Clinical trial NCT03491150
Conditions: Alzheimer's Disease
Keywords: Dementia Neurodegenerative Diseases Brain Diseases Central Nervous System Diseases Nervous System Diseases Tauopathies Neurocognitive Disorders Mental Disorders
Sponsor: Hoffmann-La Roche
Start date: 2018-04-11; Completion date: 2019-05-31
Enrollment: 149 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
In the BN40031 OLE study, a dose of crenezumab of 60 mg/kg intravenous (IV) every 4 weeks (Q4W) will be offered to all participants who complete Study BN29552 or BN29553 and who meet eligibility criteria in order to evaluate safety in participants on long-term crenezumab treatment and to investigate the effect of crenezumab on the underlying disease process and disease course as an exploratory efficacy objective.

Detailed description:

Arms: arm 1: Participants (who were treated with Placebo in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W). arm 2: Participants (who were treated with Crenezumab in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).
Interventions: intervention 1: Crenezumab
Intervention descriptions: intervention 1: Crenezumab 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 Multicenter, Open-Label, Long-Term Extension of Phase III Studies 
(BN29552/BN29553) of Crenezumab in Patients With Alzheimer’s 
Disease 
NCT Number: 
NCT03491150 
Document Date: 
Protocol Version 2: 05-August-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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 BN40031, Version 2
PROTOCOL
TITLE:
A MULTICENTER, OPEN-LABEL, LONG-TERM 
EXTENSION OF PHASE III STUDIES 
(BN29552/BN29553) OF CRENEZUMAB IN 
PATIENTS WITH ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
BN40031
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-002702-12
IND NUMBER:
100,839
TEST PRODUCT:
Crenezumab (RO5490245)
MEDICAL MONITOR:
, M.D., M.A.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1:  18 September 2017
DATE AMENDED:
See electronic date stamp below.
 
05-Aug-2018 10:16:20
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Crenezumab—F. Hoffmann-La Roche Ltd
2/Protocol BN40031, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE
Protocol BN40031 has been amended primarily to align with recent CREAD 
(BN29552/BN29553) protocol amendment completed in March 2018.  Changes to the 
protocol, along with a rationale for each change, are summarized below:

The amendment improves alignment with the recently amended CREAD and 
CREAD2 studies for the purpose of harmonization across studies.  This includes the 
following main changes:
–
Coagulation abnormalities have been added as an exclusion criterion
(Section 4.1.2).
–
The magnetic resonance imaging requirement after amyloid-related imaging 
abnormalities-hemosiderin findings has been removed (Section 5.1.1).
–
Pharmacokinetic and anti-drug antibody samples have been added at Week 13
(Appendix 1).

Since the China Extension has been activated in the parent studies, language has 
been updated for this region (Sections 1.2.2, 3.1, and 6.6).

Information has been updated to align with latest Crenezumab Investigator’s 
Brochure (Version 10) (Sections 1.2.2, 1.2.3, 1.2.3.1, 1.2.3.2, 1.2.5, 1.2.6.3, 
and 1.3.1).

Exploratory efficacy objectives have been updated to specify that efficacy analyses 
may not be limited to Week 53 (Section 2).

The number of sites has been amended to 350 centers in approximately 
40 countries (Section 3.1).

The recruitment periods in the parent studies (BN29552 and BN29553) were 
reduced from initial timelines.  Because the time between first and last participants
in the OLE has been shortened, the maximum treatment time in the OLE is now 
approximately 4 years for the first patients in.  The protocol has been updated to 
reflect this change (Section 3.3).

The first dose window has been increased from 4 to 8 weeks from the parent study 
Week 105 visit to allow sites more time to confirm patient eligibility and to allow 
more flexibility to schedule first dose (Sections 3.2 and 4.5.11).

The inclusion criteria that address female contraception have been modified to 
specify when women must refrain from donating eggs and to specify that the 
definition of childbearing potential may be adapted for alignment with local 
guidelines (Section 4.1.1).

Text has been added to recognize country variability in designation of 
non-investigational medicinal product/investigational medicinal product status to 
positron emission tomography (PET) tracers (Sections 4.3 and 4.3.2.2), and PET 
Ligand Investigator's Brochures have been added as reference documents for 
assessing and reporting adverse events (Section 5.7). 


Crenezumab—F. Hoffmann-La Roche Ltd
3/Protocol BN40031, Version 2

The physical and neurologic examination assessment has been modified to specify 
that a complete examination must be performed, and the elements comprising a 
complete examination have been specified.  These changes ensure consistency of 
examinations across visits and allow for more thorough identification of changes in 
findings over time (Sections 4.5.3 and 5.1.4 and Appendix 1).

Vitals language has been harmonized throughout protocol (Section 4.5.8 and 
Appendix 1).

A set of standard laboratory samples (screening serology [HIV, Hepatitis B and C], 
hemoglobin A1c, folic acid, vitamin B12, thyroxine 4, free thyroxine, and 
thyroid-stimulating hormone levels) have been removed as these assessments were
already performed at the screening of the parent studies (Section 4.5.7.1).

The plasma pharmacodynamic (PD) biomarker sampling schedule has been 
updated to allow collection at the early termination visit if the patient discontinues 
treatment prior to the Week 53 visit.  This change aligns the plasma PD and CSF 
PD sampling schedules (Section 4.5.7.3 and Appendix 1).

Safety data from ongoing and completed clinical studies with [18F]GTP1 have been 
updated (Section 4.5.7.4).

Instructions about patient withdrawal from the Research Biosample Repository after 
site closure have been modified to indicate that the investigator must inform the 
Sponsor of patient withdrawal by emailing the study number and patient number to 
global_rcr-withdrawal@roche.com (Section 4.5.10.6).

The recommended order of clinical assessments/rating scales for patients and 
caregivers has been clarified (Section 4.5.11.1).

Timing of brain MRI to detect ARIA-edema/effusion and ARIA-H deposition has 
been clarified (Section 5.1.1 and Appendix 1).

Instructions regarding the assessment of fluorescence-activated cell sorting (FACS)
have been updated to specify that the assessment will not be performed at baseline 
and Week 25, as this analysis has already been performed in the parent studies 
(Section 5.2.3). FACS remains a requested sample/assessment in the event of 
pneumonia.

An analysis of the change from baseline in Clinical Dementia Rating-Sum of Boxes
values recorded during the double-blind treatment period in Studies BN29552 and 
BN29553 and at specified timepoints of the open-label extension study has been 
clarified (Section 6.5.2).

Language has been added for consistency with Roche's current data retention 
policy and to accommodate more stringent local requirements (if applicable) 
(Section 7.6).

The schedule of activities (Appendix 1) has been updated to provide additional 
guidance and clarity in the footnotes as mentioned above and as follows:  Week 73 
has been corrected as Week 77.  It has been clarified that Functional Activities 
Questionnaire is for caregivers of Study BN29553, not patients.


Crenezumab—F. Hoffmann-La Roche Ltd
4/Protocol BN40031, Version 2
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


Crenezumab—F. Hoffmann-La Roche Ltd
5/Protocol BN40031, Version 2
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................. 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 23
1.1
Background on Alzheimer’s Disease..................................... 23
1.2
Background on Crenezumab................................................. 24
1.2.1
Summary of Nonclinical Studies............................................ 25
1.2.2
Summary of Clinical Studies.................................................. 26
1.2.3
Safety Overview .................................................................... 28
1.2.3.1
Adverse Event Profile ............................................................ 30
1.2.3.2
Deaths ................................................................................... 30
1.2.3.3
Pneumonia ............................................................................ 31
1.2.3.4
ARIA-E and ARIA-H .............................................................. 31
1.2.3.5
Summary ............................................................................... 32
1.2.4
Immunogenicity ..................................................................... 32
1.2.5
Pharmacokinetics .................................................................. 33
1.2.6
Biomarkers ............................................................................ 35
1.2.6.1
Summary ............................................................................... 35
1.2.6.2
Brain Imaging Pharmacodynamic Biomarkers....................... 35
1.2.6.3
Plasma and CSF Pharmacodynamic Biomarkers.................. 36
1.3
Study Rationale and Benefit-Risk Assessment...................... 36
1.3.1
Background ........................................................................... 36
1.3.2
Safety Rationale .................................................................... 37
1.3.3
Efficacy.................................................................................. 38
1.3.4
Dose ...................................................................................... 39
1.3.5
Biomarkers ............................................................................ 40
1.3.6
Risk to Patients without Alzheimer’s Disease 
Pathology............................................................................... 41
1.3.7
Overall BenefitRisk Summary.............................................. 41
2.
OBJECTIVES AND ENDPOINTS ............................................................... 43
3.
STUDY DESIGN......................................................................................... 46


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3.1
Description of the Study......................................................... 46
3.2
Study Design ......................................................................... 46
3.2.1
Independent Data Monitoring Committee .............................. 47
3.3
End of Study and Length of Study......................................... 47
3.4
Rationale for Study Design.................................................... 49
3.4.1
Rationale for Treatment Duration .......................................... 49
3.4.2
Rationale for Long-Term Follow-Up....................................... 49
3.4.3
Rationale for Patient Population ............................................ 49
3.4.4
Rationale for Safety Outcome Measures............................... 49
3.4.5
Rationale for Exploratory Efficacy Outcome 
Measures............................................................................... 50
3.4.6
Rationale for Pharmacokinetic Sampling............................... 50
3.4.7
Rationale for Biomarker, PET Assessments and
MRI Assessments.................................................................. 50
3.4.7.1
Cerebrospinal Fluid Biomarkers (for Patients 
Who Were in the BN29552 or BN29553 CSF 
Longitudinal Substudy Only).................................................. 50
3.4.7.2
Positron Emission Tomography Imaging 
Assessment........................................................................... 51
3.4.7.3
MRI Assessments for Brain Volumetry .................................. 51
4.
MATERIALS AND METHODS .................................................................... 52
4.1
Patients.................................................................................. 52
4.1.1
Inclusion Criteria.................................................................... 52
4.1.2
Exclusion Criteria................................................................... 54
4.2
Method of Treatment Assignment and Blinding..................... 54
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 55
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 55
4.3.1.1
Crenezumab.......................................................................... 55
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 55
4.3.2.1
Crenezumab.......................................................................... 55
4.3.2.2
Non-Investigational Medicinal Products................................. 56
4.3.3
Investigational Medicinal Product Accountability ................... 56


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4.3.4
Continued Access to Crenezumab ........................................ 57
4.4
Concomitant Therapy ............................................................ 58
4.5
Study Assessments ............................................................... 59
4.5.1
Informed Consent Forms and Screening Log........................ 60
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 60
4.5.3
Physical and Neurologic Examinations.................................. 60
4.5.4
Vital Signs.............................................................................. 60
4.5.5
Cognitive Assessments ......................................................... 61
4.5.5.1
Clinical Dementia Rating Scale ............................................. 61
4.5.5.2
Alzheimer’s Disease Assessment 
Scale-Cognition ..................................................................... 62
4.5.5.3
Alzheimer’s Disease Cooperative 
StudyActivities of Daily Living Inventory .............................. 62
4.5.5.4
Mini Mental State Examination .............................................. 62
4.5.5.5
Free and Cued Selective Reminding Test–
Immediate Recall................................................................... 62
4.5.5.6
Functional Activities Questionnaire........................................ 63
4.5.5.7
Neuropsychiatric Inventory Questionnaire............................. 63
4.5.5.8
Columbia−Suicide Severity Rating Scale .............................. 63
4.5.5.9
Zarit Caregiver Interview for Alzheimer’s Disease................. 63
4.5.5.10
Quality of Life–Alzheimer’s Disease ...................................... 64
4.5.5.11
EuroQOL 5-Dimension Questionnaire ................................... 64
4.5.6
Electronic Assessment of Rating Scales ............................... 64
4.5.7
Laboratory, Biomarker, PK and Other Biologic 
Samples................................................................................. 64
4.5.7.1
Standard Laboratory Samples............................................... 64
4.5.7.2
Cerebrospinal Fluid Sampling................................................ 65
4.5.7.3
Plasma Biomarker Sampling ................................................. 66
4.5.7.4
Amyloid- and Tau-PET Assessments .................................... 66
4.5.7.5
Immunogenicity Sampling...................................................... 68
4.5.7.6
Pharmacokinetic Sampling .................................................... 69
4.5.8
Electrocardiograms................................................................ 69
4.5.9
Brain Magnetic Resonance Imaging...................................... 70


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8/Protocol BN40031, Version 2
4.5.10
Optional Samples for Research Biosample 
Repository ............................................................................. 70
4.5.10.1
Overview of the Research Biosample Repository.................. 70
4.5.10.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 71
4.5.10.3
Sample Collection.................................................................. 71
4.5.10.4
Confidentiality........................................................................ 72
4.5.10.5
Consent to Participate in the Research 
Biosample Repository............................................................ 72
4.5.10.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 72
4.5.10.7
Monitoring and Oversight....................................................... 73
4.5.11
Timing of Visits and Study Assessments............................... 73
4.5.11.1
Study Assessments ............................................................... 74
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 74
4.6.1
Study Treatment Discontinuation........................................... 74
4.6.2
Patient Discontinuation.......................................................... 75
4.6.3
Study Discontinuation............................................................ 75
4.6.4
Site Discontinuation............................................................... 76
5.
ASSESSMENT OF SAFETY....................................................................... 76
5.1
Safety Plan ............................................................................ 76
5.1.1
ARIA-E and ARIA-H .............................................................. 77
5.1.2
ARIA-Related Dose Adjustments........................................... 79
5.1.2.1
ARIA-E................................................................................... 79
5.1.2.2
ARIA-H .................................................................................. 79
5.1.3
Management of Patients Who Experience 
Specific Adverse Events........................................................ 80
5.1.3.1
Hypersensitivity and Infusion Reactions ................................ 80
5.1.3.2
Amyloid-Related Imaging Abnormalities................................ 80
5.1.4
Additional Safety Monitoring.................................................. 80
5.2
Safety Parameters and Definitions ........................................ 81
5.2.1
Adverse Events ..................................................................... 81
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 81


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5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 82
5.2.4
Selected Adverse Events....................................................... 83
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 83
5.3.1
Adverse Event Reporting Period ........................................... 83
5.3.2
Eliciting Adverse Event Information....................................... 84
5.3.3
Assessment of Severity of Adverse Events ........................... 84
5.3.4
Assessment of Causality of Adverse Events ......................... 84
5.3.5
Procedures for Recording Adverse Events............................ 85
5.3.5.1
Infusion-Related Reactions.................................................... 85
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 85
5.3.5.3
Adverse Events That are Secondary to Other 
Events.................................................................................... 85
5.3.5.4
Persistent or Recurrent Adverse Events................................ 86
5.3.5.5
Abnormal Laboratory Values ................................................. 86
5.3.5.6
Abnormal Vital Sign Values ................................................... 87
5.3.5.7
Abnormal Liver Function Tests.............................................. 87
5.3.5.8
Deaths ................................................................................... 88
5.3.5.9
Preexisting Medical Conditions.............................................. 88
5.3.5.10
Lack of Efficacy or Worsening of Alzheimer’s 
Disease.................................................................................. 89
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 89
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 89
5.3.5.13
Patient-Centered or Observer-Reported Outcome 
Data....................................................................................... 90
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 90
5.4.1
Emergency Medical Contacts................................................ 91
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 91
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 91
5.4.2.2
Events That Occur after Study Drug Initiation........................ 91
5.4.3
Reporting Requirements for Pregnancies.............................. 92


