divided into aliquots onsite 
and used for the following: 

Central measurement of crenezumab levels in the CSF (see Section 
4.5.7.2) and biomarker analysis, including A1−42, t-tau, and p-tau.  This 
sample may also be used to support the development of biomarker assays 
for diagnostic use. 
Clinical Genotyping
During screening, 3 mandatory 3-mL whole blood samples will be obtained for DNA 
extraction from every patient who has consented to participate in the study.  All patients 
will be evaluated for APOE
, an exploratory diagnostic
biomarker.  Except in circumstances in which a health authority, EC, or IRB requires the 
patient be told of his or her APOE status 
, results will be 
blinded to patients, investigators, and the Sponsor in order to maintain the blind in the 
event that dose reduction is implemented.  Data arising from these analyses will be 
subject to the same confidentiality as the rest of the study. 
RNA Sampling
During screening, two 2.5-mL whole blood samples will be obtained for RNA extraction 
from every patient who has consented to participate in the study.  
 
 
Plasma Sampling
During screening, at baseline, and at subsequent visits as detailed in the schedule of 
assessments (see Appendix 1), one 6-mL whole blood sample will be obtained for 
plasma extraction from every patient who has consented to participate in the study.  
This sample will be used to evaluate plasma Alevels and other biomarkers associated with 
AD or study treatment in peripheral blood as pharmacodynamic markers.


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4.5.7.3
Immunogenicity Sampling
Blood samples will be collected to assess the possible development of ADAs in all 
patients as noted in the schedule of assessments (see Appendix 1) and in case of 
anaphylaxis, anaphylactoid, or serious hypersensitivity reactions.  In addition, for any 
patient suspected of developing anaphylaxis, anaphylactoid, or serious hypersensitivity 
reactions warranting discontinuation of dosing, a washout ADA sample (16 weeks 
postdose) and a concurrent PK sample must be collected.  Serum samples will be 
analyzed for antibodies to crenezumab using a bridging ELISA.  Samples may be tested 
for antibodies against other drug product substances.
The procedures for the collection, handling, and shipping of ADA samples are specified 
in the Sample Handling and Logistics Manual supplied to the site by the Sponsor.
4.5.7.4
Pharmacokinetic Sampling 
Serum Crenezumab 
Blood samples will be collected to evaluate the pharmacokinetics of crenezumab in 
serum as noted in the schedule of assessments (Appendix 1).  An additional PK sample 
for the assessment of serum concentrations of crenezumab may be obtained if the 
patient makes an unscheduled visit. 
Processing, storage, and shipping instructions for these PK blood samples are 
presented in a separate laboratory manual provided by the Sponsor to the clinical 
research unit.
Serum concentrations of crenezumab and immunogenicity analysis will be determined 
using validated analytical procedures.
Samples from patients who receive placebo may not be assessed at once but will be 
retained for subsequent analysis if appropriate.  Samples will not be analyzed in real 
time, but will be batched for analysis. 
Cerebral Spinal Fluid for Assessment of Crenezumab Concentration 
An aliquot of CSF obtained by lumbar puncture as detailed in Section 4.5.8.1 will be 
allocated for the measurement of crenezumab concentration, as noted in the schedule of 
assessments (Appendix 1).  Only patients who consent to the BN29552-CSF longitudinal 
substudy will provide post-baseline CSF samples for this analysis.
Screening sample and samples from patients who receive placebo may not be 
measured initially but will be retained for subsequent analysis if appropriate. 
Unused sample material may also be used for the purposes of current assay 
improvement.


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4.5.8
Timing of Study Assessments
4.5.8.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.
After giving written informed consent, patients who are willing to participate in the study 
will undergo thorough screening assessments within 8 weeks prior to the baseline visit, 
as detailed in the schedule of assessments (Appendix 1).  Patients must fulfill all the 
entry criteria for participation in the study and the results must be available prior to the 
baseline visit. 
The FCSRT assessment and MMSE may also be completed in early screening up to 
4 weeks before main screening begins. However, in this case, a separate early 
screening consent would need to be signed and the FCSRT and MMSE would not need 
to be repeated during the screening process.
In case of an abnormal laboratory or ECG result at screening that may normalize upon 
retest, investigators have the option to repeat the tests (prior to baseline and within the 
8-week screening window) 1 time to confirm the test results before randomizing a patient 
at baseline.
In rare cases in which a MRI scan needs to be repeated or any other unexpected delay 
due to logistical or technical reasons, this may necessitate extending the screening 
period by a few days.  Extending the screening period beyond 8 weeks must be 
approved by the Sponsor and should be in exceptional circumstances only; careful 
scheduling should remain a priority.


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The recommended order of clinical assessments/rating scales at screening is as follows:
Patient
Caregiver
1. FCSRT/MMSE (early screening or 
screening)
2. CDR (patient interview)
3. MMSE (if not completed in early 
screening)
4. ADAS-Cog-13
1. CDR (caregiver input)
2. ADCS-ADL
ADAS-Cog-13 Alzheimer’s Disease Activity Scale-Cognitive (subscale) 13; 
ADCS-ADL Alzheimer’s Disease Cooperative Study-Activities of Daily Living; CDR Clinical 
Dementia Rating; FCSRT Free and Cued Serial Recall Task; MMSE Mini Mental State 
Examination. 
Note:  If FCSRT and MMSE are completed during early screening and the patient is not excluded, 
these assessments do not need to be completed again during screening as long as no more than 
4 weeks has elapsed between the Early Screening Informed Consent Form being signed and the 
Main Screening Informed Consent Form being signed.  If a patient completes FCSRT during 
early screening, the patient may be asked to perform the MMSE scale even if they do not meet 
FCSRT related eligibility criteria.
Following the patient assessments on the screening visit, the clinician should complete 
the diagnosis verification form (see Appendix 4) and submit this within 48 hours of visit.  
The patient may not continue through screening including any further invasive screening 
procedures (e.g., new CSF, MRI, PET scan) until patient eligibility has been confirmed.  
If a patient does not qualify on the basis of eligibility assessments, the patient may be 
rescreened again after at least 3 months have elapsed if recruitment for the study is still 
ongoing (see Section 4.1.1 and 4.1.2).
In the event that a patient has an alternative PET scan available (e.g., from a prior 
clinical investigation), this may be used for confirmation of eligibility if the scan meets the 
criteria defined in the PET imaging charter.
As noted in the exclusion criteria (see Section 4.1.2), patients may be rescreened after 
appropriate treatment if they were originally excluded for abnormal thyroid, folic acid, 
vitamin B12, or HbA1c results.  Other laboratory tests that would exclude the patient 
may be repeated (as an unscheduled laboratory assessment) if it is suspected that the 
abnormal result is transient and likely to be normal at repeat.  The Sponsor will monitor 
the number of repeat laboratory tests during screening.
Patients may be rescreened if the protocol is amended such that they would satisfy the 
amended criteria and if recruitment for the study is still ongoing.  In this case, all 
screening assessments must be repeated other than the lumbar puncture and PET scan 
if previous results were within eligible ranges.


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Patients may be rescreened if there is a substantial change in the patient’s condition 
(e.g., a disallowed medication was stopped) and if recruitment for the study is still 
ongoing and all eligibility criteria are met.
It is suggested that the remaining screening tests with the exception of the lumbar 
puncture and MRI and PET scan be done within 1 to 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 patient from the trial, the CSF collection and/or PET 
scan and MRI scan should be done, if required.  It will 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 patients in any of the PET substudies, scans can be obtained after all other 
screening results are available, with the exception of MRI results. 
For these patients, it is recommended that the MRI appointment and lumbar puncture 
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 performed and evaluated 
before the end of the screening period. 
A Patient Eligibility Checklist that documents the investigator’s assessment of each 
screened patient with regard to the study’s inclusion and exclusion criteria is to be 
completed by the investigator.  A screen failure log must be maintained by the 
investigator.
4.5.8.2
Assessments at Baseline
In order to be randomized to receive double-blind treatment, patients must have no 
significant change in medical, psychiatric or neurological conditions or change in 
medication since screening.  The recommended order of assessments and rating scales 
is as follows:

Clinical assessments (e.g., QoL-AD, ZCI-AD, MMSE; ADAS-Cog-13; ADCS-ADL; 
CDR), including all those that require caregiver input, should be completed before 
any invasive safety assessments.

Vital signs; ECGs; blood draws for clinical laboratory assessments, pharmacokinetics, 
ADA, and plasma biomarkers; and urine samples are recommended to be collected 
following scale assessments and must be collected before study drug administration.


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The recommended order of clinical assessments/rating scales at baseline is as follows:
Patient
Caregiver
1. ADAS-Cog-13
2. CDR (patient interview)
3. MMSE
4. FCSRT
5. QoL-AD
6. C-SSRS
1. CDR (caregiver input)
2. ADCS-ADL
3.
EQ-5D
4. ZCI-AD
5. QoL-AD
6. NPI-Q
ADAS-Cog-13 Alzheimer’s Disease Activity Scale-Cognitive (subscale) 13; 
ADCS-ADL Alzheimer’s Disease Cooperative Study-Activities of Daily Living; 
C-SSRSColumbia-Suicide Severity Rating Scale; CDR Clinical Dementia Rating; 
FCSRT Free and Cued Serial Recall Task; MMSE Mini Mental State Examination; 
NPI-Q Neuropsychiatric Inventory-Questionnaire; QoL-ADQuality of Life-Alzheimer’s Disease; 
ZCI-ADZarit Caregiver Interview-Alzheimer’s Disease.
If assessments are split over 2 days, all safety assessments must be done on the same 
day as the infusion.
4.5.8.3
Assessments during Treatment
Clinical assessments (e.g., QoL-AD, ZCI-AD, MMSE, ADAS-Cog-13, ADCS-ADL, CDR), 
including all those that require caregiver input, should be completed before any invasive 
safety assessments.
The recommended order of clinical assessments/rating scales is as follows:
Patient
Caregiver
1. ADAS-Cog-13
2. CDR (patient interview)
3. MMSE
4. FCSRT
5. QoL-AD (if appropriate)
6. C-SSRS
1. CDR (caregiver input)
2. ADCS-ADL
3.
EQ-5D
4. ZCI-AD (If appropriate)
5. QoL-AD (if appropriate
6. NPI-Q (if appropriate)
ADAS-Cog-13 Alzheimer’s Disease Activity Scale-Cognitive (subscale) 13; 
ADCS-ADL Alzheimer’s Disease Cooperative Study-Activities of Daily Living; 
C-SSRSColumbia-Suicide Severity Rating Scale; CDR Clinical Dementia Rating; 
FCSRT Free and Cued Serial Recall Task; MMSE Mini Mental State Examination; 
NPI-Q Neuropsychiatric Inventory-Questionnaire; QoL-ADQuality of Life-Alzheimer’s Disease; 
ZCI-ADZarit Caregiver Interview-Alzheimer’s Disease.
Vital signs, ECGs, blood draws for clinical laboratory assessments, pharmacokinetics, 
ADA, plasma biomarkers, and urine samples are recommended to be collected following 
scale assessments and must be collected before study drug administration.
If assessments are split over 2 days, all safety assessments must be done on same day 
as the infusion.