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10/Protocol BN40031, Version 2
5.4.3.1
Pregnancies in Female Patients............................................ 92
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 92
5.4.3.3
Abortions ............................................................................... 92
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 93
5.5
Follow-Up of Patients after Adverse Events .......................... 93
5.5.1
Investigator Follow-Up........................................................... 93
5.5.2
Sponsor Follow-Up ................................................................ 93
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 93
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 93
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 94
6.1
Determination of Sample Size ............................................... 94
6.2
Summaries of Conduct of Study............................................ 94
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 95
6.4
Safety Analyses..................................................................... 95
6.5
Efficacy Analyses .................................................................. 95
6.5.1
Exploratory Efficacy Endpoints.............................................. 96
6.5.2
Exploratory Efficacy Analyses ............................................... 96
6.5.3
Exploratory Pharmacokinetic Analyses.................................. 97
6.5.4
Exploratory Biomarker Analyses............................................ 97
6.6
China Subpopulation Analysis............................................... 97
6.7
Interim Analysis ..................................................................... 98
7.
DATA COLLECTION AND MANAGEMENT ............................................... 98
7.1
Data Quality Assurance......................................................... 98
7.2
Electronic Case Report Forms............................................... 98
7.3
Electronic Patient and Clinician Reported 
Outcome Data ....................................................................... 99
7.4
Source Data Documentation.................................................. 99
7.5
Use of Computerized Systems ............................................ 100
7.6
Retention of Records........................................................... 100
8.
ETHICAL CONSIDERATIONS.................................................................. 100


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11/Protocol BN40031, Version 2
8.1
Compliance with Laws and Regulations .............................. 100
8.2
Informed Consent................................................................ 101
8.3
Institutional Review Board or Ethics Committee.................. 102
8.4
Confidentiality...................................................................... 102
8.5
Financial Disclosure ............................................................ 103
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 103
9.1
Study Documentation .......................................................... 103
9.2
Protocol Deviations.............................................................. 103
9.3
Site Inspections ................................................................... 103
9.4
Administrative Structure....................................................... 103
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 104
9.6
Protocol Amendments ......................................................... 105
10. REFERENCES ......................................................................................... 106
LIST OF TABLES
Table 1 
Objectives and Corresponding Endpoints................................... 44
Table 2
Order of Clinical Assessment and Rating Scale Collection......... 74
Table 3
Adverse Event Severity Grading Scale ....................................... 84
LIST OF FIGURES
Figure 1
Randomized Start Design ........................................................... 38
Figure 2
Pharmacokinetic Profile Based on Modeling 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 .......... 40
LIST OF APPENDICES
Appendix 1
Schedule of Activities: Open-Label Extension Study ................ 111


Crenezumab—F. Hoffmann-La Roche Ltd
12/Protocol BN40031, Version 2
PROTOCOL ACCEPTANCE FORM
TITLE:
A MULTICENTER, OPEN-LABEL, LONG-TERM 
EXTENSION OF PHASE III STUDIES 
(BN29552/BN29553) OF CRENEZUMAB IN 
PATIENTS WITH ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
BN40031
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-002702-12
IND NUMBER:
100,839
TEST PRODUCT:
Crenezumab (RO5490245)
MEDICAL MONITOR:
, M.D., M.A.S.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form to your local study monitor. 


Crenezumab—F. Hoffmann-La Roche Ltd
13/Protocol BN40031, Version 2
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, OPEN-LABEL, LONG-TERM EXTENSION OF 
PHASE III STUDIES (BN29552/BN29553) OF CRENEZUMAB IN 
PATIENTS WITH ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
BN40031
VERSION NUMBER:
2
EUDRACT NUMBER:
2017-002702-12
IND NUMBER:
100,839
TEST PRODUCT:
Crenezumab (RO5490245)
PHASE:
Phase III
INDICATION:
Alzheimer’s Disease
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will assess the long-term safety and tolerability of crenezumab administered to all 
patients with Alzheimer’s disease (AD) who completed Studies BN29552 (CREAD) and 
BN29553 (CREAD2) and who meet the eligibility criteria for this open-label extension (OLE) 
study.  An exploratory objective of this OLE study is to investigate the effect of crenezumab on 
the underlying disease process and course. Specific objectives and corresponding endpoints 
for the study are outlined below.
Primary Safety Objective
Corresponding Endpoints
To assess the long-term safety and 
tolerability of crenezumab (60 mg/kg IV 
Q4W) in eligible patients with AD who 
participated in Study BN29552 or 
BN29553 and completed the Week 105 
study visit

Nature, frequency, severity, and timing of adverse 
events and serious adverse events

Vital signs, blood tests, ECGs, and C-SSRS 

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


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14/Protocol BN40031, Version 2
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the long-term effect of 
crenezumab on global outcomes of 
disease progression

Change from baseline during the OLE in CDR-SB
To evaluate the long-term effect of 
crenezumab on cognition 

Change from baseline during the OLE as 
measured by the ADAS-Cog13

Change from baseline during the OLE using the 
MMSE

Change from baseline during the OLE using 
ADAS-Cog12
To evaluate the long-term effect of 
crenezumab on disease severity 

Change from baseline during the OLE using 
CDR-GS
To evaluate the long-term effect of 
crenezumab on patient dependence

Change from baseline during the OLE using 
scores derived from the ADCS-ADL total scale
To evaluate the long-term effect of 
crenezumab on patient function

Change from baseline during the OLE using the 
ADCS-ADL, the instrumental subscale, and/or the 
FAQ
To evaluate the long-term effect of 
crenezumab on behavior and 
neuropsychological symptoms

Change from baseline during the OLE using the 
Neuropsychiatric Inventory Questionnaire 
To evaluate the long-term effect of 
crenezumab on health-related quality of 
life 

Change from baseline during the OLE using the 
Quality of Life-AD scale
To evaluate the long-term effect of 
crenezumab on caregiver burden

Change from baseline during the OLE using the 
Zarit Caregiver Interview for AD scale
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To evaluate the serum PK 
characteristics of crenezumab

Serum concentration of crenezumab at specified 
timepoints
To evaluate the CSF PK characteristics 
of crenezumab

CSF concentrations of crenezumab at specified 
timepoints (only in patients who previously 
enrolled in substudy BN29552-CSF 
Longitudinal or BN29553-CSF Longitudinal)
To explore exposure-response 
relationships in patients with prodromal 
to mild AD 

Correlation between crenezumab concentration 
and biomarkers as well as safety and efficacy 
outcomes


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15/Protocol BN40031, Version 2
Exploratory Biomarker Objectives
Corresponding Endpoints
To evaluate the effect of crenezumab 
on biomarkers

Brain amyloid load over time measured by amyloid 
PET (only in patients who previously enrolled in 
substudy BN29552-Amyloid PET Longitudinal or 
BN29553-Amyloid PET Longitudinal) 

Brain tau load and spread over time measured by 
tau-PET (only in patients who previously enrolled 
in substudy BN29552-Tau PET Longitudinal or 
BN29553-Tau PET Longitudinal)

CSF markers of disease over time (only in patients 
who previously enrolled in substudy BN29552-
CSF Longitudinal or BN29553-CSF Longitudinal)

Plasma PD markers of disease over time

MRI-derived measurements over time such as 
volumetric changes in whole brain, ventricles, 
hippocampus, or other structures
ADAlzheimer’s disease; ADAS-CogAlzheimer’s Disease Assessment Scale-Cognition 12 or 
13; ADCS-ADLAlzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory; 
ARIA-Eamyloid-related imaging abnormalities-edema/effusion; ARIA-Hamyloid-related 
imaging abnormalities-hemosiderin deposition; CDR-GSClinical Dementia Rating-Global 
Score; CDR-SBClinical Dementia Rating-Sum of Boxes; CSFcerebrospinal fluid; 
C-SSRSColumbia-Suicide Severity Rating Scale; FAQFunctional Activities Questionnaire; 
MMSEMini Mental State Examination; MRImagnetic resonance imaging; OLEopen-label 
extension; PDpharmacodynamic; PETpositron emission tomography; PKpharmacokinetic; 
Q4Wevery 4 weeks.
Study Design
Description of Study
Study BN40031 is a Phase III, OLE, multicenter study to evaluate the long-term safety and 
tolerability of crenezumab at a dose of 60 mg/kg IV every 4 weeks (Q4W) in patients with AD 
who have participated in one of the Phase III parent studies (BN29552 or BN29553).  Efficacy 
will also be assessed.  Patients who discontinued early from study treatment during Study 
BN29552 or BN29553 but remained in the study for safety and additional efficacy evaluations 
and completed the Week 105 study visit can enter the OLE study and begin open-label 
treatment.  Patients from Study BN29552 or BN29553 who discontinued the study prior to 
completion of the Week 105 study visit are not eligible for this OLE study.
Studies BN29552 and BN29553 are ongoing Phase III, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, efficacy and safety studies of crenezumab in patients with 
prodromal AD to mild AD.  
Patients and all clinical site staff will remain blinded to the original treatment assignment in 
Studies BN29552 and BN29553 on entry into the OLE study and until a later time which will be 
determined by the Sponsor. 
Following completion of the global enrollment phase of Study BN29553, additional patients 
will continue to be enrolled in a China extension phase (i.e., China extension to the main 
Phase III study BN29553) to ensure a total enrollment sufficient to support registration in the 
People’s Republic of China.  This China subpopulation may include patients enrolled at sites in 
China during both the global enrollment phase and the China extension phase and could be 
included in this OLE, if applicable.
Number of Patients
The planned number of patients for this OLE study is not expected to exceed 1500 
(approximately 750 randomized to crenezumab 60 mg/kg IV and 750 randomized to placebo, 
i.e., the total planned number of patients in the parent studies BN29552 and BN29553, not 
including patients from the China extension study).  An estimate for the actual number of 
patients in this OLE study is approximately 925 patients (not including patients from the China 


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extension study) based on 1500 patients enrolled in both Phase III studies and an estimated 
reduction by 35% (i.e., withdrawals from double-blind treatment) and by a further 5% of 
completers who may not opt to enroll in this OLE study.  Approximately 350 centers in 
approximately 40 countries worldwide will participate in this study.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Previous participation in Study BN29552 or BN29553 and completion of the Week 105 visit. 
Patients who discontinued from one of these studies prior to completion of the 
Week 105 visit are not eligible.  Temporary halting of study drug (e.g., because of an 
adverse event) in Study BN29552 or BN29553 is not exclusionary.

Written informed 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 [EC] or Institutional Review Board [IRB]) or the patient’s authorized 
representative under applicable local law
In the course of the study, assessment of a subject’s capacity to re-consent should be 
done, and written informed re-consent signed by the patient (co-signed by the 
patient’s legally authorized representative if required by the local regulations, 
guidelines, or independent EC/IRB) or the patient’s authorized representative should 
be obtained, as per applicable local law and requirements.

Every effort should be made to have the same caregiver participate throughout the duration 
of the OLE study who also participated in Study BN29552 or BN29553
The caregiver, in the investigator's judgment, should fulfill the following:
Have frequent and sufficient contact with the patient to be able to provide 
accurate information regarding the patient’s cognitive and functional abilities, 
agree to provide information at clinic visits (which require partner input for 
scale completion), sign the necessary consent form, and have sufficient 
cognitive capacity to accurately report upon the patient’s behavior and 
cognitive and functional abilities
Be 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
If the caregiver cannot continue to participate in the OLE study and cannot be 
replaced, the patient can continue in the OLE so long as patient safety can 
be assured.

Willingness and ability to complete all aspects of the study (including magnetic resonance 
imaging [MRI], lumbar puncture [if applicable], and positron emission tomography [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 measures, and agreement to refrain from 
donating eggs, as defined below:
Women must remain abstinent 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 
final dose of study drug.  Women must refrain from donating eggs during this same 
period.


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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).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements.
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 a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for at least 8 weeks 
after the final 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 preventing drug exposure.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry or continued 
participation:

Patients who discontinued treatment permanently in Study BN29552 or BN29553 for safety 
reasons

Impaired coagulation (screening PT 1.2 the upper limit of normal (ULN) that remains 
abnormal on retest)

Evidence of more than 10 ARIA-H (microbleeds and/or leptomeningeal hemosiderin 
deposits) at the Study BN29552 or BN29553 Week 105 visit, as assessed by central review 
of MRI

Diagnosed with three recurrent, symptomatic amyloid-related imaging abnormalities-
edema/effusion (ARIA-E) events or exacerbations of previous events

Presence of intracranial lesion that could potentially increase the risk of CNS bleeding 
(e.g., intracranial aneurysm; arteriovenous malformation)

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 Version 5 criteria) within the past 2 years and during the study
Nicotine use is allowed.
Marijuana use is not allowed within the past 2 years.

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

Pregnant or lactating, or intending to become pregnant during the study


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
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, or interfere with the patient’s ability to complete the study 
assessments

Chronic use of anticoagulants or participation in any other investigational drug treatment 
trial
See the protocol for further details and other concomitant medication restrictions.
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which the last data point required for statistical analysis or safety follow-up is received from the 
last patient, whichever occurs later.  The end of the study is expected to occur approximately 
28 months after the last patient is enrolled.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years.
Investigational Medicinal Products
Test Product (Investigational Drug)
Crenezumab will be administered via IV infusion to all patients at a dose of 60 mg/kg Q4W until 
the end of the study.
Statistical Methods
Primary Analysis
The safety analysis population will include all patients who completed the double-blind 
treatment period and received at least one dose of study drug in either Study BN29552 or 
BN29553 and entered the OLE study.  Patients will be grouped according to the treatment 
actually received until the first visit of the OLE study.

Incidence, nature, and severity of adverse events

Incidence, nature, and severity of serious adverse events

Incidence of adverse events of special interest 

Incidence and nature of MRI safety findings:  ARIA-E and ARIA-H

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

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.
Determination of Sample Size  
This study is open to all patients who completed Study BN29552 or BN29553 and who meet the 
eligibility criteria.  Accordingly, the sample size for this study is not based on a formal sample 
size calculation.  The planned number of patients for this OLE study is not expected to exceed
1500 (approximately 750 randomized to crenezumab 60 mg/kg IV and 750 randomized to 
placebo, that is, the total planned number of patients in the parent studies BN29552 and 
BN29553, not including patients from the China extension study). An estimate for the actual 
number of patients in this OLE study is approximately 925 patients (not including patients from 


Crenezumab—F. Hoffmann-La Roche Ltd
19/Protocol BN40031, Version 2
the China extension study) based on 1500 patients enrolled in both Phase III studies and an
estimated reduction by 35% (i.e., withdrawals from double-blind treatment) and by a further 5% 
of completers who may not opt to enroll in this OLE study. 
Interim Analyses
No formal interim analysis of the efficacy results is planned for the OLE study.  In the event that 
an interim efficacy analysis is performed prior to the primary analysis, it will be described in the 
Statistical Analysis Plan and will include specifications for adjustment of the Type I error level at 
the time of the primary analysis.


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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-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
ADAD
autosomal dominant Alzheimer’s disease
ADL
activity of daily living
APOE4
apolipoprotein E4
APP
amyloid precursor protein
AUC
area under the concentrationtime curve
ARIA
amyloidrelated imaging abnormalities
ARIA-E
amyloidrelated imaging abnormalities-edema/effusion
ARIA-H
amyloidrelated imaging abnormalities-hemosiderin 
deposition
CDR
Clinical Dementia Rating
CDR-GS
Clinical Dementia Rating-Global Score
CDR-SB
Clinical Dementia Rating-Sum of Boxes
CL
clearance
Cmax
observed maximum serum concentration
CRO
contract research organization
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
DDI
drugdrug interaction
DBTP
double-blind treatment period
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EQ-5D
EuroQOL 5-Dimension questionnaire
EQ-5D-5L
EuroQOL 5-Dimension, 5-Level questionnaire
FAQ
Functional Activities Questionnaire
FcR
Fcreceptor
FCSRT
Free and Cued Selective Reminding Test


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Abbreviation
Definition
FCSRT-IR
Free and Cued Selective Reminding TestImmediate
Recall
FDA
U.S. Food and Drug Administration
FDG
fluordeoxyglucose
hAPP
human amyloid precursor protein
HIPAA
Health Insurance Portability and Accountability Act
HN
home nursing
iADL
instrumental activity of daily living
ICF
Informed Consent Form
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IP
intraperitoneal
IRB
Institutional Review Board
ITT
intent to treat
IxRS
interactive voice or web-based response system
LPLV
last patient, last visit
MAb
monoclonal antibody
mAD
mild Alzheimer’s disease
mH
microhemorrhage
MMRM
mixed-effect model for repeated measures
MMSE
Mini Mental State Examination
MRI
magnetic resonance imaging
NIAAA
National Institute on Aging/Alzheimer’s Association
NMDA
N-methyl-D-aspartate
NPI-Q
Neuropsychiatric Inventory Questionnaire
ObsRO
observer-reported outcome
OLE
open-label extension
pAD
prodromal Alzheimer’s disease
PD
pharmacodynamic
PET
positron emission tomography
PK
pharmacokinetic
PRO
patient-reported outcome
PS1
presenilin 1
PS2
presenilin 2
p-tau
phosphorylated tau


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Abbreviation
Definition
Q2W
every 2 weeks
Q4W
every 4 weeks
QoL
quality of life
QTcF
QT interval corrected through use of Fridericia’s 
formula
QoL-AD
Quality of LifeAlzheimer’s Disease 
RBR
Research Biosample Repository
SAP
Statistical Analysis Plan
SUVR
standardized uptake value ratio
t1/2
half-life
Tg
transgenic
TP
therapeutic protein
t-tau
total tau
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 form of dementia; it affects an estimated 
47 million people worldwide (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, with use of biomarkers to aid the 
diagnostic process increasing (Albert et al. 2011; McKhann et al. 2011).  Recent 
research suggests that AD likely represents a continuum of disease stages from an 
asymptomatic stage (changes in biomarkers such as amyloid only) through the 
prodromal AD (pAD) stage, which is clinically characterized by mild cognitive impairment, 
to the dementia stage (mild, moderate, severe dementia).
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 for 39 years after diagnosis of 
AD (Helzner et al. 2008), and some survive as long as 20 years. 
Approved medical therapies for AD dementia that inhibit acetylcholinesterase (AChE) 
activity or antagonize N-methyl-D-aspartate (NMDA) receptors in the brain may 
temporarily improve the symptoms in some patients but do not modify progression of the 
disease (Cummings 2004).  A number of investigational treatments are under study, 
among them antibodies against A.  The hypothesis is that treatment with an 
anti-amyloid antibody may interfere with key events in the disease pathophysiology and 
may therefore have an impact on the progression of disease or may modify the disease 
process.  Moreover, it is postulated that intervention early in the course of the disease, 
that is, before moderate dementia has developed, may have a higher efficacy potential 
than later intervention and may allow meaningful preservation of cognition and function.
Study BN40031 is an open-label extension (OLE) study (dosing crenezumab at 
60 mg/kg IV every 4 weeks [Q4W] for all participants) to the two randomized, 
double-blind, multinational, parent Phase III efficacy studies BN29552 (CREAD) and 
BN29553 (CREAD2) that investigate crenezumab at a dose of 60 mg/kg IV Q4W
compared with placebo over a 2-year treatment period in patients with pAD or mild AD 
(mAD) dementia.


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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), and notably with high affinity to 
oligomers.  
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).  Its 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) transgenic (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
(together referred to as ARIA-H), have been reported in recent AD trials involving MAbs
that bind aggregated forms of Aand have IgG1 backbones with fully preserved 
FcR-mediated effector function (Salloway et al. 2009; Ostrowitzki et al. 2012; Fuller et al. 
2014; Sevigny et al. 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
(Salloway et al. 2009). Crenezumab was designed as an IgG4 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 of crenezumab to date (see Section 1.2.3) allows a higher dose of 
crenezumab than the 300 mg SC every 2 weeks (Q2W) or the 15 mg/kg IV Q4W that 
were used in the Phase II studies to be used in the parent BN29552 and BN29553 
Phase III studies (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 


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achieve higher systemic exposure and therefore higher brain concentrations, which are 
predicted to result in greater efficacy than seen in the completed Phase II studies.
See the Crenezumab Investigator's Brochure 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 cerebrospinal fluid (CSF) following a single IV dose.  
Administration of two 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 
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 one dose per 
week (a total of five doses) was well tolerated at doses up to 50 mg/kg.  In a subsequent 
chronic toxicity study, 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 per week 
(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).


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A study to further evaluate the pharmacology of crenezumab in hAPP-Tg mice included 
weekly or monthly intraperitoneal (IP) administration of crenezumab for 16 weeks (a total 
of 17 weekly doses 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 were 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-A
antibodies in the AD population (i.e., ARIA-E and -H), additional studies were performed 
in Tg mouse models of AD (hAPP or hAPP/presenilin 1 [PS-1]) to evaluate for vascular 
injury (e.g., cerebral mH).  These studies were performed with PRO300491, a 
human/mouse chimeric anti-A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 four doses).  At IV doses up to 60 mg/kg, PRO300491 was well 
tolerated and no treatment-related increases in mH were observed.  In a subsequent 
chronic toxicity study, weekly IP 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
To date, crenezumab has been investigated in a total of 12 completed or ongoing 
Roche-sponsored Phase I, Phase II, and Phase III clinical trials.  Approximately 




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There are two ongoing Phase III studies evaluating the efficacy, safety, and tolerability of 
crenezumab at a dose of 60 mg/kg IV Q4W versus placebo in a pAD to mAD population 
(MMSE score, 2230). Study BN29552 (CREAD) and BN29553 (CREAD2) are
randomized, double-blind, parallel-group, placebo-controlled trials designed to evaluate 
the safety and efficacy of crenezumab in patients aged 5085 years who meet protocol-
specified criteria for pAD or mAD.
China Extension Phase (DBTP)
Following completion of the global enrollment phase of Study BN29553, additional 
patients will continue to be enrolled in a China extension phase (i.e., China extension 
to the main Phase III study BN29553) to ensure a total enrollment sufficient to support 
registration in the People's Republic of China.  This China subpopulation may include 
patients enrolled at sites in China during both the global enrollment phase and the China 
extension phase and could be included in this OLE, if applicable.
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.
For a summary and details of the clinical studies to date refer to the Crenezumab 
Investigator’s Brochure for further information.  
1.2.3
Safety Overview
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),
two ongoing Phase I studies (
 and GN29632), one ongoing Phase II study
(GN28352), and two ongoing Phase III studies (BN29552 and BN29553).
In the Phase II studies in mild to moderate AD, more fatal events and events of 
pneumonia were reported in crenezumab-treated patients than in 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).  


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
In the crenezumab Phase II program, the overall rate of ARIA-E in the DBTP was 
1/349 (0.3%) in crenezumab-treated versus 0/173 in placebo-treated patients. The 
incidence of ARIA-H was similar between crenezumab- and placebo-treated 
patients:  The number of patients with incident mH was 40/349 (11.5%) in 
crenezumab-treated and 22/173 (12.7%) in placebo-treated patients, while 
superficial siderosis of CNS was reported in 3 patients (1.7%) receiving placebo.  
The rate of ARIA-E and ARIA-H in the DBTP of the Phase II program is similar to 
the background rate in the mild to moderate AD population (0.2% 0.4%) (Doody et 
al. 2014; Salloway et al. 2014).

As of the date of release of this protocol, 4 patients have developed ARIA-E across 
the crenezumab program. In one patient, ARIA-E was considered symptomatic 
(headache).
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. 
Three serious infusion-related reactions were reported in the ongoing Phase III studies 
BN29552 and BN29553 as of the date of release of this protocol.  One reaction was 
reported as "anaphylaxis." The patient recovered rapidly after administration of 
epinephrine via auto-injector (EpiPen). Two additional patients experienced serious 
acute hypotension during infusion with the blinded study drug. Both patients 
recovered within the next hour without the need for additional treatment. In all three 
cases, the study treatment was discontinued (see the Crenezumab Investigator’s 
Brochure for additional details on these cases).
No population trend or pattern in clinically relevant changes has been observed in 
laboratory parameters, physical and neurologic examinations, vital signs, and ECG 
parameters. 
An ongoing Phase Ib study (GN29632) is evaluating doses higher than those used in the 
Phase II studies, including 60 mg/kg IV Q4W and 120 mg/kg IV Q4W.  This study is 
now in the OLE phase.  The 60 mg/kg IV Q4W dose is also being used in both Phase III 
studies (BN29552 and BN29553). As of the date of the release of this protocol 
(BN40031), no new or unexpected safety findings were observed in Study GN29632.
Specifically, no dose-limiting toxicities, drugrelated serious adverse events, or ARIA-E 
events have been reported in Study GN29632.  
Detailed safety data from all studies are reported in the Crenezumab Investigator’s 
Brochure.  
The Sponsor performs a regular review of blinded data from the ongoing studies to
identify any new or unexpected safety findings.  Furthermore, Study GN29632 is 
overseen by an internal Safety Monitoring Committee, while independent Data 
Monitoring Committees (iDMCs) regularly review unblinded data from Studies GN28352, 
BN29552, and BN29553.


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1.2.3.1
Adverse Event Profile
The Phase II program in mild to moderate AD (Studies ABE4869g and ABE4955g) 
consists of the largest completed studies conducted to date with crenezumab.
The DBTP 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 DBTP excluded the safety run-in arm of 
Study ABE4869g. 
In the DBTP, 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. 
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 DBTP of the 
Phase II program, 9 patients (2.6%) who received crenezumab and 9 patients (5.1%) 
who received placebo withdrew because of adverse events.  There were no imbalances 
in the overall rates of adverse events between patients who received crenezumab and 
patients who received 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 program (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 falls and urinary tract infections being the most 
frequently recorded adverse events.  
Details on the safety data from all completed and ongoing trials with crenezumab are 
provided in the most recent version of the Crenezumab Investigator’s Brochure.
1.2.3.2
Deaths
During the DBTP of the Phase II program, 5 patients died.  All five deaths occurred in 
patients treated with crenezumab; none was assessed by the investigator as related to 
study drug.  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).  


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In the OLE study GN28525, 15 patients (4.2%) died.  Ten of the 15 patients had 
received active crenezumab, and 5 patients had received placebo. This represents 4.0% 
of patients who received crenezumab compared with 4.5% of patients who received 
placebo during DBTP of the Phase II study.  All deaths were assessed as not related to 
study drug by the investigator.  
Details on deaths reported in the completed and ongoing clinical studies with 
crenezumab are presented in the most recent Crenezumab Investigator’s Brochure.
1.2.3.3
Pneumonia
An imbalance in the rates of serious adverse events of pneumonia was observed in the 
DBTP 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 DBTP 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.
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 DBTP 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; 
Salloway et al. 2014; Henley et al. 2015).  The pneumonia rates in the placebo-treated 
population were slightly lower (0.6%; Henley et al. 2012; Doody et al. 2014; Salloway et 
al. 2014; Henley et al. 2015).  However, the precision of these estimates is limited by the 
relatively smaller sample size in crenezumab Phase II data compared with 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 
frequency and details of pneumonia events from all ongoing and completed studies is 
provided in the most recent version of the Crenezumab Investigator’s Brochure.
1.2.3.4
ARIA-E and ARIA-H
In the DBTP 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 and 12.7% 


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(N22) of placebo-treated patients.  The proportion of patients with superficial siderosis 
of CNS was 0% in crenezumab-treated patients versus 1.7% (N3) in placebo-treated
patients.  All findings in crenezumab-treated patients were asymptomatic.
An overview of ARIA-H and ARIA-E cases from all ongoing and completed studies is 
provided in the most recent version of the Crenezumab Investigator’s Brochure. 
1.2.3.5
Summary
The safety and tolerability profile of crenezumab to date supports its continued 
development in AD.  
More fatal events and pneumonia cases were observed during the DBTP of the Phase II 
program in crenezumab-treated versus placebo-treated patients.  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 within each 
dose cohort.  In addition, rates of death and pneumonia in crenezumab-treated patients 
were within the expected ranges for the elderly AD population.
Further details are presented in the Crenezumab Investigator’s Brochure.
1.2.4
Immunogenicity
The immunogenicity of crenezumab was assessed in the completed Phase I and 
Phase II studies ABE4427g, ABE4662g, ABE4869g, ABE4955g, GP29172, and 
  It is being further assessed in the ongoing Phase I, II, and III trials.
A positive 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 the total number of patients with a sample available at the 
baseline timepoint.  The incidence of ADAs postdose with crenezumab, or 
treatment-emergent ADAs, was calculated from the total number of patients who tested 
positive for ADAs postdose divided by the total number of crenezumab-treated patients
who had postbaseline samples available for ADA analysis.

In Study ABE4427g, a positive ADA response was detected in 1 of 36 patients 
(2.8%) given crenezumab.  Presence of ADAs had no apparent impact on 
pharmacokinetics and safety in this patient.

In Study ABE4662g, no incidence of the formation of ADAs was detected.