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4.5.8.4
Assessments at Week 105 (or Early Termination) Visit
Clinical assessments (e.g., QoL-AD, ZCI-AD, MMSE, ADAS-Cog-13, ADCS-ADL, CDR), 
including all those that require caregiver input, should be completed before any invasive 
safety assessments.
The recommended order of clinical assessments/rating scales is as follows:
Patient
Caregiver
1. ADAS-Cog-13
2. CDR (patient interview)
3. MMSE
4. FCSRT
5. QoL-AD
6. C-SSRS
1. CDR (caregiver input)
2. ADCS-ADL
3.
EQ-5D
4. ZCI-AD 
5. QoL-AD
6. NPI-Q 
ADAS-Cog-13 Alzheimer’s Disease Activity Scale-Cognitive (subscale) 13; 
ADCS-ADL Alzheimer’s Disease Cooperative Study-Activities of Daily Living; 
C-SSRSColumbia-Suicide Severity Rating Scale; CDR Clinical Dementia Rating; 
FCSRT Free and Cued Serial Recall Task; MMSE Mini Mental State Examination; 
NPI-Q Neuropsychiatric Inventory-Questionnaire; QoL-ADQuality of Life-Alzheimer’s Disease; 
ZCI-ADZarit Caregiver Interview-Alzheimer’s Disease.
Vital signs, ECGs, blood draws for clinical laboratory assessments, pharmacokinetics, 
ADA, plasma biomarkers, and urine samples are recommended to be collected following 
scale assessments.
4.5.9
Confidentiality 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4.
4.5.10
Brain Magnetic Resonance Imaging 
The MRI should be performed using a scanner with a field strength of 1.5 T or higher 
and where practical the same scanner should be used for an individual patient for the 
entire duration of the study.  MRI will be conducted at patient screening to provide a 
baseline for future safety monitoring, as a baseline measure of structural brain volumes, 
and as baseline information for the PET substudy concordance analysis (for the 
schedule of assessments, see Appendix 1).  In addition, the screening MRI will be used 
to help determine whether the exclusion criteria have been met (number of microbleeds, 
presence of mass lesions, etc.).  MRI will be used during the study to help assess safety 
such as the occurrence of microbleeds or signs potentially indicative of inflammation or 
ARIA-E.  Additional unscheduled MRI scans may be utilized to better understand 
relevant CNSrelated adverse events (such as increased confusion) or to follow a sign 
that emerges 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 patient according to local 
standards.  Finally, MRI will be performed at multiple timepoints to determine potential 
treatment effects on various MRI outcome measures (see Appendix 1). 


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Patients who are enrolled using CSF-amyloid criteria should either undergo lumbar 
puncture for CSF sample and then wait for 3 days before having MRI or, ideally, undergo 
MRI before the CSF sample is taken.  
During study conduct, within 3 days prior to the scheduled MRI visit, site staff should 
contact the patient or caregiver to prospectively determine whether the patient is 
experiencing any CNS-related symptoms. MRI results must be available for review by 
site staff before dosing can occur.  
Details regarding image acquisition and data transfer by the scanning facilities, and the 
procedures, clinical assessments, and quantitative measurements performed by the core 
laboratory can be found in the MRI Charter and Scanning Manuals.
4.5.11
Electrocardiograms
In all patients who do not participate in the ECG substudy, a routine ECG monitoring 
approach will be used.  Single ECG recordings will be obtained at specified timepoints, 
as outlined in the schedule of assessments (see Appendix 1) and may be obtained at 
unscheduled timepoints as clinically indicated. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 5 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws).  Circumstances that may induce changes 
in heart rate, including environmental distractions (e.g., television, radio, conversation) 
should be avoided during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be analyzed at the central ECG laboratory 
and data transmitted to Roche.
The following should be recorded by the electrocardiograph machine:  heart rate, 
RR interval, QRS interval, PR duration, uncorrected QT interval, and QT interval 
corrected using Fridericia’s formula (QTcF) and Bazett’s formula based on the machine 
readings of the individual ECG tracings. 
In the case of triplicate ECG recordings, if the mean QTcF is500 ms and/or60 ms 
longer than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on 
2 successive ECGs.  The Medical Monitor should be notified.  Standard-of-care 
treatment may be instituted per the discretion of the investigator.  If a PK sample is not 
scheduled for that timepoint, an unscheduled PK sample should be obtained.  When 


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12-lead ECGs are scheduled at the same time as blood draws, the blood draws will be 
obtained at the scheduled timepoint, and the ECGs will be obtained prior to but as close 
to the scheduled blood draw as possible.  
4.5.12
Samples for Roche Clinical Repository
4.5.12.1
Overview of the Roche Clinical Repository
The RCR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection and analysis of RCR specimens will 
facilitate the rational design of new pharmaceutical agents and the development of 
diagnostic tests, which may allow for individualized drug therapy for patients in the future.
In this study, all specimens for the RCR will come from retaining the residual samples 
remaining after the protocol-specified analysis has been performed on protocol-specified 
mandatory samples.  These residual samples will be retained from patients who give 
specific consent to participate in this optional research.  RCR specimens will be used to 
achieve the following objectives:

To study the association of biomarkers with efficacy, adverse events, or 
disease progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug 
absorption and disposition

To develop biomarker or diagnostic assays and establish the performance
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RCR sampling, this section of the protocol 
(Section 4.5.11) will not be applicable at that site.
4.5.12.3
Sample Collection
Three types of residual samples will be retained by the RCR for identification of dynamic 
(non-inherited) biomarkers:  CSF, plasma, and RNA. 

Plasma and CSF samples may be used for exploratory biomarker assays, 
including but not limited to determination of markers of amyloid deposition 
and/or clearance, markers of oxidative stress, neurodegeneration, 
inflammation, or other processes implicated in the pathogenesis of AD.  
These samples will be used to further the Sponsor’s understanding of AD 
and the response to treatment and may also be used to support the 
development of biomarker and diagnostic assays.


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
RNA samples may be tested using techniques such as RNAseq, 
microarray profiling and/or quantitative reverse transcription polymerase 
chain reaction to study the expression profile of genes known to be 
involved in AD.  These samples will be used to further our understanding of 
AD and the response to treatment and may also be used to support the 
development of biomarker and diagnostic assays. 
The following sample type will be retained by the RCR for identification of inherited 
genetic biomarkers: 

DNA:  DNA samples may be used to explore the associations of specific 
variants of genes implicated in susceptibility and pathogenesis of AD with 
therapy response.   DNA samples in the RCR may also be used for whole 
genome sequencing to explore how genetic changes affect diseases or 
response to treatment.
For all samples, dates 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 the laboratory manual. 
RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below. 
4.5.12.4
Confidentiality
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for RCR specimens and associated data.  Upon receipt 
by the RCR, each specimen is "double-coded" by replacing the patient identification 
number with a new independent number.  Data generated from the use of these 
specimens and all clinical data transferred from the clinical database and considered 
relevant are also labeled with this same independent number.  A "linking key" between 
the patient identification number and this new independent number is stored in a secure 
database system.  Access to the linking key is restricted to authorized individuals and is 
monitored by audit trail.  Legitimate operational reasons for accessing the linking key are 
documented in a standard operating procedure.  Access to the linking key for any other 
reason requires written approval from the Pharma Repository Governance Committee 
and Roche's Legal Department, as applicable.
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.


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Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  
The aggregate results of any research conducted using RCR specimens will be available 
in accordance with the effective Roche policy on study data publication.
 
 
4.5.12.5
Consent to Participate in the Roche Clinical Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF.
In the event of an RCR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RCR research.
4.5.12.6
Withdrawal from the Roche Clinical Repository
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the RCR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the RCR Research 
Sample Withdrawal of Informed Consent eCRF.  The patient will be provided with 
instructions on how to withdraw consent after the trial is closed.  A patient's withdrawal 
from Study BN29552 does not, by itself, constitute withdrawal of specimens from the
RCR. Likewise, a patient's withdrawal from the RCR does not constitute withdrawal from 
Study BN29552.
4.5.12.7
Monitoring and Oversight
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 


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management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples.
4.6
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Patient Discontinuation
Patients have the right to voluntarily withdraw from the study at any time for any reason. 
In addition, the investigator has the right to withdraw a patient from the study at any time.
Study treatment discontinuation does not imply discontinuation from the study as described in
Section 4.6.2. Reasons for withdrawal from the study may include, but are not limited to, 
the following:

Patient withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may 
jeopardize the patient’s safety if he or she continues in the study 

Investigator or Sponsor determines it is in the best interest of the patient.
Patients should be informed of circumstances under which their participation may be 
terminated by the investigator without the patient’s consent.  Any administrative or other 
reasons for withdrawal must be explained to the patient.
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn. 
Patients who withdraw from the study will not be replaced.
4.6.2
Study Treatment Discontinuation
Patients must discontinue study treatment permanently if they experience any of the 
following: 

Pregnancy

Evidence of more than 10 microbleeds and/or areas of leptomeningeal 
hemosiderosis (ARIA-H), including any present at baseline, as assessed by 
central review of MRI.