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
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 of 441 (0.5%).  The 
incidence of ADAs postbaseline 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 pharmacokinetics or in the 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).  ADAs were not observed at 
postbaseline in either placebo or crenezumab-treated patients.
All planned and ongoing studies will assess ADAs to crenezumab and components of 
drug product, including impurities.  
Further details are presented in the Crenezumab Investigator’s Brochure.
1.2.5
Pharmacokinetics
The pharmacokinetics of crenezumab have been evaluated in five Phase I studies 
(ABE4427g, ABE4662g, GP29172, 
and GN29632) and in two Phase II 
studies (ABE4869g and ABE4955g).  Overall, the observed serum pharmacokinetics in 
the Phase I and II studies have appeared to be dose proportional (IV: 0.310 mg/kg 
single dose and 15120 mg/kg Q4W; SC: 1.8 mg/kg single dose and 6007200 mg 
single dose) and the PK parameters (e.g., clearance [CL], half-life [t1/2]) in the Phase I 
studies have been consistent with those for other humanized IgG MAbs that exhibit 
kinetics in the linear concentration range (Mould and Sweeney 2007; Dirks and Meibohm 
2010; Deng et al. 2011). 
In the Phase I study ABE4427g, the serum pharmacokinetics of crenezumab in patients 
with mild to moderate AD were dose proportional across the dose range tested in both 
the single-dose (0.310 mg/kg) and multi-dose (0.55 mg/kg weekly for four doses) 
phases of the study.  Crenezumab CL was slow (2.53.3 mL/day/kg) with a long terminal 
t1/2 (1726 days) following a single IV dose.  With weekly administration, there did not 
appear to be any time-dependent change in crenezumab pharmacokinetics relative to 
single-dose administration, as evidenced by similar terminal elimination t1/2 estimates 
(1823 days) relative to the single-dose arm.  
 
 
The Phase I study GP29172 demonstrated that crenezumab serum PK parameters 
following administration of the Phase III drug product (180 mg/mL) were bioequivalent to 
the Phase II drug product (150 mg/mL) following a single 720-mg SC injection in healthy 
volunteers.  These results were supportive of a change of drug product in ongoing 
clinical studies. 




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anti-inflammatory drugs, NMDA antagonists, or cholinesterase inhibitors) 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 F 18 amyloidpositron emission tomography (PET), 
18F-fluordeoxyglucose (FDG)-PET, and volumetric magnetic resonance imaging (MRI) 
measurements were evaluated as PD biomarkers in the Phase II studies in patients with 
mild to moderate AD. 
1.2.6.2
Brain Imaging Pharmacodynamic Biomarkers
Florbetapir F 18-PET, FDG-PET, and volumetric MRI measurements were evaluated in 
Study ABE4955g.  
No evidence of differences was noted between the crenezumab and placebo groups 
based on the mean changes from baseline at Weeks 23, 47, and 73 of the hippocampal, 
ventricular, and whole brain volumes (MRI). 
Florbetapir F 18-PET
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 
prespecified 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 mAD subpopulation (MMSE score, 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 F 18-PET standardized uptake value ratio (SUVR) was 
observed for patients in both the placebo and crenezumab treatment arms.  
The estimated mean change in florbetapir F 18-PET SUVR from baseline was less for 
the crenezumab arm than for 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 mAD 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-PET
There was no evidence of a treatment difference between crenezumab and placebo 
mean changes from baseline for either the SC or IV cohorts.


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1.2.6.3
Plasma and CSF Pharmacodynamic Biomarkers
Plasma and CSF biomarker measurements were evaluated in Study ABE4955g.  
Concentrations of A42, total tau (t-tau), and phosphorylated tau (p-tau) in CSF were 
assessed in 55 patients with mild to moderate AD (MMSE score, 1826) 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 indicate an 
overall increase in CSF A42 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 t-tau or on
p-tau.
Data from the 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 on the basis that when A42 and A40 bind to 
crenezumab, it takes on the slow half-life of the antibody and therefore stays in the 
circulation longer.  Please refer to the Crenezumab 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 
progression of AD (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 slow AD progression and potentially modify the disease course.
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, but notably with high affinity to oligomers 
(Adolfsson et al. 2012; Ultsch et al. 2016).  Crenezumab’s IgG4 backbone confers 


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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 based 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 transgenic 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 signal 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 subsequent Phase I dose-escalation study (GN29632), these data 
suggest that the therapeutic window had not been explored fully.  Therefore, use of a 
higher dose of crenezumab (60 mg/kg IV Q4W) is proposed for the Phase III studies in 
order to investigate whether greater efficacy can be obtained while maintaining a 
favorable benefitrisk profile (see Section 1.3.4 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.
Crenezumab is currently being studied at a dose of 60 mg/kg IV Q4W (compared with
placebo) in two randomized, placebo-controlled multinational Phase III studies 
(BN29552 and BN29553) in patients with pAD or mAD dementia (for details, see 
Section 1.2 and the Crenezumab Investigator’s Brochure). The primary endpoint in 
these 24-month treatment studies is the Clinical Dementia Rating-Sum of Boxes 
(CDR-SB), a clinical scale assessing cognition and function.
In this OLE study, a dose of crenezumab of 60 mg/kg IV Q4W will be offered to all 
patients who complete one of the parent studies BN29552 or BN29553 and who meet 
eligibility criteria for this study in order to evaluate safety in patients on long-term 
crenezumab treatment and to investigate the effect of crenezumab on the underlying 
disease process and disease course as an exploratory efficacy objective.
1.3.2
Safety Rationale
AD is a chronic condition with any efficacious therapy likely necessitating many years of 
treatment. Therefore, it is important to understand the long-term safety of any potential 
AD treatment beyond the 2-year DBTP in Studies BN29552 and BN29553. 


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Safety assessments in this OLE study will be the same as in Studies BN29552 and 
BN29553 including adverse event reporting, regular MRIs, close monitoring for 
pneumonia-related events, and assessment of immunogenicity. As patients who 
received placebo in Studies BN29552 and BN29553 will receive crenezumab for the first 
time in the OLE, the schedule of events has an MRI approximately 12 weeks after the 
first dose.
1.3.3
Efficacy
An exploratory objective of this OLE study is to investigate the effect of crenezumab on 
the underlying disease process and course.
The purpose of Studies BN29552 and BN29553 is to establish the efficacy and safety of 
crenezumab in patients with pAD to mAD who may or may not be treated concurrently 
with approved symptomatic treatments for AD, over a treatment period of 104 weeks 
(26 doses). This DBTP was selected to demonstrate an enduring clinical benefit of 
crenezumab treatment on the basis of the mechanism of action and available data to
date.  Crenezumab may slow clinical decline rather than provide improvement over 
baseline.
There is considerable scientific and clinical interest in understanding the impact of the 
intervention under study on the underlying disease process. It has been proposed that 
demonstration of a disease-modifying effect (rather than a reversible "symptomatic"
effect) may be achieved in studies using a two-period design (Leber 1997; see Figure 1). 
Figure 1
Randomized Start Design
Therefore, an exploratory randomized start analysis is proposed, using the 2-year DBTP 
in Studies BN29552 and BN29553 as Period 1 (i.e., Treatment Initiation Group 1 in the 


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above diagram), and 1 or 2 year(s) of treatment in Study BN40031 as Period 2 (i.e.,
Treatment Initiation Group 2 in the above diagram). The intent is to demonstrate that 
patients who received placebo treatment in Period 1 will not achieve in the medium term
the same clinical benefit as those patients who received active drug treatment in 
Period 1. Period 2 has to provide sufficient time for crenezumab to exert its effect on the 
patient group who previously received placebo. At the same time, it is important to keep 
the amount of missing data low to enable a robust analysis. The duration of Period 2 
(1 or 2 years) is to be confirmed in the Statistical Analysis Plan (SAP).
The efficacy assessments in Study BN40031 will use the same scales as in the prior 
Phase III studies with the CDR-SB being the primary efficacy endpoint for this 
exploratory two-period design.
1.3.4
Dose
Considering the evidence from the Phase II studies and clinical modeling, and based on 
supportive safety data from Study GN29632, the dose of 60 mg/kg IV Q4W was selected 
for the global Phase III program (60 mg/kg IV Q4W is a dose resulting in exposure 
approximately 4-fold higher than the high dose in the Phase II program, see Figure 2). A 
higher dose than that used in the Phase II program is expected to result in increased 
brain exposure and thus in increased target engagement and has the potential for better 
efficacy. This dose is currently used in Studies BN29552 and BN29553, and it is also 
the planned dose in this OLE.


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Figure 2
Pharmacokinetic Profile Based on Modeling 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; EC50 50% effective concentration; Q4W every 4 weeks; 
Note:  Dashed red lineEC50.
1.3.5
Biomarkers
In AD, core biomarkers have been developed that reflect amyloid and neurofibrillary 
tangle pathology and neuronal degeneration.  Additional biomarkers that reflect other 
aspects of AD pathology are also being developed.
Two imaging modalities are mainly used as secondary or exploratory endpoints in 
clinical trials of AD:  MRI and 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 F 18, approved for use by the U.S. 
Food and Drug Administration [FDA] in 2012 and European Medicines Agency in 2013)
are thought to represent accumulation of the Aplaques (Joshi et al. 2012).  PET tracers 
that have more recently become available and may bind to tau in the brain (e.g., 
[18F]GTP1, an investigational radiotracer) are thought to enable assessment of local tau 
burden as well as its spreading throughout the brain.


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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 AD pathology (Shaw et al. 2009; Le Bastard et al. 2013).  
Thus, CSF Alevels may provide information relevant to diagnosis and could potentially 
act as a biomarker for target engagement and for the impact of crenezumab on A
retention and aggregation.  Changes in CSF t-tau and p-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. 
1.3.6
Risk to Patients without Alzheimer’s Disease Pathology
On account of the rigorous screening procedures in the parent studies BN29552 and 
BN29553, including the measurement of CSF A1-42 and/or 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 side effects related to the product (e.g., infusion reactions, 
development of ADAs), similar to patients with AD pathology.
1.3.7
Overall BenefitRisk Summary
The overall benefitrisk profile of investigation of crenezumab at a dose of 60 mg/kg IV 
Q4W in a population of pAD to mAD patients is favorable.
Overall, the benefitrisk assessment of crenezumab is based on the following.
In Phase II studies (DBTP):

The primary endpoints were not met.

In further analyses, a consistent effect on cognitive scales including the Alzheimer’s 
Disease Assessment ScaleCognition 12 (ADAS-Cog12) scale was observed in 
patient subsets with mild disease who were treated with crenezumab 15 mg/kg IV 
Q4W versus placebo.
A 4-fold higher dose is being investigated in Phase III studies, including this 
OLE. A higher dose than that used in the Phase II program is expected to
result in increased brain exposure and thus in increased target engagement 
and has the potential for better efficacy.

Treatment with crenezumab was associated with an increase in CSF-A42 relative to 
placebo, which was suggestive of target engagement in the CNS.

While more deaths and pneumonia cases were observed with crenezumab than 
with 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. 2015) 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 


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pneumonia in 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 is 
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.
The benefitrisk assessment of crenezumab is also based on the following.

Pneumonia cases, other serious respiratory infections, and deaths will be closely 
monitored in the study, with the requirement to report these cases to the Sponsor 
within 24 hours with a full description of the case (see Section 5.3.5).

In the DBTP 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.  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 and 12.7% (N22) of placebo-treated patients.  The 
proportion of patients with superficial siderosis of CNS was 0 in crenezumab-treated 
patients versus 1.7% (N3) in placebo-treated patients.  All findings in 
crenezumab-treated patients were asymptomatic.

In the other ongoing or completed studies of crenezumab, the majority of ARIA-H 
cases were asymptomatic and their incidence is within the rate observed in the 
Phase II program.  Cases of ARIA-E were mostly asymptomatic.  An overview of 
ARIA-H and ARIA-E cases from all ongoing and completed studies is provided in 
the most recent version of the Crenezumab Investigator’s Brochure. 

ARIA events appear 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. 2012).
Patients will undergo regular brain MRI monitoring, and discontinuation rules 
are in place in case of ARIA.

Per the Crenezumab Investigator’s Brochure (Version 10, August 2017), one event
of a serious hypersensitivity reaction (adverse event verbatim term "anaphylaxis") 
considered related to the study drug was reported in the ongoing Phase III study 
BN29552. This case concerns a patient who, upon further investigation of this 
adverse event, reported a history of allergy to bee sting (requiring epinephrine
treatment) and reactions of pruritus and fatigue to unspecified medications.  No 
signs and/or symptoms were reported after the first administration of blinded study 
drug. At the second infusion visit (approximately 4 weeks after the first visit), the 
patient reported dizziness and subjective sensation of "throat closing up" 2 minutes 
after initiation of the infusion. The patient was noted to be diaphoretic and anxious 
and to have bright red flushing of the face, neck, and chest. The infusion was 
stopped immediately and epinephrine via autoinjector (EpiPen) was administered 1 
minute after onset of symptoms, followed by immediate resolution of the subjective 
symptom and complete resolution of the flushing within 23 minutes. No 
antihistamines, steroids, oxygen, or other treatments were administered, and the 
patient was not hospitalized.  


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Crenezumab should be administered to subjects under close medical 
supervision in a setting with access to emergency equipment and staff who 
are trained to monitor and respond to medical emergencies.
Please refer to the latest version of the Crenezumab Investigator’s Brochure
for additional information on serious infusion-related reactions.
2.
OBJECTIVES AND ENDPOINTS
This study will assess the long-term safety and tolerability of crenezumab administered 
to all patients who completed Studies BN29552 (CREAD) and BN29553 (CREAD2) and 
who meet the eligibility criteria for this OLE study. An exploratory objective of this OLE 
study is to investigate the effect of crenezumab on the underlying disease process and 
course. Specific objectives and corresponding endpoints for the study are outlined in 
Table 1.


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Table 1 Objectives and Corresponding Endpoints
Primary Safety Objective
Corresponding Endpoints
To assess the long-term safety and 
tolerability of crenezumab (60 mg/kg IV
Q4W) in eligible patients with AD who 
participated in Study BN29552 or 
BN29553 and completed the Week 105 
study visit

Nature, frequency, severity, and timing of adverse 
events and serious adverse events

Vital signs, blood tests, ECGs, and C-SSRS 

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
Exploratory Efficacy Objectives
Corresponding Endpoints
To evaluate the long-term effect of 
crenezumab on global outcomes of 
disease progression

Change from baseline during the OLE in CDR-SB
To evaluate the long-term effect of 
crenezumab on cognition 

Change from baseline during the OLE as 
measured by the ADAS-Cog-13

Change from baseline during the OLE using the 
MMSE

Change from baseline during the OLE using 
ADAS-Cog-12
To evaluate the long-term effect of 
crenezumab on disease severity 

Change from baseline during the OLE using 
CDR-GS
To evaluate the long-term effect of 
crenezumab on patient dependence

Change from baseline during the OLE using scores 
derived from the ADCS-ADL total scale
To evaluate the long-term effect of 
crenezumab on patient function

Change from baseline during the OLE using the 
ADCS-ADL, the instrumental subscale, and/or the 
FAQ
To evaluate the long-term effect of 
crenezumab on behavior and 
neuropsychological symptoms

Change from baseline during the OLE using the 
Neuropsychiatric Inventory Questionnaire 
To evaluate the long-term effect of 
crenezumab on health-related quality of 
life 

Change from baseline during the OLE using the 
Quality of Life-AD scale


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Table 1 Objectives and Corresponding Endpoints (cont.)
Exploratory Efficacy Objective (cont.)
Corresponding Endpoints (cont.)
To evaluate the long-term effect of 
crenezumab on caregiver burden

Change from baseline during the OLE using the 
Zarit Caregiver Interview for AD scale
Exploratory Pharmacokinetic 
Objectives
Corresponding Endpoints
To evaluate the serum PK 
characteristics of crenezumab

Serum concentration of crenezumab at specified 
timepoints
To evaluate the CSF PK characteristics 
of crenezumab

CSF concentrations of crenezumab at specified 
timepoints (only in patients who previously 
enrolled in substudy BN29552-CSF 
Longitudinal or BN29553-CSF Longitudinal)
To explore exposure-response 
relationships in patients with prodromal 
to mild AD 

Correlation between crenezumab concentration 
and biomarkers as well as safety and efficacy 
outcomes
Exploratory Biomarker Objectives
Corresponding Endpoints
To evaluate the effect of crenezumab 
on biomarkers

Brain amyloid load over time measured by 
amyloid PET (only in patients who previously 
enrolled in substudy BN29552-Amyloid PET 
Longitudinal or BN29553-Amyloid PET 
Longitudinal)

Brain tau load and spread over time measured by 
tau-PET (only in patients who previously enrolled 
in substudy BN29552-Tau PET Longitudinal or 
BN29553-Tau PET Longitudinal)

CSF markers of disease over time (only in 
patients who previously enrolled in substudy 
BN29552-CSF Longitudinal or BN29553-CSF 
Longitudinal)

Plasma PD markers of disease over time

MRI-derived measurements over time such as 
volumetric changes in whole brain, ventricles, 
hippocampus, or other structures
ADAlzheimer’s disease; ADAS-CogAlzheimer’s Disease Assessment Scale-Cognition 12 or 
13; ADCS-ADLAlzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory; 
ARIA-Eamyloid-related imaging abnormalities-edema/effusion; ARIA-Hamyloid-related imaging 
abnormalities-hemosiderin deposition; CDR-GSClinical Dementia Rating-Global Score; 
CDR-SBClinical Dementia Rating-Sum of Boxes; CSFcerebrospinal fluid; C-SSRSColumbia-
Suicide Severity Rating Scale; FAQFunctional Activities Questionnaire; MMSEMini Mental 
State Examination; MRImagnetic resonance imaging; OLEopen-label extension; 
PDpharmacodynamic; PETpositron emission tomography; PKpharmacokinetic; Q4Wevery 
4 weeks.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
Study BN40031 is a Phase III, OLE, multicenter study to evaluate the long-term safety 
and tolerability of crenezumab at a dose of 60 mg/kg IV Q4W in patients with AD who 
have participated in one of the Phase III parent studies (BN29552 or BN29553). 
Efficacy will also be assessed. Patients who discontinued early from study treatment 
during Study BN29552 or BN29553 but remained in the study for safety and additional 
efficacy evaluations and completed the Week 105 study visit can enter the OLE study 
and begin open-label treatment. Patients from Study BN29552 or BN29553 who
discontinued the study prior to completion of the Week 105 study visit are not eligible for 
this OLE study.
Studies BN29552 and BN29553 are ongoing Phase III, multicenter, randomized, 
double-blind, placebo-controlled, parallel-group, efficacy and safety studies of 
crenezumab in patients with pAD to mAD. The planned number of patients for this OLE 
study is not expected to exceed 1500 (approximately 750 randomized to crenezumab 
60 mg/kg IV and 750 randomized to placebo, i.e., the total planned number of patients in 
the parent studies BN29552 and BN29553, not including patients from the China
extension study). An estimate for the actual number of patients in this OLE study is 
approximately 925 patients (not including patients from the China extension study)
based on 1500 patients enrolled in both Phase III studies and an estimated reduction by 
35% (i.e., withdrawals from double-blind treatment) and by a further 5% of completers 
who may not opt to enroll in this OLE study. Approximately 350 centers in approximately 
40 countries worldwide will participate in this study. 
Patients and all clinical site staff will remain blinded to the original treatment assignment 
in Studies BN29552 and BN29553 on entry into the OLE study and until a later time 
which will be determined by the Sponsor.
Following completion of the global enrollment phase of Study BN29553, additional 
patients will continue to be enrolled in a China extension phase (i.e., China extension to 
the main Phase III study BN29553) to ensure a total enrollment sufficient to support 
registration in the People’s Republic of China.  This China subpopulation may include 
patients enrolled at sites in China during both the global enrollment phase and the China 
extension phase and could be included in this OLE, if applicable.
3.2
STUDY DESIGN
All patients who are enrolled in the OLE study will receive crenezumab 60 mg/kg 
administered by IV infusion Q4W.


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Data collected at Week 105 of the DBTP of Studies BN29552 and BN29553 and results 
from a coagulation blood test taken before the first OLE infusion will be used to assess 
patient eligibility for the OLE study. This Week 105 data will also be used as OLE 
baseline data. 
Prior to administering the first infusion in the OLE, eligibility will be ensured by reviewing
Week 105 assessment results (including MRI results), OLE screening coagulation 
blood test results, and any other significant patient changes.
Once a patient is identified as eligible for the OLE study, the following will occur:

Patients can receive the first infusion of crenezumab at any time on or up to 
8 weeks after the Week 105 visit of the double-blind studies. Any extensions to this 
period must be approved by the Sponsor. Sites can arrange an infusion visit as 
soon as eligibility assessment results are available (including MRI results and 
results from the coagulation test) to assess OLE eligibility. Details of the visit 
schedule and associated assessments are given in Appendix 1.

The day that the first dose of crenezumab is administered will be Visit 1, Week 1 of 
the OLE.

On Visit 1, Week 1 of OLE (i.e., the first open-label infusion of crenezumab), safety 
assessments must be done as indicated in the schedule of activities (see
Appendix 1).
For details on the schedule of activities, see Appendix 1.  For details on the length of the 
study, see Section 3.3.
3.2.1
Independent 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, and 
laboratory abnormalities will be assessed on a regular basis by an iDMC.  It is 
anticipated that these assessments will occur approximately every 3 months until 
Studies BN29552 and BN29553 are unblinded.
The details of iDMC will be provided in the iDMC Charter.
3.3
END OF STUDY AND LENGTH OF STUDY
The OLE study will continue until crenezumab is commercially available in the patient’s 
country, as per local regulation, or should the Sponsor decide to terminate the program 
for pAD to mAD. However, all patients will have the opportunity to complete 
approximately 2 years of treatment even if crenezumab is commercially available in the 
patient's country. The study will not exceed approximately 2 years after the last patient 
enrolled during the global enrollment phase (in Study BN29552 or BN29553) enters 
the OLE study.


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For United Kingdom only: The OLE study will not exceed approximately 2 years after 
the last patient enrolled during the global enrollment phase in Study BN29552 or
BN29553 enters the OLE study or until a decision to terminate the program for pAD to 
mAD is made by the Sponsor.
For the first patient entering the OLE study, the maximum duration would be 
approximately 4 years, depending on the date of commercialization or the date of the
last patient enrolled in Study BN29553 (12 July 2018). 
The 2-year duration of the OLE study serves to evaluate long-term safety, tolerability, 
and efficacy of crenezumab treatment in patients with AD and allows for all patients to 
reach the 2-year treatment duration in the OLE study for the efficacy analysis.
Patients who discontinue crenezumab treatment during Year 1 of the OLE study will be 
followed for 16 weeks after their last dose of crenezumab and will also be asked to 
complete the remaining scheduled efficacy assessments at Week 53 of the OLE as per 
the schedule of activities (see Appendix 1).
Patients who discontinue crenezumab treatment during Year 2 of the OLE study will be 
followed for 16 weeks after their last dose of crenezumab and will also be asked to 
complete the remaining scheduled efficacy assessments at Week 105 of the OLE as per 
the schedule of activities (see Appendix 1).
Patients who discontinue treatment after Year 2 (Week 105) of the OLE study will be 
followed up for safety for 16 weeks. Patients who complete the OLE study and continue 
treatment with crenezumab thereafter will not be followed up.
Patients and sites will remain blinded to their assignment in Study BN29552 or BN29553 
until permitted by the Sponsor.
Every effort should be made to have the same caregiver participate throughout the 
duration of the OLE study who also participated in Study BN29552 or BN29553.  If the 
caregiver cannot continue to participate in the OLE study and cannot be replaced, the
patient can continue in the OLE as long as patient safety can be assured. 
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is 
received from the last patient, whichever occurs later.  The end of the study is expected 
to occur approximately 28 months after the last patient is enrolled.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 4 years.


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3.4
RATIONALE FOR STUDY DESIGN
This study is the OLE study of BN29552 (CREAD) and BN29553 (CREAD2), the 
Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
studies of the efficacy and safety of crenezumab in patients with a diagnosis of pAD to 
mAD.
3.4.1
Rationale for Treatment Duration
AD is a chronic condition with any efficacious therapy likely necessitating many years of 
treatment.  Therefore, it is important to understand the long-term safety of any potential 
AD treatment beyond the 2-year DBTP in Studies BN29552 and BN29553.
See Section 3.3 for information about the end of the study.
3.4.2
Rationale for Long-Term Follow-Up
The primary objective of the study is to evaluate the long-term safety and tolerability of 
crenezumab.  If a patient discontinues treatment early, or if a patient completes the 
study and does not continue treatment with crenezumab thereafter, assessments
performed at 4 and 16 weeks after the last dose of treatment will evaluate the relevant 
safety parameters over an extended period when no study drug is administered.  
Efficacy 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. 
If a patient discontinues treatment before Week 105, assessments performed at the next 
annual visit will inform the exploratory efficacy analysis (see Section 1.3.3). For details of 
the schedule of activities, see Appendix 1.
3.4.3
Rationale for Patient Population
The patient population for this OLE study will comprise patients who completed 
Week 105 in either Study BN29552 or BN29553 and who meet the inclusion criteria of 
this Study BN40031 protocol. 
3.4.4
Rationale for Safety Outcome Measures
Adverse event data will be gathered in this OLE study, including adverse events related 
to MRIs (ARIA-E and ARIA-H) to allow collection of long-term safety data in patients who 
continue to receive crenezumab after completing the main study DBTPs. This data will 
allow evaluation of the long-term safety and tolerability of exposure to crenezumab in 
this population. After Week 105 of the OLE study, assessment frequency is reduced to 
minimize patient burden but to continue safety monitoring. For details of the schedule of 
activities, see Appendix 1.


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3.4.5
Rationale for Exploratory Efficacy Outcome Measures
Efficacy assessments/scales in the OLE replicate those in Studies BN29552 and 
BN29553, allowing a full profile of efficacy data to be collected for all patients, including 
those who received placebo in Studies BN29552 and BN29553 but will receive 
crenezumab 60 mg/kg during the OLE. As with Studies BN29552 and BN29553, 
assessments in clinical trials for AD should be obtained across several domains of 
neurologic function, including cognition and functioning. After Week 105 of the OLE 
study, assessment frequency is reduced to minimize patient burden but continue efficacy 
monitoring. For details of the schedule of activities, see Appendix 1.
3.4.6
Rationale for Pharmacokinetic Sampling
A sparse sampling schedule for serum concentrations of crenezumab is being utilized to 
minimize patient burden and yet still provide an adequate assessment of crenezumab
exposure.  
The serum PK data will be needed for interpretation of the ADA impact of 
pharmacokinetics and may be compared with available data from other crenezumab 
studies as well as for the assessment of exposure-response relationships for relevant 
imaging, plasma PD biomarkers, ECG, and efficacy and safety outcomes in patients with 
pAD to mAD, as appropriate.
Crenezumab concentration in CSF will be measured at Week 53 only in patients who 
were in the CSF longitudinal substudy (see Section 3.4.7.1), provided they consent to 
continue in the substudy during the OLE. The CSF measurement will contribute to the 
longitudinal CSF substudy and the assessment of crenezumab partitioning into the CSF 
at 60-mg/kg Q4W dosing as well as of the exploratory exposure-response relationship 
between crenezumab concentration and CSF biomarkers.
3.4.7
Rationale for Biomarker, PET Assessments and MRI 
Assessments
The biomarker, PET, and MRI assessments described in Section 3.4.7.1 (CSF), 
Section 3.4.7.2 (PET imaging), and Section 3.4.7.3 (brain volumetry) will be used to 
investigate the effect of crenezumab on the underlying pathology of AD in the clinical 
trial population.
3.4.7.1
Cerebrospinal Fluid Biomarkers (for Patients Who Were in the 
BN29552 or BN29553 CSF Longitudinal Substudy Only)
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. 


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The planned additional CSF assessment at Week 53 of the OLE study will contribute to 
the CSF longitudinal data collected in the substudy associated with Protocols BN29552 
and BN29553 (CSF Longitudinal Substudy) and will be taken for patients who have 
completed the following:

The CSF Longitudinal Substudy in either Study BN29552 or BN29553

Consented to additional CSF samples during the OLE study
3.4.7.2
Positron Emission Tomography Imaging Assessment
The definitive postmortem diagnosis of AD requires the presence of progressive 
dementia during life and the presence of neuropathologic lesions (i.e., neuritic plaques 
composed of Aaggregates and neurofibrillary tangles formed from 
hyperphosphorylated tau protein).  However, imaging approaches using ligands that 
demonstrate high affinity for aggregated amyloid are able to provide an assessment of 
deposition in vivo, which can be evaluated over time (Clark et al. 2011).  
The planned additional PET imaging assessment will contribute to the substudies 
associated with Protocols BN29552 and BN29553, the Amyloid-PET Longitudinal
Substudy and the Tau-PET Longitudinal Substudy and will be taken for patients who 
have completed the following:

The Amyloid-PET Longitudinal Substudy and/or the Tau-PET Longitudinal Substudy 
for either Study BN29552 or BN29553

Consented to additional PET imaging assessments during the OLE study
3.4.7.3
MRI Assessments for 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).  On the 
basis of volumetric MRI measurements, the two 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 
screening and following treatment with crenezumab.  All MRI reads and volume 
measures will be conducted by the central reading facility.