Diagnosed with three recurrent, symptomatic ARIA-E events or 
exacerbations of previous events.


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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients who discontinue from the study drug or who complete the study treatment and do not 
enter the OLE will be asked to return for the collection of safety and efficacy data 4, 16, and 52 
weeks after administration of the last dose of study treatment. 
Additionally, all patients who discontinue from study drug early will be encouraged to return for 
subsequent visits, especially the Week 105 visit (early discontinuation of study treatment does 
not imply study discontinuation).
4.6.2.1
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced.
4.6.3
Study and Site Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies 
indicates a potential health hazard to patients

Patient enrollment is unsatisfactory

Futility analyses from this or other studies with crenezumab suggest that 
treatment with crenezumab is likely not effective

Sponsor determines it is in the best interest of the patients.
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program. 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Conference on Harmonisation (ICH) 
guideline for Good Clinical Practice

No study activity (i.e., all patients have completed and all obligations have 
been fulfilled).


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety of patients who participate in this trial will be ensured through the use of 
stringent inclusion and exclusion criteria, close monitoring of patients, and 
implementation of study drug discontinuation rules.  Investigators will assess the 
occurrence of adverse events and serious adverse events at all patient evaluation 
timepoints during the study.  All adverse events and serious adverse events, whether 
volunteered by the patient, discovered by study personnel during questioning, or 
detected through physical examination, laboratory test, or other means, will be recorded 
in the patient’s medical record and on the appropriate adverse event or serious adverse 
event eCRF.  Each recorded adverse event or serious adverse event will include a 
description of its duration (i.e., start and end dates), severity, seriousness according to 
regulatory criteria, if applicable, and suspected relationship to the investigational product, 
as well as any actions taken.  Patients will be carefully followed for adverse events 
during the study, including a safety follow-up period of 52 weeks after the last dose of 
study drug. 
An iDMC will review unblinded safety and efficacy data at regular intervals (see 
Section 3.1.4 and the iDMC charter for further details).
5.1.1
Amyloid-Related Imaging Abnormalities-Edema/Effusion and 
Amyloid-Related Imaging Abnormalities-Hemosiderin 
Deposition
The occurrence of imaging abnormalities believed to represent ARIA-E has been 
reported in association with the investigational use of compounds that are intended to 
treat AD through the reduction of Ain the brain.  These imaging abnormalities 
(Salloway et al. 2009; Sperling et al. 2011) have, in the majority of instances, been 
asymptomatic, and their presence has been detected by brain MRI.  These MRI signal 
hyperintensities seen in the parenchyma and leptomeninges are named ARIA-E to cover 
the MRI alterations seen in the FLAIR sequence thought to represent edema in the gray 
and white matter and effusion or extravasated fluid in the sulcal space 
(Sperling et al. 2011).  Symptoms, when present in association with such imaging 
abnormalities, have been reported to include headache, worsening cognitive function, 
alteration of consciousness, seizures, unsteadiness, and vomiting. 
Cerebral microhemorrhages (mH) in AD have a point prevalence of 23% 
(Vernooij et al. 2008).  One longitudinal study found that in patients with AD the 
incidence of 1 mH after a mean follow up of 2 years was 12% (Goos et al. 2010).  
Recently, the occurrence of mH has also been identified as an adverse event in 
anti-amyloid vaccination trials, and together with superficial siderosis, these events have 
been termed ARIA-H (Sperling et al. 2011).  Limited data on ARIA-H occurrence are 
available, but a retrospective analysis in patients with AD who were treated with anti-A
antibodies with full effector function reported that 24 out of 207 patients (11.6%) 


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developed ARIA-H (Sperling et al. 2012a).  Acute occurrence of cerebral mH is not 
always considered clinically significant (Greenberg et al. 2009).  Study patients who 
received bapineuzamab and developed ARIA-H without ARIA-E were clinically 
asymptomatic (Sperling et al. 2012a).  However, the clinical significance of cerebral mH 
is not yet fully understood.  
Recent population-based studies have shown that cerebral mHs are common in 
community-dwelling elderly people, with high prevalence ranging 
from 10%25% (Greenberg et al. 2009).  Among those patients, approximately 
70%80% had 1 or 2 cerebral mHs (Cordonnier et al. 2011) and high numbers of 
cerebral mHs have been associated with future risk of ischemic and hemorrhagic strokes 
(Greenberg et al. 2009).  In a longitudinal study in patients visiting a memory clinic, the 
incidence of new cerebral mHs (range, 119 per patient) within 2 years of that visit was 
approximately 12%, and the incidence was not related to diagnosis (type of dementia or 
disease severity) or APOE4 status (Goos et al. 2010).  Taken together, accumulating 
evidence suggests that cerebral mHs are common in cross-sectional observational 
studies of healthy elderly subjects, and the increase in prevalence over time may be part 
of the natural history of aging, which indicates a specific underlying vascular pathologic 
state, in particular hypertensive vasculopathy or cerebral amyloid angiopathy.
In addition, variable levels of diagnostic certainty are inherent in any radiological 
diagnosis.  Therefore, cerebral mH may be definitely present or absent, but often 
uncertainty exists on whether hypointense, homogeneous foci in T2-weighted images 
actually represent cerebral mH.  This variability is reflected by a modest inter- and 
intra-rater reliability for these MRI findings (as expressed as Cohen of 0.600.75 and 
0.650.86, respectively; Yakushiji et al. 2008).
When anti-Aantibodies bind to amyloid deposited around blood vessels, an 
FcRmediated immune response may be elicited.  This compromises vascular integrity 
and results in ARIA-E or ARIA-H.  The hypothesis that FcRmediated immune 
response may contribute to the occurrence of ARIA-E and/or ARIA-H is supported by 
results from clinical studies that have shown that AD patients who were treated with 
anti-Aantibodies with full effector function developed ARIA-E (symptomatic and 
asymptomatic). In these patients ARIA events tend to occur early after treatment initiation, 
and are dose-dependent and APOE4 dependent.
Crenezumab, a human IgG4, has reduced FcR binding compared with IgG1/IgG2 and, 
thus, has reduced effector function that theoretically might lower the risk of ARIA-E. A 
lack of binding to vascular amyloid, noted following in vivo dosing in PS2APP Tg mice 
(Study 15-2817B), may similarly reduce crenezumab’s risk of inducing ARIA.  This has been 
supported by emergent safety data observed in both clinical and nonclinical studies.  In 
the completed Phase I and II studies, only a single case of ARIA-E has been observed 
as of 27 May 2017 (a case of asymptomatic sulcal effusion observed in the IV cohort of 


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ABE4869g in a patient treated with crenezumab). This same patient had a second ARIA-
E during the OLE.
Since development of asymptomatic cerebral mHs may occur within the natural history 
of AD at a rate of approximately 10% per year, the appearance of new cerebral mHs 
should not automatically disqualiy a patient from further treatment.  However, as the 
occurrence of new cerebral mHs may also result from amyloid clearance associated with 
amyloid-lowering therapy and high numbers of new cerebral mHs might impose a risk for 
future ischemic and hemorrhagic strokes, study drug must be discontinued in specific 
circumstances (refer to Section 5.1.2 for details of withdrawal rules).
In this Phase III study, a safety monitoring plan has been designed to monitor the 
potential risk of ARIA-E and ARIA-H.  This plan consists of the following key elements:

Exclusion criteria: 
According to the MRI central reader, MRI evidence of a)2 lacunar infarcts, 
b) any territorial infarct1 cm3, or c) any white matter lesion that corresponds to 
an overall Fazekas score of 3 that requires at least 1 confluent hyperintense 
lesion on the FLAIR sequence, which is≥20 mm in any dimension 
Evidence of more than 4 microbleeds and/or areas of leptomeningeal 
hemosiderosis (ARIA-H) as assessed by central review of T2* GRE MRI (see 
MRI Charter for further details) 

Prior to all MRI evaluations, the patient and caregiver will be contacted to 
determine if the patient has any CNS-related symptoms.  If present, a 
symptom-led assessment will be performed at the visit

Brain MRI (including FLAIR and T2*-weighted GRE sequences) will be 
performed every 3 months in the first year and at least every 6 months in 
subsequent years to detect ARIA-E and ARIA-H (see Appendix 1) 

All MRIs will be read in a timely fashion and will evaluate ARIA-E, ARIA-H 
as well as other abnormalities.  Assessments will be made by independent 
blinded radiologists at a central contract imaging vendor

Patients who exhibit new ARIA-E or ARIA-H (but do not qualify for 
treatment discontinuation as defined below) will be rescanned within 
approximately 4 weeks after the last MRI scan to evaluate the evolution of 
the findings. 
ARIA-E or ARIA-H findings may require dose modification or treatment discontinuation.
The rules to be applied in specific cases are detailed in Section 5.1.2.
5.1.2
Management of Amyloid-Related Imaging Abnormalities 
including Required Dose Adjustments
To date, there has been limited clinical experience of amyloid-related imaging abnormalities with 
crenezumab; however, data from studies on other monoclonal antibody treatments reveal that 
amyloid-related imaging abnormalities events tend to occur early after treatment initiation, are 


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dose-dependent and APOE4 dependent, are manageable with magnetic resonance imaging 
monitoring, and do not lead to significant adverse outcomes (see Section 5.1.1).
All clinical trials with crenezumab include APOE4 genotyping, magnetic resonance imaging 
safety monitoring, and an ARIA-based dose-intervention algorithm.
The following dose adjustments and discontinuation rules for MRI-related findings will 
apply:
ARIA-E
Asymptomatic ARIA-E with Barkhof Grand Total Score 4 (BGTS; Barkhof et al. 2013):

Continue study drug at the same dose (i.e., 60 mg/kg crenezumab)

Repeat MRI 4 weeks later
If ARIA-E is stable or decreased, continue study drug and monthly MRI monitoring until 
event resolves.  Once ARIA-E completely resolved, conduct MRI monitoring as per 
Appendix 1.
If ARIA-E increases (BGTS4) or symptoms develop, refer to the rule below.
Symptomatic ARIA-E (any size) or asymptomatic ARIA-E with BGTS 4:

Temporarily interrupt study drug and implement monthly MRI monitoring

Once symptoms and ARIA-E resolve, reintroduce study drug at the same 
dose and perform an MRI after 4 weeks of dosing.  If no new ARIA-E is 
detected, resume MRI monitoring as per Appendix 1.
Any new onset of ARIA-E:  Treat the same as the first event, based on symptoms and 
BGTS.  However, in the case where a patient is diagnosed with three recurrent, 
symptomatic ARIA-E events or exacerbations of previous events, permanently 
discontinue the study drug.  Implement monthly MRI monitoring until resolution of both 
symptoms and ARIA-E.  As per the protocol (please refer to Section 4.6.2), maintain the 
patient in the study until study end and perform assessments as per the schedule of 
assessments.
ARIA-H
Dose reduction:  Patients who develop8 ARIA-H cumulatively* will receive a lower 
dose of the study drug (i.e., 30 mg/kg) at any dosing visits for the rest of the study.
Study drug discontinuation:  Patients who develop10 ARIA-H cumulatively* will be 
discontinued from the study drug.
*Sum of ARIA-H at baseline and newly detected ARIA-H during the study.