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Patients who completed the Week 105 study visit of Study BN29552 or BN29553 and 
meet the eligibility criteria are eligible to participate in this OLE study. Patients who 
discontinued the study prior to completion of the Week 105 visit will not be eligible for 
this OLE study.
Concomitant acute and chronic diseases (including significant laboratory abnormalities) 
should be monitored and treated towards treatment targets as per local guidance.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Previous participation in Study BN29552 or BN29553 and completion of the 
Week 105 visit. 
Patients who discontinued from one of these studies prior to completion of the 
Week 105 visit are not eligible. Temporary halting of study drug (e.g., because 
of an adverse event) in Study BN29552 or BN29553 is not exclusionary.

Written informed 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 [EC] or Institutional Review Board [IRB]) or the 
patient’s authorized representative under applicable local law
In the course of the study, assessment of a subject’s capacity to re-consent
should be done, and written informed re-consent signed by the patient
(co-signed by the patient’s legally authorized representative if required by the 
local regulations, guidelines, or independent EC/IRB) or the patient’s 
authorized representative should be obtained, as per applicable local law and 
requirements.

Every effort should be made to have the same caregiver participate throughout the 
duration of the OLE study who also participated in Study BN29552 or BN29553.
The caregiver, in the investigator's judgment, should fulfill the following:
–
Have frequent and sufficient contact with the patient to be able to 
provide accurate information regarding the patient’s cognitive and 
functional abilities, agree to provide information at clinic visits 
(which require partner input for scale completion), sign the 
necessary consent form, and have sufficient cognitive capacity to 
accurately report upon the patient’s behavior and cognitive and 
functional abilities.
–
Be 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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–
If the caregiver cannot continue to participate in the OLE study 
and cannot be replaced, the patient can continue in the OLE so 
long as patient safety can be assured.

Willingness and ability to complete all aspects of the study (including MRI, lumbar 
puncture [if applicable], 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 measures, and agreement to refrain 
from donating eggs, as defined below:
Women must remain abstinent 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 final dose of study drug.  Women must refrain from donating eggs 
during this same period.
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).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
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 a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for at 
least 8 weeks after the final 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 preventing drug 
exposure. 


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry or 
continued participation:

Patients who discontinued treatment permanently in Study BN29552 or BN29553 for 
safety reasons

Impaired coagulation (screening PT 1.2 the upper limit of normal (ULN) that 
remains abnormal on retest)

Evidence of more than 10 ARIA-H (microbleeds and/or leptomeningeal
hemosiderin deposits) at the Study BN29552 or BN29553 Week 105 visit, as 
assessed by central review of MRI

Diagnosed with three recurrent, symptomatic ARIA-E events or exacerbations of 
previous events

Presence of intracranial lesion that could potentially increase the risk of CNS 
bleeding (e.g., intracranial aneurysm; arteriovenous malformation)

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 Version 5 criteria) within the past 2 years and 
during the study
Nicotine use is allowed.
Marijuana use is not allowed within the past 2 years.

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

Pregnant or lactating, or intending to become pregnant during the study

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, or interfere with the patient’s 
ability to complete the study assessments

Chronic use of anticoagulants or participation in any other investigational drug 
treatment trial
See Section 4.4 for further details and other concomitant medication 
restrictions. 
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
All patients who meet the eligibility criteria will receive 60 mg/kg of crenezumab IV Q4W.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is crenezumab. According to 
E.U. guidance, the PET ligands used in the context of this study have been designated 
as non-IMPs.  In some regions, according to local regulations, these PET tracers may 
be considered as IMPs.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Crenezumab 
Crenezumab 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 Investigator’s Brochure.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimen is summarized in Section 3.1.
4.3.2.1
Crenezumab
Crenezumab will be administered via IV infusion to all patients at a dose of 60 mg/kg 
Q4W until the end of the study (see Section 3.3).  
All IV infusions of crenezumab will be administered by appropriately trained staff in the 
clinic or other agreed environment (e.g., the patient’s home if that option becomes 
available at a later time).  The first four infusions of study drug must be administered at 
the clinic for all patients as a minimum.  
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.  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 weight at Week 105 of Study BN29552 or
BN29553 (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 appropriate 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 


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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 who 
develops anaphylaxis, anaphylactoid, or serious or severe hypersensitivity reactions, a 
blood sample will be collected at the time of the event for analyses of antibodies to 
crenezumab and/or other components of the drug product, and crenezumab serum 
concentration.  In addition, for any patient suspected of developing anaphylaxis, or 
anaphylactoid or serious or severe hypersensitivity reactions warranting discontinuation 
of dosing, a washout ADA sample (16 weeks postdose) and concurrent PK sample must 
be collected.
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.
At applicable sites, following the first four 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 and once that 
option is available (please see Section 4.5 for details).
4.3.2.2
Non-Investigational Medicinal Products
All patients who are assessed by PET imaging (as described in Section 3.4.7.2) will be 
assessed using an appropriate PET ligand.
According to E.U. guidance, the PET ligands used in the context of this study have 
been designated as non-IMPs.  In some regions, according to local regulations, these 
PET tracers may be considered as IMPs.
Regarding the safety profile of and reporting requirements for the PET ligands 
administered in this study, please refer to Section 5.7.
4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (crenezumab) will be provided by the 
Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs supplied by the Sponsor, using the interactive voice or 
web-based response system (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 be returned to the Sponsor (if supplied by the Sponsor) 
with the appropriate documentation.  The site's method of destroying Sponsor-supplied 


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IMPs must be agreed to by the Sponsor.  The site must obtain written authorization from 
the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP destruction must 
be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Crenezumab
The Sponsor will offer post-trial access to the Roche IMP (crenezumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below.
A patient will be eligible to receive Roche IMP (crenezumab) after completing the study if 
all of the following conditions are met:

The patient has a life-threatening or severe medical condition and requires 
continued Roche IMP 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 him or her.
A patient will not be eligible to receive Roche IMP after completing the study if any of the 
following conditions are met:

The Roche IMP 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 IMP or data suggest that the IMP
is not effective for AD.

The Sponsor has reasonable safety concerns regarding the IMP as treatment for AD.

Provision of Roche IMP 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


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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 from the 
first OLE visit through the study completion/early termination visit.  All concomitant 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF page.
Adding a new medication or changing the dose of a medication should occur only for the 
treatment of an adverse event.  
For the entire OLE period, the following medications are prohibited:

Anti-coagulation medications
Anti-platelet treatments (e.g. aspirin, clopidogrel, dipyridamole) are permitted.
Under certain circumstances, anti-coagulation therapy (e.g., temporary usage 
during surgery or for treatment of deep vein thrombosis) may be permitted.  In 
these circumstances, appropriate safety assessments should be made (e.g., 
prior to a lumbar puncture).

Any other investigational drug treatment throughout participation in the trial
For the first year of the OLE study, the following medications are prohibited. After 
Year 1 of the OLE study, initiation of new therapy should be proactively discussed with 
the Sponsor:

Any other therapeutic that targets Aor tau

Stimulant medications (amphetamine, methylphenidate preparations, or modafinil)

Typical antipsychotic and/or neuroleptic medication except as brief treatment for a 
non-psychiatric indication (e.g., emesis)

Tricyclic antidepressants (amtriptyline, imipramine, timipramine, doxepin)
Secondary amines (e.g., desipramine, nortriplyline) may be permitted for use in 
treatment of chronic pain. 

Chronic and/or daily use of opiates or opioids (including long-acting opioid 
medication) 

Chronic and/or daily use of benzodiazepines
The following medications are permitted under certain conditions:

Atypical anti-psychotics are permitted if assessed as not clinically affecting the 
patient’s cognitive symptoms.

Intermittent use of centrally acting antihistamines is permitted but should not be 
used 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) 


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
Intermittent short-term use of benzodiazepines, buspirone, or short-acting hypnotic 
medication for sleep or anxiety is allowed, except in the 2 days or 5 half-lives 
(whichever is the longer) prior to any cognitive assessment. Individual cases of 
concomitant intermittent barbiturate use should be discussed with the Sponsor.

Dose of benzodiazepine for pre-surgical and pre-imaging sedation at appropriate 
visits is permitted if allowed by the EC or IRB
Concomitant and excluded therapies for determination of patient eligibility are described 
in Sections 4.1.1 and 4.1.2. 
4.5
STUDY ASSESSMENTS 
Please see Appendix 1 for the schedule of activities 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 from patient-centered outcome data.  For 
further details, see Section 5.3.2.
In this study, patient-centered outcomes instruments will be completed in the order 
specified in Sections 4.5.11 and as specified in the schedule of activities (see 
Appendix 1). 
At a time to be determined by the Sponsor, at applicable sites, study infusions and 
associated 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 relevant assessments to be 
performed by the HN professional.  At the time the Sponsor initiates HN visits, specific 
visits and assessments that may be performed by an HN professional will be described 
in a HN manual.


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Rescue medications and equipment to treat anaphylactic and anaphylactoid reactions 
must be available for HN visits.  Patients or 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, caregivers, and others as specified on the ICFs must review, sign, and date 
the most current IRB/EC-approved written informed consent for participation in the study 
before any 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, Concomitant Medication, and Demographic 
Data
Medical history and demographic data was collected as part of the main study protocols 
(BN29552 or BN29553).
4.5.3
Physical and Neurologic Examinations
In the OLE, complete physical and neurologic examinations will be performed as per the 
schedule of activities and should be conducted in the same manner on each occasion to 
ensure comparability to previous examinations.  The scheduled examinations should 
include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  
Neurologic examinations should include assessment of mental status, level of 
consciousness, cranial nerve function (including fundoscopic examination), motor 
function, sensory function, reflexes, coordination, and assessment of gait.  Other 
examination components or systems may be assessed as clinically indicated.  
Symptom-directed physical and neurologic examinations may be done at any other visit 
as needed to assess the safety of the participant. Any significant changes from prior 
examinations 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 activities indicates when weight should be recorded as part of the vital 
sign assessments (see Appendix 1).
4.5.4
Vital Signs
Vital signs, including systolic and diastolic blood pressure, pulse rate, body temperature, 
respiratory rate, and oxygen saturation will be measured according to the schedule of 
activities (see Appendix 1).  Vital signs should be measured per clinic standard operating 


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procedures as long as the patient is supine, at rest, and at least 15 minutes have passed 
since a blood draw.
4.5.5
Cognitive Assessments
Cognition will be assessed using the Alzheimer’s Disease Assessment Scale—Cognition 
13 (ADAS-Cog13), Free and Cued Selective Reminding Test (FCSRT), Clinical 
Dementia Rating (CDR), MMSE, and those instruments listed below. 
The cognitive assessments described in this section are recommended in the order 
specified in Section 4.5.11 and in the schedule of activities (see Appendix 1). 
The scales and assessments for this study will be provided unless otherwise specified.  
Consistency of raters and caregivers for each patient throughout the duration of the 
DBTP in Study BN29552 or BN29553 and the OLE study is important for collecting 
high-quality cognitive and functional outcomes.  Every effort should be made to have
the same CDR rater and caregiver participate throughout the duration of the OLE 
study who also participated in Study BN29552 or BN29553.  
New potential raters must complete training and be approved by the rating scale 
contract research organization (CRO) prior to administering any cognitive assessments 
or rating scales in the study. 
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 a global 
score (i.e., CDR-Global Score [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 (Morris 1993; Lynch et al. 2006; O'Bryant et al. 2010).  The 
CDR characterizes six 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 interview of the patient and a reliable 
informant or collateral source (e.g., a caregiver).  Details of the CDR can be found at the 
web site:  http://knightadrc.wustl.edu/CDR/CDR.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, 
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(ADCS-ADL), or Functional Activities Questionnaire (FAQ).  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. 
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 (Rosen et al. 1984; Connor and Sabbagh 2008; Cano et al. 2010;
Ihl et al. 2012).  The modified version will be used; it has 13 items and includes the 
addition of delayed word recall and number cancellation and the use of only one trial for 
word recognition.  This is the version used in the Alzheimer’s Disease Neuroimaging 
Initiative protocol (http://www.adni-info.org/Scientists/ADNIStudyProcedures.html).  
Equivalent alternate forms of the word recall, word recognition, and number cancellation 
subtests will be used in successive test administrations. 
The 12-item version of ADAS-Cog (without number cancellation) will be also be 
analyzed for comparison with Phase II data.
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 
activities of daily living (ADL) (e.g., eating and toileting) and more complex ADL or 
instrumental ADL (iADL; e.g., using the telephone, managing finances, preparing a 
meal). 
4.5.5.4
Mini Mental State Examination 
The MMSE (Version 9.8, including serial 7s) is a set of standardized questions used to 
evaluate possible cognitive impairment and help stage the severity level of this 
impairment (Folstein et al. 1975).  The questions target six areas:  orientation, 
registration, attention, short-term recall, language, and constructional praxis/visuospatial 
abilities. 
4.5.5.5
Free and Cued Selective Reminding Test–Immediate Recall 
The FCSRTImmediate Recall (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 dementia in several longitudinal epidemiologic studies (Grober and Buschke 
1987; Sarazin et al. 2007). 
Free, cued, and total recall are the measures from this assessment.  The cueing index 
can be calculated from these scores. Lower scores imply poorer performance on all 
aspects of the test.


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4.5.5.6
Functional Activities Questionnaire 
Impairment in daily functioning is a key clinical feature of AD.  Early in AD, impairments 
are seen in so-called iADL (e.g., handling of finances, using transportation).  This loss of 
iADL leads to a loss in independence, resulting in increased burden to caregivers and 
increased costs (Marshall et al. 2011).
The FAQ is an informant-based assessment that presents a forced choice of four levels 
of functioning for 10 iADLs.  The FAQ total score is calculated by adding together the 
scores of each item; higher scores indicate worse function (Pfeffer et al. 1982).
4.5.5.7
Neuropsychiatric Inventory Questionnaire 
The Neuropsychiatric Inventory Questionnaire (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 caregiver’s distress is rated on a 6-point scale (no distress, minimal, mild, 
moderate, severe, or extreme or very severe). 
4.5.5.8
Columbia−Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS; http://www.cssrs.columbia.edu) 
is an assessment tool used to assess any new instances of suicidality since the last visit.  
The structured interview prompts recollection of suicidal ideation, including the intensity 
of the ideation, behavior, and attempts with actual or potential lethality.  The C-SSRS will 
be collected as indicated in the schedule of activities (see Appendix 1).  The assessment 
will be completed by a certified C-SSRS rater after he or she interviews the patient and,
if necessary, the patient’s caregiver during the study visit. 
4.5.5.9
Zarit Caregiver Interview for Alzheimer’s Disease 
The Zarit Caregiver Interview for Alzheimer’s Disease (ZCI-AD) is a modified version of 
the Zarit Burden Interview, which was originally designed to reflect the stresses 
experienced by caregivers 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 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. 