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5.1.3
Prevention and Management of Hypersensitivity and Infusion 
Reactions
Crenezumab will be administered to patients under close medical supervision in a 
setting with access to emergency equipment and staff who are trained to monitor and 
respond to medical emergencies.  In the event that a patient experiences a mild infusion 
related reaction, the infusion will be halted.  Once the reaction has resolved, the infusion 
rate will be resumed at half of the most recently used rate (
).  
Patients who experience a moderate infusion-related reaction (e.g., fever or chills) 
should have the infusion stopped immediately and should receive aggressive 
symptomatic treatment.  The infusion should not be restarted before all symptoms have 
disappeared, and then it should be restarted at half the initial rate.  Patients who 
experience serious or severe hypersensitivity reactions (e.g., hypotension, mucosal 
involvement) should not receive additional study drug.
5.1.4
Additional Safety Monitoring
Laboratory tests, including hematology and chemistry, will be performed throughout the 
study.  ECGs will be recorded regularly (see Appendix 1).  Symptom-led examinations will 
be performed as required during the study to assess physical and neurologic events that 
are not consistent with normal disease progression.  The C-SSRS will be used for 
prospective suicidality assessment.  Pregnancy testing will be performed at each visit in 
women of child-bearing potential.  Samples to assess immunogenicity will be collected 
prior to and throughout the treatment and follow-up periods.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocolspecified safety laboratory assessments, measuring protocolspecified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.2.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal 
product


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
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as 
described in Section 5.3.5.11

Recurrence of an intermittent medical condition (e.g., headache) not 
present at baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, 
X-ray) that is associated with symptoms or leads to a change in study 
treatment or concomitant treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, 
including those that occur prior to assignment of study treatment 
(e.g., screening invasive procedures such as biopsies).
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, 
places the patient at immediate risk of death)
This does not include any adverse event that had it occurred in a more severe 
form or was allowed to continue might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

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 in a neonate/infant born to a mother 
exposed to study drug

Is a significant medical event in the investigator's judgment (e.g., may 
jeopardize the patient or may require medical/surgical intervention to 
prevent one of the outcomes listed above)
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe; the event itself may be of 
relatively minor medical significance (such as severe headache without any further 
findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following:

Cases of potential druginduced liver injury that include an elevated ALT or 
AST in combination with either an elevated bilirubin or clinical jaundice, as 
defined by Hy’s law (see Section 5.3.5.7)

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.

Pneumonia:  In the Phase II program, a numerical imbalance in pneumonia 
cases was observed, with more events reported in crenezumab-treated 
patients versus placebo-treated patients.  It is of paramount importance to 
carefully document any pneumonia cases and other serious respiratory 
infections that occur in this study, by means of providing all relevant 
information required by the eCRF.  A chest X-ray is required under the 
following circumstances:
Serious and non-serious pneumonia
Serious and non-serious lower respiratory tract infections
Serious upper respiratory infections.

In addition, whenever possible, additional relevant investigations should be 
conducted (e.g., WBC counts, pathogen identification by means of 
hemocultures, bronchoalveolar lavage). 

When a pneumonia case is diagnosed, a blood sample for fluorescence-
activated cell sorting (FACS) analysis must be collected as soon as 
feasible for the site and the patient. 
In addition, in order to investigate any potential effects of study drug on the immune 
system, blood samples for B and T cells’ phenotyping (i.e., FACS analysis) will be 
collected in all enrolled patients at Baseline and Week 25.
5.2.4
Selected Adverse Events
To further elucidate potential clinical implications of ARIA findings, patients will be asked 
if they experience CNS adverse events up to 1 week before each MRI is performed.  
The eliciting of these adverse events should be according to Section 5.3.2.  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 


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symptoms (as defined on the eCRF) and safety MRI scans will be collected for the 
following selected adverse events:

ARIA-E:  Amyloid-related imaging abnormalities suggestive of vasogenic 
edema and sulcal effusions

ARIA-H:  Amyloid-related imaging abnormalities suggestive of mH and 
hemosiderin deposits.
New ARIA-E or ARIA-H deposition noted on study-related MRI scans should be 
reported as an adverse event in the following circumstances:

They are symptomatic (i.e., accompanied by CNS symptoms).
and/or 

They result in a change in study treatment (dose modification, interruption or 
discontinuation).
Any accompanying symptoms should also be captured as separate adverse events.
ARIA-E should be reported separately from ARIA-H. 
It is possible that more than one new area of ARIA-H is identified on the same MRI. If meeting 
the criteria above, these should be reported collectively as one new adverse event, and the number 
of areas should be specified. The same should be done separately for ARIA-E. 
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
In addition, after initiation of a PET ligand but prior to initiation of study drug, all serious 
adverse events occurring within 48 hours of PET ligand administration should be reported 


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regardless of relatedness to the PET ligand (see Section 5.4.2). After this 48-hour timepoint, only 
serious adverse events considered related to the PET ligand should be reported. Non-serious 
adverse events (occurring at any timepoint) considered to be related to the PET ligand should also 
be reported. 
After initiation of study drug, all adverse events will be reported until 2 elimination 
half-lives after the last dose of study drug (8 weeks).  After this period, the investigator 
should report any serious adverse events that are believed to be related to prior study 
drug treatment (see Section 5.6).
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all 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?" 
5.3.3
Assessment of Severity of Adverse Events
Table 1 provides guidance for assessing adverse event severity.
Table 1
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer 
to definition of a serious adverse event (see Section 5.2.2).
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar 
treatments

Known association of the event with the disease under study


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
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 
with the occurrence of the event
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis (e.g., 
"infusion-related reaction") on the Adverse Event eCRF.  If possible, avoid ambiguous 
terms such as "systemic reaction."  Associated signs and symptoms should be recorded 
on the dedicated Infusion-Related Reaction eCRF.  If a patient experiences both a local 
and systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Infusion-Related Reaction eCRF.
5.3.5.2
Diagnosis versus Signs and Symptoms
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a 
healthy adult, only vomiting should be reported on the eCRF

If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF


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
If a severe gastrointestinal hemorrhage leads to renal failure, both events 
should be reported separately on the eCRF

If dizziness leads to a fall and consequent fracture, all 3 events should be 
reported separately on the eCRF

If neutropenia is accompanied by an infection, both events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events 
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.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported. If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, 
treatment interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy

Is clinically significant in the investigator’s judgment. 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, 
treatment interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment. 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3 ULN in combination with total 
bilirubin 2 ULN

Treatment-emergent ALT or AST 3 ULN in combination with clinical 
jaundice.


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocolspecified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2). 
This includes death attributed to progression of AD.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.
If the death is attributed to progression of AD, "Alzheimer’s disease progression" should 
be recorded on the Adverse Event eCRF.  The iDMC will monitor the frequency of 
deaths from all causes.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Alzheimer’s Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on diagnostic criteria (e.g., NIAAA New Diagnostic Criteria and 


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Guidelines for AD; Appendix 2).  In rare cases, the determination of clinical progression 
will be based on symptomatic deterioration.  However, every effort should be made to 
document progression through use of objective criteria.  If there is any uncertainty as to 
whether an event is due to disease progression, it should be reported as an adverse 
event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
The following hospitalization scenarios are not considered to be adverse events:

Hospitalization for respite care

Planned hospitalization required by the protocol (e.g., for study drug 
administration or insertion of access device for study drug administration

Hospitalization for a preexisting condition, provided that all of the following 
criteria are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event.
5.3.5.12
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 study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).
5.3.5.13
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety analyses will 
not be performed using PRO data.  Investigators and site staff are not expected to review the 
PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
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place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (see Section 5.4.2 for further details)

Adverse events of special interest (see Section 5.4.2 for further details)

Pregnancies (see Section 5.4.2 for further details).
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor:
 M.D. (Primary)
Telephone No.:
Mobile Telephone No.:
Medical Monitor:
, M.D. (Secondary)
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls. The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week. Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events, Adverse 
Events of Special Interest, and PET Ligand Adverse Events
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, serious 
adverse events caused by a protocol-mandated intervention as well as all serious adverse 
events that occur within 48 hours of PET ligand administration regardless of causality should 
be reported.  The Serious Adverse Event/Adverse Event of Special Interest Reporting 


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paper Form provided to investigators should be completed and submitted to the Sponsor 
or its designee immediately (i.e., no more than 24 hours after learning of the event),
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators.
For adverse events considered related to PET ligands, the clinical site will complete a PET-
ligandspecific non-serious adverse event reporting paper form and submit it to the Sponsor or 
its designee by scanning and emailing the form using the email address provided on the form. 
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 2 elimination half-lives (i.e., 8 weeks) after the last dose of 
study drug.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system. 
Instructions for reporting post-study adverse events are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 8 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.


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5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 8 
weeks after the last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2). 
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the 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.


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All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case.
5.6
POST-STUDY ADVERSE EVENTS
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
8 weeks after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment. 
These events should be reported through use of the Adverse Event eCRF. However, if the EDC 
system is not available, the investigator should report these events directly to the Sponsor 
or its designee, either by faxing or by scanning and emailing the Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the crenezumab IB. To determine 
reporting requirements for PET ligands usedin those countries that have health authority 
approval of the PET ligandsthe approved local Product Information will be used. In countries 
where the PET ligand does not have health authority approval, the Investigator’s Brochure will be 
used. 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The purpose of this study is to investigate the treatment effect of crenezumab relative to 
placebo.  The primary efficacy analysis will be based on an intent-to-treat (ITT) 
population, which will include all randomized patients who receive at least 1 dose of 
study drug, with patients grouped according to their randomly assigned treatment.
Approximately 750 patients will be randomized in the Global Enrollment Phase of this 
study.  
 
 
 
 This China subpopulation may include patients enrolled at sites in China 
during both the Global Enrollment Phase and the China Extension Phase.
The primary analyses of this study will include patients enrolled during the Global 
Enrollment Phase; data from patients enrolled during the China Extension Phase will be 
included in analyses separate from the primary analyses.
6.1
DETERMINATION OF SAMPLE SIZE
Determination of sample size is based on patients enrolled in the Global Enrollment 
Phase.  In this study, 750 patients will be enrolled with 375 patients per treatment arm 
(crenezumab or placebo) during the Global Enrollment Phase.  
 
 
The estimate of sample size required to demonstrate efficacy with regard to CDR-SB is 
based on the following assumptions:

The mean change in CDR-SB from baseline to Week 105 is 2.6 points in 
the placebo arm

A common SD across treatment arms for change from baseline to Week 
105 in CDR-SB of approximately 3.07 (this corresponds to a coefficient of 
variation of 118% for change in CDR-SB from baseline to Week 105 in a 
prodromal to mild AD population in the placebo arm)

The dose level has a true effect of a 30% relative reduction in deterioration 
of CDR-SB

35% of randomized patients will dropout by Week 105
This sample size will have 80% power to detect a true treatment effect of 30% relative 
reduction in deterioration of CDR-SB at 2-sided of 0.05. 
In the event that the rescue strategy or change in dose is required, the number of 
patients enrolled in the new dose group and its concurrently enrolled placebo arm will be 
750 patients (375 patients per treatment arm) during the Global Enrollment Phase.  All 


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patients already enrolled on 60 mg/kg of study treatment and their corresponding 
concurrently enrolled placebo patients will be replaced with new patients.
A blinded assessment of the pooled SD of CDR-SB change from baseline will be performed by the 
Sponsor at a specified timepoint prior to unblinding. As a result, the sample size may be 
increased from 750 up to 1126 patients (563 patients per arm). Further details will be described 
in the Statistical Analysis Plan (SAP). The sample size will not be reduced on the basis of this 
assessment. Other factors external to the study may also trigger a decision to increase sample 
size.
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, patient disposition and incidence of protocol deviations will be summarized 
for all randomized patients and grouped according to randomized treatment assignment.
6.3
SUMMARIES OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (such as age, sex, race, disease severity, 
APOE4 status, use and non-use of background therapy for AD) will be summarized 
descriptively for the ITT population, grouped according to the assigned treatment arm.
Descriptive summaries of continuous data will present the mean, standard deviation, 
median, minimum and maximum.  Descriptive summaries of discrete data will include 
frequencies expressed in terms of number and percentage of subjects.
6.4
EFFICACY ANALYSES
The primary and secondary efficacy analyses will include all randomized patients, with 
patients grouped according to the treatment assigned at randomization.
6.4.1
Primary Efficacy Endpoint
The primary efficacy outcome measure is the change in CDR-SB from baseline (Week 1) 
to Week 105.  For this primary outcome measure, the difference in mean change from 
baseline to Week 105 between crenezumab and placebo treated patients will be 
estimated.  Mixed model repeated measures (MMRMs) adjusting for disease severity, 
APOE4 status, geographic region, and the use or non-use of anti-dementia medications 
at baseline will be used to estimate the mean change from baseline for the primary 
endpoint.  The analysis will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization.
The MMRM model will be used to estimate the mean change from baseline for the 
primary endpoint.  The model will include the change from baseline in CDR-SB as the 
dependent variable.  The effects in the model will include baseline score, treatment 
group, visit, treatment-by-visit interaction and baseline score-by-visit interaction.  Visit 
week will be treated as the repeated variable within a patient.  Patient, treatment, and 
visit week will be treated as class variables. An unstructured variance-covariance 


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structure will be applied to model the within-patient errors; in case of non-convergence, 
compound symmetry will be used. 
The difference in the changes from baseline of each dose group from placebo will be 
estimated at each time point.  The 95% CI and p-value for treatment difference will be 
presented.
All efforts will be made to minimize missing data.  The Sponsor plans to request patients 
who discontinued early from study treatment to return for collection of safety and limited 
efficacy data until Week 105.  To explore the robustness of MMRM results for the 
primary efficacy conclusions, sensitivity analyses (for example, using multiple imputation 
and pattern mixture models) will be performed.  Descriptive summaries of the number of 
patients with missing data, the timing and reasons for discontinuation from study by 
treatment group will also be provided.
Additional details will be documented in the SAP.
6.4.2
Secondary Efficacy Endpoints
The absolute change from baseline in the continuous secondary efficacy endpoints listed 
in Section 2.1.2 (including cognition endpoints, global endpoints, disease pathology 
biomarkers, and endpoints measuring other AD symptoms and effects) will be analyzed 
using an MMRM analysis model similar to that described above for the primary efficacy 
endpoint.
In order to protect the overall type I error rate for the study when incorporating the 
hypothesis testing of the primary endpoints and the key secondary endpoints into the 
analysis, the fixed sequence testing procedure (Westfall and Krishen 2001) will be used 
to adjust for multiple comparisons.  These endpoints were tested in the following order:

Change from baseline to Week 105 in CDR-SB

Change from baseline to Week 105 in ADAS-Cog-13 and ADAS-Cog-11

Change from baseline to Week 105 in iADL

Change from baseline to Week 105 in ADCS-ADL total score
The treatment difference in the primary endpoint (change from baseline to Week 105 in 
CDR-SB) will be tested at a 2-sided 5% overall significance level using the 
O’Brien−Fleming boundary.  If this test result is statistically significant at either the 
interim or the final analysis, the treatment difference in change from baseline to 
Week 105 in ADAS-Cog-13 will be tested at a 2-sided 5% significance level.  If the 
treatment effect on ADAS-Cog-13 is statistically significant, the effect on ADCS-iADL
total score will be tested at a 2-sided 5% significance level and likewise for ADL if iADL is 
significant.  If any test result is not statistically significant, testing of the subsequent 
endpoints will not occur.


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6.4.3
Exploratory Efficacy Analyses
Subgroup analyses of efficacy results may also be performed based on clinically relevant 
baseline factors. Subgroups will be defined by factors which may include one or more of the 
following: age, sex, race, dementia status (pAD vs. mAD), APOE4 status, geographic 
region, use and non-use of background therapies for AD, or other clinically relevant 
factors at baseline.
6.5
SAFETY ANALYSES
The safety analysis population will include all randomized patients who received at least 
1 dose of study drug, with patients grouped according to the treatment actually received.

Incidence and nature of MRI safety findings:  ARIA-E and ARIA-H

Incidence, nature, and severity of serious adverse events

Incidence, nature, and severity of adverse events

Incidence of adverse events of special interest 

Incidence of treatment discontinuations due to adverse events

Mean changes in clinical laboratory tests from baseline over time; 
incidence of treatment-emergent abnormal laboratory values and abnormal 
laboratory values reported as adverse events

Mean change in ECG assessments from baseline over time and incidence 
of abnormal ECG assessments

Incidence of immunogenicity as evidenced by antibodies to crenezumab or 
other components of drug product

Physical and neurologic examination abnormalities

Mean change in vital signs (blood pressure, heart rate) from baseline over 
time and incidence of abnormal vital sign measurements

Changes in CSSR-S scores from baseline over time.  

Numbers and proportions of ADA-positive and ADA-negative patients 
during both the treatment and follow-up periods will be summarized by 
treatment group.
6.6
PHARMACOKINETIC ANALYSES
Serum concentration data for crenezumab will be tabulated and summarized. 
Descriptive summary statistics will include the arithmetic mean, median, range, SD, and 
coefficient of variation, as appropriate. Since a sparse PK sampling design is being used, 
population (non-linear mixed-effects) modeling will be used to analyze the dose 
concentration-time data of crenezumab.  Information from other clinical studies may be 
incorporated to establish the PK model.  The selection of parameters and the derivation 
of individual measures of exposure, such as AUC, Cmax, and trough serum concentration, 
will depend on the final PK model used for this analysis.  The results of this modeling 
analysis may be reported separately from the clinical study report. 


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CSF concentrations of crenezumab will be tabulated and summarized as appropriate 
from the substudy (BN29552-CSF longitudinal).
The influence of background medication on the pharmacokinetics of crenezumab will be 
explored and, if appropriate, concentration-effect relationships may be assessed post 
hoc for PD, efficacy, or safety measures.
Additional PK analyses will be conducted as appropriate and may be reported separately 
from the clinical study report.
6.7
BIOMARKER ANALYSES
Plasma Aconcentrations and MRI-derived measurements over time, such as volumetric 
changes in whole brain, ventricles, hippocampus, or other structures, will be analyzed using the 
same methods used for the primary analysis. Brain amyloid load, brain tau load, and CSF 
markers of disease will be analyzed in their respective substudies (BN29552/BN29553-Amyloid 
PET longitudinal, BN29552/BN29553-tau PET longitudinal, and BN29553-CSF longitudinal).  
Further details can be found in the pertinent substudy protocol.
 