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If a patient’s caregiver is replaced during the study, the ZCI-AD will not be completed by 
his or her new caregiver. 
4.5.5.10
Quality of Life–Alzheimer’s Disease
The Quality of Life-Alzheimer’s Disease (QoL-AD) was developed to assess quality of 
life (QoL) in patients who have dementia (Logsdon et al. 1999, 2002).  The QoL-AD 
consists of 13 items that cover aspects of 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. 
4.5.5.11
EuroQOL 5-Dimension Questionnaire
The EuroQOL 5-Dimension questionnaire (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 5-Level (EQ-5D-5L) proxy Version 1, 
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, C-SSRS,
EQ-5D-5L, FAQ, FCSRT, MMSE, NPI-Q, QoL-AD, and ZCI-AD.  
4.5.7
Laboratory, Biomarker, PK and Other Biologic 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, ALP, total protein, total bilirubin, serum albumin, CPK, 
sodium, potassium, calcium, BUN or urea, and serum creatinine (and creatinine 
clearance calculated by the central laboratory) 


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
Hematology:  hemoglobin, hematocrit, RBC (with morphology), WBC counts, 
platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBC (other 
total counts)

Coagulation:  PT (pre-first infusion)

Immunophenotyping, including CD4, CD8, CD3, CD19, CD1656  

Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and 
pH.  Microscopic examination will be 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.

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
Cerebrospinal Fluid Sampling 
This section applies for patients who took part in the substudy associated with 
Study BN29552 or BN29553 and have opted to allow a further CSF sample to be taken
during the OLE study. CSF samples will be collected in the OLE study at Week 53 or at 
the early termination visit if prior to Week 53 and at least 6 months have elapsed since 
the previous lumbar puncture (see Appendix 1).
Lumbar puncture will be performed by an individual who meets all local requirements 
and is proficient in the procedure.  Lumbar puncture procedures and post-lumbar 
puncture care will be performed in accordance with local practice.  CSF sampling should 
be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal 
variation of CSF parameters.  
Approximately 12 mL of CSF will be collected from patients.
The samples will be used to study the effect of crenezumab on biomarkers associated 
with AD; for research purposes to identify biomarkers that may be predictive of response 
to treatment with crenezumab; to better understand the pathogenesis, course, and 
outcome of AD and related diseases; and to support the development of biomarker 
assays for diagnostic use.
CSF samples (i.e., 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). For patients who consent to the optional Research 
Biosample Repository (RBR), residual biomarker samples may be kept longer for future 
biomarker research (see Section 4.5.10).


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The procedures for the collection, handling, and shipping of biomarker samples are 
specified in the Sample Handling and Logistics Manual.
4.5.7.3
Plasma Biomarker Sampling
Plasma sampling will be conducted at Week 53 of the OLE study or at the early 
termination visit if prior to Week 53 only as detailed in the schedule of activities (see 
Appendix 1).  One whole blood sample will be obtained for plasma extraction from all 
patients.   
This sample will be used to evaluate plasma Alevels in peripheral blood as PD 
markers and to evaluate other exploratory AD biomarkers. 
Plasma samples (i.e., 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). For patients who consent to the optional RBR 
samples, residual biomarker samples may be kept longer for future biomarker research 
(see Section 4.5.10).
The procedures for the collection, handling, and shipping of biomarker samples are 
specified in the Sample Handling and Logistics Manual.
4.5.7.4
Amyloid- and Tau-PET Assessments
This section applies for patients who took part in either the amyloid- and/or tau-PET 
substudies associated with Study BN29552 or BN29553 and have opted to have a 
further amyloid- and/or tau-PET assessment during the OLE study.
The amyloid- and tau-PET assessments will allow longitudinal evaluation of the effect of 
crenezumab on cerebral fibrillar amyloid deposition as measured by florbetapir F 18-PET 
in this study population and tau burden as measured by [18F]GTP1 (an investigational
radioligand for in vivo imaging of tau protein aggregates).  
The PET data collected are expected to help in understanding the effects of crenezumab 
on amyloid and tau pathology over time as well as the relationship between change in 
florbetapir F 18/[18F]GTP1-PET and change in other endpoints in the Phase III studies 
and OLE study.
PET Imaging Procedures: For Amyloid-PET and Tau-PET Assessments
The Sponsor in conjunction with the CRO will prepare and distribute a detailed Imaging 
Manual for image acquisition and reconstruction procedures and parameters for each 
center prior to the start of the study.  All imaging data will be transferred to the imaging 
CRO for quality control and image analysis as documented in the PET Imaging Charter.


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Amyloid-PET Assessments 
One further amyloid-PET scan is included in this OLE study. This assessment will be 
done at Week 53 of the OLE study or at the early termination visit if prior to Week 53
and at least 6 months have elapsed since the previous amyloid-PET scan (see 
Appendix 1) and annual radiation exposure limits as per local guidelines are not 
exceeded.
The selective amyloid-PET radioligand florbetapir F 18 must be used for this assessment.
During the DBTP in Study BN29552 or BN29553, substudy patients will have had
screening, treatment, and post-treatment imaging studies. With the addition of the 
amyloid scan during the OLE study, each patient may have received florbetapir F 18 on 
four occasions over the course of 3 years (or less in case of early termination).  
Detailed methodology, including scanning procedures, is included in the Imaging Manual.
Source of Production of Florbetapir F 18
Florbetapir F 18 will be provided in accordance with approved national and/or local 
standards.
Warnings and Precautions Associated with Florbetapir F 18 (AMYVID) 
The most commonly reported adverse reactions after injection of florbetapir F 18 are
headache (2%), musculoskeletal pain (1%), fatigue (1%), and nausea (1%). 
For more information, see the Amyvid (Florbetapir F 18 Injection) for Intravenous Use 
U.S. Package Insert or Amyvid Summary of Product Characteristics.
Tau-PET Assessments
The selective tau-PET radioligand [18F]GTP1 will be used in this OLE study as an 
additional PET assessment to be done at Week 53 or the early termination visit if prior 
to Week 53 and at least 6 months have elapsed since the previous tau-PET scan (see 
Appendix 1), and annual radiation exposure limits as per local guidelines are not 
exceeded.
During the DBTPs of Study BN29552 and BN29553, patients received [18F]GTP1 and 
had tau-PET scans on up to three occasions (at baseline, Week 53, and Week 105 or 
the early termination visit). With the addition of the tau scan during the OLE study, each 
patient may have received [18F]GTP1 on four occasions over the course of 3 years (or 
less in case of early termination).  
If occurring in the same visit, [18F]GTP1 PET scans will be performed after administration 
of clinical scales.  [18F]GTP1 PET scans should not be performed on the same day as 
other PET scans.


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Source of Production of [18F]GTP1
[18F]GTP1will be provided under contract with a tau-PET imaging CRO in accordance 
with approved national and/or local standards.
Warnings and Precautions Associated with [18F]GTP1
[18F]GTP1 is not approved by any health authority, and clinical development is ongoing.  
The safety plan for participants in this study is based on clinical experience with 
[18F]GTP1 in three completed and three ongoing studies, and the safety experience to 
date is detailed in the [18F]GTP1 Investigator’s Brochure.  
As of the most recent Investigator’s Brochure (Version 5 dated April 2018) for 
[18F]GTP1, 23 healthy volunteers, 96 patients with AD, and 3 patients with progressive 
supranuclear palsy have been exposed to at least one dose of [18F]GTP1, with a total of 
251 doses across all studies.  Two of the patients with AD were enrolled in more than 
one study.  Available safety data from ongoing and completed clinical studies with 
[18F]GTP1 show that exposure to [18F]GTP1 and imaging procedures are generally well 
tolerated.  As of 1 February 2018, there have been no deaths, no adverse events of 
special interest, and no hypersensitivity reactions. One serious adverse event was 
reported in Study GN30009: a Grade 3 urinary tract infection, reported in a 
-year-
old 
 patient with moderate AD. The serious adverse event was assessed as not 
related to study drug. One 
-year-old 
 patient with pAD discontinued the 
study due to a non-serious moderate headache and non-serious cervical neck pain 
4 days after a baseline [18F]GTP1 PET scan; both events were assessed as not related to 
study drug.
More details are provided in the [18F]GTP1 Investigator’s Brochure. 
Radiation Risk: For Amyloid-PET and Tau-PET
Radioligands, similar to other radiopharmaceuticals, contribute to a patient’s overall 
long-term cumulative radiation exposure. Long-term cumulative radiation exposure is 
associated with an increased risk of cancer. Safe handling of radioligands should be 
ensured to protect patients and health care workers from unintentional radiation 
exposure.
Radiation exposure for [18F]GTP1 doses can be found in the [18F]GTP1 Investigator’s 
Brochure.  For florbetapir F 18, see the Amyvid (Florbetapir F 18 Injection) for 
Intravenous Use U.S. Package Insert or Amyvid Summary of Product Characteristics.
Refer to local guidelines for recommended annual radiation exposure.
4.5.7.5
Immunogenicity Sampling
Blood samples will be collected to assess the possible development of ADAs in all 
patients as noted in the schedule of activities (see Appendix 1). In addition, in case of 
anaphylaxis, anaphylactoid, or serious or severe hypersensitivity reactions, an ADA 


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sample with a concurrent serum PK sample should be collected at the time of the event 
and at washout (16 weeks) in the case of discontinuation for anaphylaxis.  Serum 
samples will be analyzed for antibodies to crenezumab using a validated 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. 
4.5.7.6
Pharmacokinetic Sampling 
Serum Crenezumab
Blood samples will be collected to evaluate the pharmacokinetics of crenezumab in 
serum as noted in the schedule of activities (see Appendix 1).  An additional PK sample 
for the assessment of serum concentrations of crenezumab may be obtained if the 
patient makes an unscheduled visit.  Unscheduled PK samples should be taken in the 
event of anaphylaxis, anaphylactoid, or serious or severe hypersensitivity reactions and 
at washout (16 weeks) in the case of discontinuation for anaphylaxis.
Serum concentrations of crenezumab will be determined using validated analytical 
procedures.
4.5.8
Electrocardiograms
In all patients, a routine ECG monitoring approach will be used.  Single ECG recordings 
will be obtained at specified timepoints, as outlined in the schedule of activities (see 
Appendix 1) and may be obtained at unscheduled timepoints as 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., weight, pulse rate, systolic and diastolic blood pressure, respiratory rate, oxygen 
saturation, and body temperature).  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,
respiratory rate interval, QRS interval, pulse rate duration, uncorrected QT interval, and 
QT interval corrected through use of Fridericia’s formula (QTcF) and Bazett’s formula 
based on the machine readings of the individual ECG tracings.


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If the 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 two 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 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.
4.5.9
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 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). 
Patients who have a CSF sample taken at Week 53 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.
4.5.10
Optional Samples for Research Biosample Repository
4.5.10.1
Overview of the Research Biosample Repository
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.


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In this study, for those patients who have previously consented to the RBR in the parent 
studies BN29552 and BN29553 and consent to RBR in Study BN40031, all specimens 
for the RBR will come from retaining the residual sample 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.  
RBR samples 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
4.5.10.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.10) will not be applicable at that site.
4.5.10.3
Sample Collection
In the OLE study, two types of residual sample will be retained by the RBR for 
identification of dynamic (non-inherited) biomarkers:  CSF and plasma. 

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.
RBR samples will be destroyed no later than 15 years after the date of final closure of the 
associated clinical database.  The RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).
For all samples, dates of consent should be recorded on the associated RBR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the laboratory manual.  


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4.5.10.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient
or legally authorized representative, unless permitted or required by law.
Given the complexity and exploratory nature of the analyses, data derived from RBR 
samples will generally not be provided to study investigators or patients unless required 
by law.  The aggregate results of any conducted research will be available in accordance 
with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.10.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  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 consent will be required 
to document a patient's agreement to provide optional RBR samples.  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 and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. In participants who lack the capacity to consent, the 
patient’s legally authorized representative may provide consent, per local requirements.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.10.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  However, if RBR samples have been tested prior to 
withdrawal of consent, results from those tests will remain as part of the overall research 
data.  If a patient wishes to withdraw consent to the testing of his or her RBR samples 
during the study, the investigator must inform the Medical Monitor in writing of the 


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patient's wishes through use of the appropriate RBR Subject Withdrawal Form and must 
enter the date of withdrawal on the RBR Research Sample Withdrawal of Informed 
Consent eCRF.  If a patient wishes to withdraw consent to the testing of his or her RBR 
samples after closure of the site, the investigator must inform the Sponsor by emailing 
the study number and patient number to the following email address:
global_rcr-withdrawal@roche.com
A patient's withdrawal from this study does not, by itself, constitute withdrawal of 
consent for testing of RBR samples.  Likewise, a patient's withdrawal of consent for 
testing of RBR samples does not constitute withdrawal from this study.
4.5.10.7
Monitoring and Oversight
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.5.11
Timing of Visits and Study Assessments
Written informed consent for participation in the OLE study must be obtained before 
performing any OLE studyspecific tests or evaluations by the patient or legally 
authorized representative, per local requirements.  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 assessments as per the schedule of activities (see Appendix 1). 
Following completion of the parent studies BN29552 or BN29553 Week 105 assessments 
and review of the Week 105 MRI results and OLE screening coagulation blood test 
results, the patient’s eligibility for OLE can be assessed. 
If needed (e.g., for completion of Week 105 visit assessments and/or the OLE study 
screening coagulation blood test), an unscheduled visit can be done after consent and 
before Week 1, Visit 1 of the OLE study. 
If assessed as eligible, patients may receive the first crenezumab infusion on or up to 
8 weeks after the parent study Week 105 visit. Visit 1 of the OLE safety assessments 


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must be done on the day of infusion as indicated on the schedule of activities (see
Appendix 1). 
4.5.11.1
Study Assessments
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; and blood draws for clinical laboratory assessments, 
pharmacokinetics, ADA and urine samples are recommended to be collected 
following scale assessments and must be collected before study drug administration.
The recommended order of clinical assessments/rating scales during treatment and at 
the early termination visit is described in Table 2.
Table 2
Order of Clinical Assessment and Rating Scale Collection
Patient
Caregiver
1.
ADAS-Cog13
2.
CDR (patient interview)
3.
MMSE
4.
FCSRT a
5.
QoL-AD 
6.
C-SSRS
1.
CDR (caregiver input)
2.
ADCS-ADL
3.
FAQ
4.
EQ-5D-5L
5.
ZCI-AD
6.
QoL-AD
7.
NPI-Q
ADAS-Cog-13 Alzheimer’s Disease Activity Scale-Cognition 13; ADCS-ADL Alzheimer’s 
Disease Cooperative Study-Activities of Daily Living; CDR Clinical Dementia Rating; 
C-SSRSColumbia-Suicide Severity Rating Scale; EQ-5D-5LEuroQoL 5-Dimension, 5-Level
questionnaire; FAQFunctional Activities Questionnaire; 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 for Alzheimer’s 
Disease.
a If appropriate per schedule of activities.
If assessments are split over 2 days, all safety assessments must be done on same day 
as the infusion.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Pregnancy


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
Evidence of more than 15 ARIA-H (microbleeds and/or areas of leptomeningeal 
hemosiderosis) 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
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
All patients who discontinue from the study treatment early will be asked to return at 4
and 16 weeks from the time of the last dose of study treatment for safety assessments.   
Patients that discontinue before Week 105 will also be asked to return for their next 
scheduled annual assessment (Week 53 or Week 105).  If the next annual follow-up visit 
(Week 53 or Week 105) is expected within 3 months of the 4-week safety visit, the 
annual and 4-week safety visits can be combined.    
4.6.2
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.  
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.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients.