 
 
Exploratory analyses of the relationship between crenezumab exposure and biomarker (imaging, 
plasma PD, CSF PD, or genetic), efficacy, or safety measures will be performed as appropriate. 
The results of these analyses may be reported separately from the Clinical Study Report.
6.8
INTERIM ANALYSIS
An interim analysis for futility will be performed approximately 18 months after 50% of the 
study enrollment has been reached.  No adjustment for multiple comparisons will be made to 
the level for this analysis, given that the decision rules for the futility analysis will not 
allow for the opportunity to stop the study early for overwhelming efficacy.  Study results 
at these interim analyses will be reviewed by the iDMC. 
Based on availability of information pertaining to other compounds with similar mode of 
action that may emerge during the course of this study, the Sponsor may choose to 
conduct an additional interim futility analysis, in case such information external to the 
study would put the hypothesized mode of action of crenezumab in question.  Below are 
the specifications in place to ensure the study continues to meet the highest standards 
of integrity when the optional interim analysis is executed.
The Sponsor will remain blinded.  The futility interim analyses will be conducted by an 
independent data coordinating center and reviewed by iDMC.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC Charter.  The iDMC 


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Charter will document potential recommendations the iDMC can make to the Sponsor as 
a result of the analyses (e.g., stop the study for futility).
At the time of futility analyses, the threshold for declaring futility will be based the 
probability of erroneously stopping the study being lower than a pre-specified level, 
when crenezumab has a true treatment effect on CDR-SB (false negative rate).  If the 
observed treatment effect at the futility analysis is smaller than the derived threshold, the 
iDMC may recommend that the study be stopped for futility.  Additional criteria for 
recommending that the study be stopped for futility may be added to the iDMC Charter. 
Further details of the interim analysis, the rationale, timing, and statistical details for the 
analyses (e.g., data to be reviewed by the iDMC, futility thresholds, etc.) will be 
documented in the SAP.  The SAP will be submitted to relevant health authorities at 
least 2 months prior to the conduct of the interim analysis. 
As information external to the study (e.g., from other compounds) becomes available 
during the conduct of the study, the Sponsor may implement changes to the protocol to 
incorporate such learnings into the study, if possible.  Such learnings may be concerned 
with endpoints, biomarkers, and sample size reassessment due to the variability and 
size of treatment effect observed in other compounds, for example.  The Sponsor could 
implement such learnings through a protocol amendment while being blinded, but 
without consultation with the iDMC.
6.9
CHINA SUBPOPULATION ANALYSIS
Approximately 750 patients will be randomized during the Global Enrollment Phase of 
this study. 
 
 
 
  This China subpopulation may include patients enrolled at sites in 
China during both the Global Enrollment Phase and the China Extension Phase.
The objective of the China Extension Phase and the China subpopulation analyses is to 
assess the treatment effects of crenezumab in a population of patients in the People’s 
Republic of China and to investigate the consistency in treatment effects between the 
China subpopulation and the global population for the purpose of registration in the 
People’s Republic of China.
Methods for analyzing data from the China subpopulation will be provided in the SAP.  
Results from these analyses will be summarized in a separate report.


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7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and other 
electronic data will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. 
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
Electronic patient-centered outcomes research data will be collected through use of an 
electronic device provided by an electronic patient-centered outcomes research vendor.  
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with FDA regulations for electronic records (21 CFR Part 11).  
The electronic patient-centered outcomes research device data are available for view 
access only via secure access to a webserver.  Only identified and trained users may 
view the data, and their actions become part of the audit trail.  The Sponsor will have 
view access only.  System backups for data stored by the Sponsor and records retention 
for the study data will be consistent with the Sponsor’s standard procedures.
Data from paper patient-centered questionnaires will be entered into the EDC system by 
site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.


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7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-centered outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities.
7.4
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic patient-centered outcomes data (if applicable), 
Informed Consent Forms, laboratory test results, and medication inventory records, must 
be retained by the Principal Investigator for at least 15 years after completion or 


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discontinuation of the study, or for the length of time required by relevant national or 
local health authorities, whichever is longer.  After that period of time, the documents 
may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a 
U.S. Investigational New Drug (IND) application will comply with FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such Caregiver’s Informed Consent Form or Home Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.


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


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Data generated by this study must be available for inspection upon request by 
representatives of the FDA and other national and local health authorities, Sponsor 
monitors, representatives, and collaborators, and the IRB/EC for each study site, as 
appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.


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9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
The overall procedures for quality assurance of clinical study data are described in the 
Roche standard operating procedures.  This study will be sponsored by F. Hoffmann-La 
Roche Ltd.  Roche will provide clinical operations oversight, site monitoring and 
management, data management support, and medical monitoring.
Drug distribution may occur through an IxRS (see Section 4.2).  Central facilities may be 
used for study assessments (i.e., ECG, MRI, lumbar puncture, specified laboratory tests, 
pharmacokinetics, rating scales evaluation, and PET, as applicable). 
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site:
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective clinical study report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 


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of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
 
 
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Zarit SH, Zarit JM. The memory and behavior problems checklist and the burden 
interview. Gerontology Center, Penn State University, 1990.
Zwan M, van Harten A, Ossenkoppele R, et al. Concordance Between Cerebrospinal 
Fluid Biomarkers and [11C]PIB PET in a Memory Clinic Cohort. J. Alzheimer’s 
Disease 2014;41:8017.


Crenezumab—F. Hoffmann-La Roche Ltd
136/Protocol BN29552, Version 5
Appendix 1
Schedule of Assessments
Table 1:  Year 1 Assessments
Assessment/ Procedure
Screen
BL
Treatment Period
ET
Wk-8 
to Wk-
1
Day 1 
Wk1
Day 2
Wk 1
Wk
5
Wk
9
Wk
13
Wk
17
Wk
21
Wk
25
Wk
29
Wk
33
Wk
37
Wk
41
Wk
45
Wk
49
Wk
53
Dose Number
1 a

2
3
4
5 b
6 b
7 a
8 b
9 b
10
11 b
12 b
13 b
14 a
a
Informed consents
x
Review of inclusion/exclusion 
criteria
x
x
Medical history, AD history, 
personal status, and 
demographics c
x
Diagnosis Verification Form
x
Vital signs d
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma biomarker sample e
x
x
x f
x
x
x
Clinical genotyping sample
x g
Clinical RNA sample
x h
12-lead ECG i
x
x
x
x
x
x
PK serum sample e
x 
x f
x
x
x
x
Immunogenicity sample j
x
x
x
x
x
x
Serum chemistry and 
hematology  k, l
x
x
x
x
x
Urinalysis m
x
Urine sample for drugs of 
abuse n
x
Urine pregnancy test o
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulation (PT)
x
Physical / neurological exam p
x
x


Appendix 1
Schedule of Assessments (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
137/Protocol BN29552, Version 5
Assessment/ Procedure
Screen
BL
Treatment Period
ET
Wk-8 
to Wk-
1
Day 1 
Wk1
Day 2
Wk 1
Wk
5
Wk
9
Wk
13
Wk
17
Wk
21
Wk
25
Wk
29
Wk
33
Wk
37
Wk
41
Wk
45
Wk
49
Wk
53
Dose Number
1 a

2
3
4
5 b
6 b
7 a
8 b
9 b
10
11 b
12 b
13 b
14 a
a
MRI q, r
x
x
x
x
x
x
PET / CSF sample q, s
x t
x u, v
x u, v
Clinical Dementia Rating
x
x
x
x
x
ADAS-Cog-13
x
x
x
x
x
ADCS-ADL
x
x
x
x
x
MMSE
x
x
x
x
x
NPI-Q
x
x
x
FCSRT
x w
x
x
x
x
EQ5D
x
x
x
x
QOL-AD
x
x
x
ZCI-AD
x
x
x
C-SSRS BL/SLV x
x
x
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Study drug administration y
x
x
x
x
x
x
x
x
x
x
x
x
x
x
ADAS-Cog13 Alzheimer’s Disease Activity Scale Cognition (subscale) 13; ACDS-ADL Alzheimer’s Disease Cooperative Study – Activities of Daily Living; 
APOEapolipoprotein E; BL baseline; CDR Clinical Dementia Rating; CSF cerebrospinal fluid; C-SSRSColumbia Suicide Severity Rating Scale; 
ECG electrocardiogram; ET = early termination; FCSRT-IR Free and Cued Selective Reminding TestImmediate Recall; IV = intravenous; MMSE Mini-Mental 
State Examination; MRI magnetic resonance imaging; NPI = Neuropsychiatric Inventory; PET positron emission tomography; QoL-AD Quality of 
LifeAlzheimer’s Disease; RCR Roche Clinical Repository; Scr = screening; Unsc unscheduled; SLV since last visit; ZCI-AD Zarit Caregiver Interview for 
Alzheimer’s Disease.
Note:  The visit window is 7 days for dosing days and 3 days for all other visits. Patients should return to initial planned schedule per randomization for 
subsequent visits. For patients who terminate early, assessments listed in the ET visit (week 105) should be completed.


Appendix 1
Schedule of Assessments (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
138/Protocol BN29552, Version 5
In case of rescreening a patient, all screening assessments must be repeated other than the lumbar puncture and amyloid PET scan if previous results were within 
eligible ranges.
Does not have to be a site visit – telephone call to patient following first infusion
a
Visit may be split over 2 days. All cognitive and functional assessments should be completed first. All safety assessments (e.g. vitals, blood tests and ECGs) 
should be completed on the day of dosing.
b
Visit suitable for home administration of crenezumab.
c
Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures), smoking history, use 
of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, nutritional supplements) used 
by the patient within 3 months prior to the screening visit. Demographics include age, sex, and self-reported race/ethnicity. Demographics of caregiver will also 
be collected.
d
Vital signs include measurements of weight, pulse rate, systolic and diastolic blood pressure, respiratory rate, oxygen saturation, and body temperature.  The 
same arm should be used for all blood pressure measurements.  Heart rate and blood pressure should not be measured unless 15 minutes have passed since 
the last blood draw. Vital sign assessments should be performed just prior to study drug administration, at the end of infusion, and 60−90 minutes after the end of 
infusion.  Weight need only be measured prior to study drug administration.  All vitals should be recorded in the eCRF. Height should be recorded at the 
screening visit only. Vital sign assessments should be performed at the site or by the health care provider who is administering study drug; such assessments 
should not be captured separately at the site if such administration is done at a different location (e.g. by a home nurse).
e
All scheduled pharmacokinetic (PK) and plasma biomarker samples should be obtained just prior to study drug administration, if possible.  Accurate recording of 
the time of study drug administration and PK sample is critical. 
f
Pharmacokinetic and plasma biomarker samples will be taken pre- and 60-90 minutes post-infusion.
g
At screening, 3 mandatory 3-mL whole blood samples will be obtained for DNA extraction for analysis of APOE status 
. 
h
At screening, 2 mandatory 2.5-mL RNA samples will be taken for analysis of mRNA 
 (paxgene tubes).
i
Perform after the patient has been in a supine position for 5 minutes.  ECGs for each patient should be obtained from the same machine whenever possible and 
performed prior to any blood draws, brain MRI scans, and lumbar puncture.
j
Immunogenicity samples should be obtained prior to study drug administration; Samples are taken to measure antibody development to crenezumab (ADAs) and 
other drug component products.  Unscheduled samples should be taken in the event of anaphylaxis, anaphylactoid, or serious hypersensitivity reactions.  In 
addition, for any patient suspected of developing anaphylaxis, anaphylactoid, or serious hypersensitivity reactions warranting discontinuation of dosing, a 
washout ADA sample (16 weeks post-dose) and a concurrent PK sample must be collected.


Appendix 1
Schedule of Assessments (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
139/Protocol BN29552, Version 5
k
Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatinine phosphokinase, sodium, potassium, calcium, 
BUN/urea, and serum creatinine (and creatinine clearance calculated by the central laboratory). At the screening, and Week 53, hemoglobin A1C, folic acid, 
vitamin B12, T4, free T4, and thyroid-stimulating hormone levels will also be assessed.  At screening only, serum samples will be tested for HIV and hepatitis B 
and C virus. 
l
Hematology includes hemoglobin, hematocrit, RBC (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBC–
other total counts.  At baseline and Week 25, immunophenotyping analysis of peripheral blood cells.  In the event of a pneumonia diagnosis, 
immunophenotyping analysis of peripheral blood cells should be repeated.
m Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and pH. Microscopic examination performed at the central laboratory if blood and/or 
protein results are positive or strongly positive.  Results do not need to be recorded on the eCRF.
n
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 patient eligibility pertaining to drugs of abuse.  Inconclusive results may be repeated once during the 
screening period. Investigators should use their best clinical judgment in cases where results may be erroneous (e.g., permitted use of opiates or ingestion of 
food/food supplements).
o
Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory. Results are to be recorded only in 
the source documents. Urine pregnancy testing must also be performed and a negative result obtained prior to receiving injection of a PET radioligand.
p
At visits between Week 5 and Week 101, assessment of neurological or physical adverse events will be symptom-led.
q
CSF sampling, new PET and MRI scans at screening should be performed once all other screening results are available and none exclude the patient from the 
trial.
r
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI should be performed 
before or at least 3 days following a lumbar puncture.  The patient must be called in advance of the MRI to ask if he or she is experiencing any CNS symptoms.
s
Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters.  For post baseline 
visits, lumbar puncture should be performed prior to dosing.  Only one method (CSF or PET) confirming amyloid is necessary in all patients.
t
For patients enrolled in the concordance substudy, either assessment may be performed first and there is no requirement for either result to be available before 
the other assessment.  For entry into the study, the patient must be positive by at least one method. 
u
CSF sample only in those who have consented to participate in the BN29552-CSF longitudinal substudy.
v
PET assessment only in those who have consented to participate in the BN29552/BN29553-Amyloid PET longitudinal substudy or BN29552/BN29553-tau PET 
longitudinal substudy.


Appendix 1
Schedule of Assessments (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
140/Protocol BN29552, Version 5
w If FCSRT and MMSE is completed during early-screening, and patient is not excluded, this assessment does not need to be completed again during screening 
as long as no more than 4 weeks has elapsed between the Early Screening Informed Consent Form being signed and the Main Screening Informed Consent 
Form being signed.
x
C-SSRS-Baseline form should be used on the baseline visit; subsequent visits should use the “since-last-visit” form.
y
Study drug administration should be performed only after all assessments/rating scales for the patient are completed (unless indicated otherwise).  Study drug 
will be administered to patients as infusion (full details in the pharmacy manual).  Patients should be observed for a minimum of 1 hour after dosing and vitals 
should be assessed immediately after infusion is completed, and then ≥60 minutes post-infusion.


Appendix 1
Schedule of Assessments (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
141/Protocol BN29552, Version 5
Table 2:  Year 2 Assessments
Assessment/Procedure
Treatment Period
Follow-up for those not 
entering OLE
Wk
57
Wk
61
Wk
65
Wk
69
Wk
73
Wk
77
Wk
81
Wk
85
Wk
89
Wk
93
Wk
97
Wk
101
Wk 105
+4 wks 
(or ET)
Wk 117
+16 wks
Wk 153
+52 wks
Dose number
15 a
16 a
17 a
18 a
19 a
20 b
21 a
22 a
23 a
24 a
25 a
26 a
b, c
Vital signs d
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis e
x
Urine pregnancy test f
x
x
x
x
x
x
x
x
x
x
x
x
x
Plasma biomarker sample
x
x
x
x
PK serum sample g
x
x
x
Immunogenicity sample h
x
x
x
12-lead ECG i
x
x
x
Physical / neurological 
exam j
x
Serum chemistry and 
hematology  k, l
x
x
MRI q
x
x
PET / CSF sample m
x n, o
Clinical Dementia Rating
x
x
x
x
ADAS-Cog-13
x
x
x
x
ADCS-ADL
x
x
x
x
MMSE
x
x
x
x
NPI-Q
x
x
FCSRT
x
x
EQ5D
x
x
x
x


Appendix 1
Schedule of Assessments (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
142/Protocol BN29552, Version 5
Assessment/Procedure
Treatment Period
Follow-up for those not 
entering OLE
Wk
57
Wk
61
Wk
65
Wk
69
Wk
73
Wk
77
Wk
81
Wk
85
Wk
89
Wk
93
Wk
97
Wk
101
Wk 105
+4 wks 
(or ET)
Wk 117
+16 wks
Wk 153
+52 wks
Dose number
15 a
16 a
17 a
18 a
19 a
20 b
21 a
22 a
23 a
24 a
25 a
26 a
b, c
QOL-AD
x
x
x
x
ZCI-AD
x
x
C-SSRS SLV 
x
x
Concomitant medications
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events 
x
x
x
x
x
x
x
x
x
x
x
x
x
Study drug administration p
x
x
x
x
x
x
x
x
x
x
x
x
ADAS-Cog13 Alzheimer’s Disease Activity Scale Cognition (subscale) 13; ACDS-ADL=Alzheimer’s Disease Cooperative Study – Activities of Daily Living; 
APOE apolipoprotein E; BL baseline; CDR = Clinical Dementia Rating; CSF cerebrospinal fluid; C-SSRSColumbia Suicide Severity Rating Scale; 
ECG electrocardiogram; ET =- early termination; FCSRT-IR Free and Cued Selective Reminding TestImmediate Recall; IV = intravenous; MMSE Mini-
Mental State Examination; MRI magnetic resonance imaging; NPI-Q = Neuropsychiatric Inventory-Questionnaire; PET positron emission tomography; QoL-
AD Quality of LifeAlzheimer’s Disease; RCR Roche Clinical Repository; SLV since last visit;; Unsc unscheduled; W = week; ZCI-AD Zarit Caregiver 
Interview for Alzheimer’s Disease.
Note: The visit window is 7 days for dosing days and 3 days for all other visits.  Patients should return to initial planned schedule per randomization for 
subsequent visits.  For patients who terminate early, assessments listed in the ET visit should be completed.
In case of rescreening a patient, all screening assessments must be repeated other than the lumbar puncture and amyloid PET scan if previous results were within 
eligible ranges.
a
Visit suitable for home administration of crenezumab.
b
Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., visits, blood tests, and ECGs) 
should be completed on the day of dosing.
c Transition to OLE protocol for those eligible to participate.
d
Vital signs include measurements of weight, pulse rate, systolic and diastolic blood pressure, respiratory rate, oxygen saturation, and body temperature.  The 
same arm should be used for all blood pressure measurements.  Heart rate and blood pressure should not be measured unless 15 minutes have passed since 
the last blood draw.  Vital sign assessments should be performed just prior to study drug administration, at the end of infusion, and 60−90 minutes after the end 
of infusion. All vitals should be recorded in the eCRF.  Vital sign assessments should be performed at the site or by the health care provider who is administering 


Appendix 1
Schedule of Assessments (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
143/Protocol BN29552, Version 5
study drug; such assessments should not be captured separately at the site if such administration is done at a different location (e.g., by a home nurse).
e
Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and pH. Microscopic examination performed at the central laboratory if blood and/or 
protein results are positive or strongly positive.  Results do not need to be recorded on the eCRF.
f
Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in 
the source documents. Urine pregnancy testing must also be performed and a negative result obtained prior to receiving injection of a PET radioligand.
g
All scheduled PK samples should be obtained just prior to study drug administration, if possible.  Accurate recording of the time of study drug administration and 
PK sample is critical.
h
Immunogenicity samples should be obtained prior to study drug administration; samples are taken to measure antibody development to crenezumab (ADAs) and 
other drug component products.  Unscheduled samples should be taken in the event of anaphylaxis, serious anaphylactoid, or hypersensitivity reactions.  In 
addition, for any patient suspected of developing anaphylaxis, anaphylactoid, or serious hypersensitivity reactions warranting discontinuation of dosing, a 
washout ADA sample (16 weeks post-dose) and a concurrent PK sample must be collected.
i
Perform after the patient has been in a supine position for 5 minutes.  ECGs for each patient should be obtained from the same machine whenever possible and 
performed prior to any blood draws, brain MRI scans, and lumbar puncture.
j
At visits between Week 5 and Week 101, assessment of neurological or physical adverse events will be symptom-led.
k
Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, creatine phosphokinase, sodium, potassium, calcium, 
BUN/urea, and serum creatinine (and creatinine clearance calculated by the central laboratory). 
l
Hematology includes hemoglobin, hematocrit, RBC (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBC–
other total counts. In the event of a pneumonia diagnosis, immunophenotyping analysis of peripheral blood cells should be repeated.
m Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters.  For post baseline 
visits, lumbar puncture should be performed prior to dosing.  LP should be performed 3 days before MRI – or after MRI has been done. 
n
CSF sample only in those who have consented to participate in the BN29552-CSF longitudinal substudy
o
PET assessment only in those who have consented to participate in the BN29552/BN29553-amyloid PET longitudinal substudy or BN29552/BN29553-tau PET 
longitudinal substudy.
p
Study drug administration should be performed only after all assessments/rating scales for the patient are completed (unless indicated otherwise).  Study drug 
will be administered to patients as infusion (full details in the pharmacy manual).  Patients should be observed for a minimum of 1 hour after dosing and vitals 
should be assessed immediately after infusion is completed, and then ≥60 minutes post infusion.
q
MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed. The patient must be called 
in advance of the MRI to ask whether he or she is experiencing any CNS symptoms.


Crenezumab—F. Hoffmann-La Roche Ltd
144/Protocol BN29552, Version 5
Appendix 2
National Institute on Aging/Alzheimer’s Association Criteria for 
Dementia due to Alzheimer’s Disease
NIA-AA category
Description
Probable Dementia: 
core Clinical Criteria
Meets criteria for 
dementia described 
earlier in the text, 
and in addition, has 
the following 
characteristics:
A. Insidious onset. Symptoms have a gradual onset over months to years, 
not sudden over hours or days;
B. Clear-cut history of worsening of cognition by report or observation; 
and
C. The initial and most prominent cognitive deficits are evident on history 
and examination in one of the following categories.
a. Amnestic presentation: It is the most common syndromic 
presentation of AD dementia. The deficits should include impairment 
in learning and recall of recently learned information. There should 
also be evidence of cognitive dysfunction in at least one other 
cognitive domain, as defined earlier in the text.
b. Non-amnestic presentations:
Language presentation: The most prominent deficits are in 
word-finding, but deficits in other cognitive domains should be 
present.
Visuospatial presentation: The most prominent deficits are in 
spatial cognition, including object agnosia, impaired face 
recognition, simultanagnosia, and alexia. Deficits in other 
cognitive domains should be present.
Executive dysfunction: The most prominent deficits are impaired 
reasoning, judgment, and problem solving. Deficits in other 
cognitive domains should be present.
D. The diagnosis of probable AD dementia should not be applied when 
there is evidence of (a) substantial concomitant cerebrovascular disease, 
defined by a history of a stroke temporally related to the onset or 
worsening of cognitive impairment; or the presence of multiple or 
extensive infarcts or severe white matter hyperintensity burden; or (b) 
core features of Dementia with Lewy bodies other than dementia itself; or 
(c) prominent features of behavioral variant frontotemporal dementia; or 
(d) prominent features of semantic variant primary progressive aphasia or
nonfluent/agrammatic variant primary progressive aphasia; or (e) 
evidence for another concurrent, active neurological disease, or a non-
neurological medical comorbidity or use of medication that could have a 
substantial effect on cognition.
Probable AD 
dementia with 
increased level of 
certainty
Probable AD dementia with documented decline
In persons who meet the core clinical criteria for probable AD dementia, 
documented cognitive decline increases the certainty that the condition 
represents an active, evolving pathologic process, but it does not 
specifically increase the certainty that the process is that of AD 
pathophysiology.
Probable AD dementia with documented decline is defined as follows: 
evidence of progressive cognitive decline on subsequent evaluations 
based on information from informants and cognitive testing in the context 
of either formal neuropsychological evaluation or standardized mental 
status examinations.


Appendix 2
National Institute on Aging/Alzheimer’s Association Criteria for
Dementia due to Alzheimer’s Disease (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
145/Protocol BN29552, Version 5
Probable AD dementia in a carrier of a causative AD genetic mutation
In persons who meet the core clinical criteria for probable AD dementia, 
evidence of a causative genetic mutation (in APP, PSEN1, or PSEN2), 
increases the certainty that the condition is caused by AD pathology. The 
workgroup noted that carriage of the ɛ4 allele of the apolipoprotein E 
gene was not sufficiently specific to be considered in this category.
Probable AD 
dementia with 
evidence of the AD 
pathophysiological 
process
AD dementia is part of a continuum of clinical and biological phenomena. 
AD dementia is fundamentally a clinical diagnosis. To make a diagnosis 
of AD dementia with biomarker support, the core clinical diagnosis of AD 
dementia must first be satisfied.
Relevant biomarkers include amyloid-β(CSF or PET); tau (CSF or PET) 
Source:  McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due 
to Alzheimer’s disease: Recommendations from the National Institute on 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimer’s & Dement 2011;7:2639.


Crenezumab—F. Hoffmann-La Roche Ltd
146/Protocol BN29552, Version 5
Appendix 3
National Institute on Aging/Alzheimer’s Association Criteria for 
Prodromal Alzheimer’s Disease (Mild Cognitive Impairment due 
to Alzheimer’s Disease)
NIA-AA category
Clinical and cognitive criteria
Clinical Criteria
:
Cognitive concern reflecting a change in cognition reported by patient or
informant or clinician (i.e., historical or observed evidence of decline
over time)
Objective evidence of Impairment in one or more cognitive domains,
typically including memory (i.e., formal or bedside testing to establish
level of cognitive function in multiple domains)
Preservation of independence in functional abilities
Not demented
Etiology of MCI 
consistent with AD 
pathophysiological 
process
Rule out vascular, traumatic, medical causes of cognitive decline, where
possible
Provide evidence of longitudinal decline in cognition, when feasible
Report history consistent with AD genetic factors, where relevant
Prodromal AD 
dementia with 
evidence of the AD 
pathophysiological 
process
pAD is part of a continuum of clinical and biological phenomena. pAD is 
fundamentally a clinical diagnosis. To make a diagnosis of pAD with 
biomarker support, the core clinical diagnosis of pAD must first be 
satisfied.
Relevant biomarkers include amyloid-β(CSF or PET); tau (CSF or PET) 
Source:  Albert MS, DeKosky ST, Dickson B, et al. The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimer’s & Dement 2011;7:270-279.


Crenezumab—F. Hoffmann-La Roche Ltd
147/Protocol BN29552, Version 5
Appendix 4
Diagnostic Verification Form
Date
Please list all dates as DD-MMM-
YYYY
Subject Screening Number
Name of Person submitting 
request
Email of Person submitting 
request
Principal Investigator email
Investigator Direct Contact 
Number
Site Telephone Number
Site Fax Number
I have evaluated this patient and confirm that the information 
documented on this form represents the best information (based on 
clinical evaluation and other information sources) available at this 
time
Investigator (or Sub-Investigator or 
CDR Rater) Name 
Investigator (or Sub-Investigator or 
CDR Rater)
(Electronic signature)
Instructions 
The Medical Monitor or assignee will review the form and indicate whether a subject 
may continue with screening.  Approval must be given by the reviewer before any 
invasive procedures are conducted.  The clinical team or assignee will confirm eligibility 
based on the diagnostic verification form with the site.


Appendix 4
Diagnostic Verification Form (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
148/Protocol BN29552, Version 5
Roche Use only
Verification of diagnosis
Based upon the review of the screening information made available by the site, I 
confirm the above noted patient has been reviewed and conclude:
Yes, the patient may continue with screening
No, the patient cannot continue with screening
Reviewer
(electronic signature)
Date of Approval
CLINICAL HISTORY
1
By patient, caregiver, clinician report, when did the patient first experience or 
exhibit symptoms of cognitive dysfunction (month/year)?
AFFECTED COGNITIVE DOMAINS
NIA-AA criteria require the involvement of at least one cognitive domain for mild 
cognitive impairment, or at least two domains for dementia. Please indicate which of 
the following cognitive domains are affected AND which test(s) was/were used; if 
known please provide dates of assessment.
Memory (impaired ability to acquire and remember new information)
Executive function / complex attention (e.g. impaired reasoning, impaired 
problem solving, inability to plan and organize): 
Visuospatial function (inability to recognize faces or common objects, to find 
objects in direct view despite adequate visual acuity, to operate simple tools, or 
to orient clothes on the body): 
Language (impairments in comprehension, naming, word retrieval, verbal 
fluency, grammar; disturbances in understanding emotional content of speech): 
Praxis


Appendix 4
Diagnostic Verification Form (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
149/Protocol BN29552, Version 5
2
Does the patient currently have Dementia [
] or Mild Cognitive Impairment? 
[
].When was the diagnosis in (2) first made (month/year)?
3
If the patient has dementia, please detail how functional impairment has been 
established (include patient/caregiver history, and any standardized 
assessment, e.g., CDR) and which areas of the patient’s life have been 
affected:
4
Has there been cognitive or functional decline in the past 12 months? [yes 
/no 
]
If yes, please give examples of specific deficits that have emerged or 
deteriorated in the past year as reported by the caregiver or clinician:
If yes, please report any available objective evidence of progression (e.g., 
MMSE or MoCA scores at two time points, with dates):
5
SUPPORTIVE INFORMATION
Please provide details of any other supportive diagnostic information (e.g., MRI, 
amyloid-PET, tau-PET, FDG-PET, CSF biomarkers, etc.)