Patient enrollment is unsatisfactory.

Futility analyses from this or other studies with crenezumab suggest that treatment 
with crenezumab is likely not effective.


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
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.
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)
5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
Crenezumab is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with crenezumab in completed and 
ongoing studies.  The anticipated important safety risks for crenezumab are outlined 
below.  Refer to the Crenezumab Investigator's Brochure for a complete summary of 
safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Patients will undergo safety monitoring during the study, including assessment of the 
nature, frequency, and severity of adverse events.  In addition, guidelines for managing 
adverse events, including criteria for dosage modification and treatment interruption or 
discontinuation, are provided below.
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 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 16 weeks after the last dose of 
study drug. 


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An iDMC will review unblinded safety and efficacy data at regular intervals (see 
Section 3.2.1 and the iDMC Charter for further details).
5.1.1
ARIA-E and ARIA-H
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 have, in 
the majority of instances, been asymptomatic, and their presence has been detected by 
brain MRI (Salloway et al. 2009; Sperling et al. 2011).  These MRI signal hyperintensities 
seen in the parenchyma and leptomeninges are named ARIA-E to cover the MRI
alterations seen in the fluidattenuated inversion recovery 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 mHs 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 deposition 
(Sperling et al. 2011).  
Limited data on ARIA-H deposition 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 of 207 patients (11.6%) developed ARIA-H deposition (Sperling et al. 
2012).  Acute occurrence of cerebral mH is not always considered clinically significant 
(Greenberg et al. 2009).  Study patients who received bapineuzamab and developed 
ARIA-H deposition without ARIA-E were clinically asymptomatic (Sperling et al. 2012).  
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 and van der Flier 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 APOE4 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 


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specific underlying vascular pathologic state, in particular hypertensive vasculopathy or 
cerebral amyloid angiopathy.
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 deposition.  The hypothesis that FcRmediated 
immune response may contribute to the occurrence of ARIA-E and/or ARIA-H deposition 
is supported by results from clinical studies that have shown that patients with AD who 
were treated with anti-Aantibodies with full effector function developed ARIA-E
(symptomatic and asymptomatic) that were dependent on the dose level and related to 
APOE4 status.
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.  
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 2016 (a case of asymptomatic sulcal effusion 
observed in the intravenous cohort of Study ABE4869g in a patient treated with 
crenezumab).  This same patient had recurrences of ARIA-E effusion during the 
corresponding OLE study.
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 disqualify 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 (see Section 5.1.2 for details of withdrawal rules).
In this Phase III OLE study, a safety monitoring plan has been designed to monitor the 
potential risk of ARIA-E and ARIA-H deposition.  This plan consists of the following key 
elements:

Exclusion criteria: 
Evidence of 10 ARIA-H (microbleeds and/or areas of leptomeningeal 
hemosiderosis) as assessed by central review of T2* gradientrecalled echo 
MRI (see Magnetic Resonance Imaging Charter for further details) 

Prior to all MRI evaluations, the patient or 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 fluidattenuated inversion recovery sequence and 
T2*-weighted gradient-recalled echo sequences) will be performed at Weeks 13, 25, 
53, 105, and yearly thereafter to detect ARIA-E and ARIA-H deposition.


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
All MRI scans will be read in a timely fashion and will evaluate ARIA-E and ARIA-H
deposition 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 (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 deposition findings that lead to dose modification or treatment 
discontinuation and study drug discontinuation rules in specific cases are detailed in 
Section 5.1.2.
5.1.2
ARIA-Related Dose Adjustments
The following dose adjustments and discontinuation rules for MRIrelated findings will 
apply.
5.1.2.1
ARIA-E
Asymptomatic ARIA-E with Barkhof Grand Total Score < 4 (Barkhof et al. 2013):

Continue study drug at the same dose (i.e., 60 mg/kg crenezumab)

Repeat magnetic resonance imaging 4 weeks later
If ARIA-E is stable or decreased, continue study drug and monthly MRI 
monitoring until event resolves.  Once ARIA-E completely resolves, conduct 
MRI monitoring as per Section 4.5.9.
If ARIA-E increases (Barkhof Grand Total Score4) or symptoms develop, 
refer to the rule below.
Symptomatic ARIA-E (any size) or ARIA-E with Barkhof Grand Total Score 4:

Temporarily interrupt study drug and implement monthly MRI monitoring

Once symptoms and ARIA-E resolve, reintroduce study drug at the same dose (i.e., 
60 mg/kg crenezumab) and perform an MRI after 4 weeks of dosing.  If no new 
ARIA-E is detected, MRI monitoring as per Section 4.5.9.
Any new onset of ARIA-E:  Treat the same as the first event on the basis of symptoms 
and Barkhof Grand Total Score.  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, maintain the patient 
in the study until study end and perform assessments as per the schedule of activities.  
5.1.2.2
ARIA-H
Dose reduction:  Patients who develop 10 ARIA-H cumulatively will receive a lower 
dose of the study drug.  Of note, patients who received a reduced dose of blinded study 
drug can start the OLE phase with the full dose of 60 mg/kg crenezumab.


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Study drug discontinuation:  Patients who develop15 ARIA-H cumulatively will be 
permanently discontinued from the study drug.
Cumulative ARIA-H is the sum of ARIA-H at baseline (of Study BN29552 or BN29553) 
and newly detected ARIA-H during the studies.
The rules in Sections 4.1.2 and 5.1, coupled with frequent MRI monitoring and 
collection of CNS symptoms, are put in place by the Sponsor to ensure safety 
while maximizing benefit for patients.
5.1.3
Management of Patients Who Experience Specific Adverse 
Events
5.1.3.1
Hypersensitivity and Infusion Reactions
Crenezumab will be administered to patients under close medical supervision in a 
setting with access to appropriate 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.
5.1.3.2
Amyloid-Related Imaging Abnormalities
To date, there has been limited clinical experience ARIAs with crenezumab; however, 
data from studies on other MAb treatments reveal that ARIA events tend to occur early 
after treatment initiation, are dose dependent and APOE4 dependent, are manageable 
with MRI monitoring, and do not lead to significant adverse outcomes.
All clinical trials with crenezumab include APOE4 genotyping, MRI safety monitoring, 
and an ARIA-based dose-intervention algorithm. 
5.1.4
Additional Safety Monitoring
Laboratory tests, including hematology and chemistry, will be performed throughout the 
OLE study.  ECGs will be recorded regularly (see Section 4.5.8).  Complete examinations 
will be performed as required per the schedule of activities to assess physical and 
neurologic events that are not consistent with normal disease progression.  
Symptom-directed physical and neurologic examinations may be done at any other visit 
as needed to assess the safety of the participant.  The C-SSRS will be used for 
prospective suicidality assessment.  Pregnancy testing will be performed at each visit in 
women of childbearing potential.  Samples to assess immunogenicity will be collected 
throughout the OLE study.


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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 
Sections 5.2.2 and 5.2.3.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition; see Sections 5.3.5.9 and 
5.3.5.10)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
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)


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
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, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events; see Table 3); the 
event itself may be of relatively minor medical significance (such as severe headache 
without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
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.


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
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 analysis must be collected as soon as feasible for the site and the 
patient. 
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 assessment 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 symptoms (as defined on the eCRF) and safety MRI scans will be 
collected for the following selected adverse events:

ARIA-E:  ARIAs suggestive of vasogenic edema and sulcal effusions

ARIA-H deposition:  ARIAs suggestive of mH and hemosiderin deposits
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.


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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 4 elimination 
half-lives after the last dose of study drug and collected on the occasion of the safety 
follow-up visit (16 weeks after the last dose of study drug).
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all 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 3 provides guidance for assessing adverse event severity.
Table 3
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 an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration.

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event


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
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.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.


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
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
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.  Details regarding any increases or decreases in severity will be captured on the 
Adverse Event Intensity or Grade Changes 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., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.


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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 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 an 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. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of AD, "Alzheimer’s disease progression" should 
be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
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").


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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 guidelines (e.g., National Institute on Aging and 
Alzheimer’s Association [NIAAA] New Diagnostic Criteria and Guidelines for AD).  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., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

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.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
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 


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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-Centered or Observer-Reported Outcome Data
Adverse event reports will not be derived from patient-centered outcome (or 
observed-reported outcome) data by the Sponsor, and safety analyses will not be 
performed using patient-centered outcome (or observed-reported 
outcome) data. Although sites are not expected to review the patient-centered 
outcome (or observed-reported outcome) data, it is possible that an investigator could 
become aware of patient-centered outcome (or observed-reported outcome) data that 
may be indicative of an adverse event.  Under these circumstances, the investigator will 
determine whether the criteria for an adverse event have been met and, if so, will report 
the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.2; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
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.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites 
Medical Monitor:
, M.D., M.A.S. (Primary)
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 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
Investigators should report to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event).
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 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 paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 8 weeks after the last dose 
of study treatment are provided in Section 5.6.


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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 final 
dose of study drug.  A paper Clinical Trial Pregnancy Reporting Form should be 
completed and submitted to the Sponsor or its designee immediately (i.e., no more than 
24 hours after learning of the pregnancy), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Pregnancy 
should not be recorded on the Adverse Event eCRF.  The investigator should 
discontinue study drug and counsel the 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.  
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 final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  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.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should 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).  


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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.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious
adverse event that occurs after the end of the adverse event reporting period (defined as 
16 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 paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 


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communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Crenezumab Investigator's Brochure

PET Ligand Investigator's Brochures
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The safety analysis population will include all patients who consented to the OLE study, 
including those who enrolled in the OLE but did not receive open-label treatment. The 
intent-to-treat (ITT) population includes all patients who consented to the OLE study and 
received at least one dose of open-label treatment.
Safety will be assessed by monitoring adverse events, clinical laboratory evaluations, 
clinical assessments such as ECG and vital signs measurements, MRI evaluations and 
immunogenicity as measured by ADAs.  Patients will be analyzed according to actual 
treatment received. All safety data will be summarized using descriptive statistics.
6.1
DETERMINATION OF SAMPLE SIZE
This study is open to all patients who completed Study BN29552 or BN29553 and who 
meet the eligibility criteria. Accordingly, the sample size for this study is not based on a 
formal sample size calculation. The planned number of patients for this OLE study is not 
expected to exceed 1500 (approximately 750 randomized to crenezumab 60 mg/kg IV 
and 750 randomized to placebo, that is, the total planned number of patients in the 
parent studies BN29552 and BN29553, not including patients from the China extension 
study). An estimate for the actual number of patients in this OLE study is approximately 
925 patients (not including patients from the China extension study) based on 1500 
patients enrolled in both Phase III studies and an estimated reduction by 35% (i.e.,
withdrawals from double-blind treatment) and by a further 5% of completers who may 
not opt to enroll in this OLE study. 
6.2
SUMMARIES OF CONDUCT OF STUDY
Enrollment, patient disposition, and incidence of protocol deviations will be summarized 
descriptively for the ITT population.


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6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (such as age, sex, race, disease severity, 
APOE4 status, and use and non-use of background therapy for AD) will be summarized 
descriptively for the ITT population.
Descriptive summaries of continuous data will present the mean, SD, median, minimum, 
and maximum.  Descriptive summaries of discrete data will include frequencies 
expressed in terms of number and percentage of patients.
The primary and exploratory analyses will include all randomized patients, with patients 
grouped according to the treatment assigned at randomization until the OLE study.
6.4
SAFETY ANALYSES
The safety analysis population will include all patients who completed the DBTP and
received at least one dose of study drug in either Study BN29552 or BN29553 and 
entered the OLE study.  Patients will be grouped according to the treatment actually 
received until the first visit of the OLE study.

Incidence, nature, and severity of adverse events

Incidence, nature, and severity of serious adverse events

Incidence of adverse events of special interest 

Incidence and nature of MRI safety findings:  ARIA-E and ARIA-H

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

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.
6.5
EFFICACY ANALYSES
All efficacy data during the open-label study will be summarized using descriptive 
statistics for the ITT population. Observed values and change from the OLE baseline 
values at each scheduled visit will be summarized.
For all continuous safety parameters, efficacy parameters, and biomarkers, descriptive 
statistics for the change from baseline will be generated using the baseline value for the 


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OLE study (defined as the last value recorded during the DBTP). Descriptive statistics 
may also be generated for the change from the DBTP baseline.
All efforts will be made to minimize missing data.  Descriptive summaries of the number 
of patients with missing data and the timing and reasons for discontinuation from study 
will also be provided. Additional details will be documented in the SAP.
6.5.1
Exploratory Efficacy Endpoints
The absolute change from baseline in the continuous exploratory efficacy endpoints 
listed in Section 2 (including cognition endpoints, global endpoints, disease pathology 
biomarkers, and endpoints that measure other AD symptoms and effects) will be 
summarized using descriptive statistics. Additional exploratory analysis of selected 
endpoints may also be performed using an MMRM analysis model similar to that 
described in the following section for the change from baseline in CDR-SB.
For time-to-event endpoints, the Kaplan-Meier method will be used to estimate the 
median time to event for each treatment arm. The Cox proportional hazard model 
stratified by the randomization stratification factors will be used to estimate the hazard 
ratio and its 95% CI.  
6.5.2
Exploratory Efficacy Analyses
An analysis of the change from baseline in CDR-SB values recorded during the DBTP 
in Studies BN29552 and BN29553 and at specified timepoints of the OLE study will be 
performed.  In this case, a mixed-effect model for repeated measures (MMRM) will be 
used to compare the change from the double-blind baseline at OLE timepoints, relative 
to the change from the double-blind baseline to the end of double-blind treatment.  This 
analysis will compare the patients randomized to placebo during the DBTP (delayed 
start patients) with those randomized to crenezumab during the DBTP (early start 
patients).  This analysis will be performed using all data from the ITT populations of 
Studies BN29552 and BN29553 as well as the ITT population from the OLE study.  
Details of this analysis will be specified in the SAP.
The effect of randomization stratification factors (dementia status [pAD vs. mAD], patient 
APOE4 status [presence or absence of 4 allele], background medication at baseline 
[present, absent], and geographic region) may be explored by adding each of these 
covariates to this MMRM model.
Subgroup analysis of efficacy results will also be performed for subgroups defined by 
age, sex, race, dementia status (pAD vs. mAD), APOE4 status, geographic region, use 
and non-use of background therapies for AD, and other clinically relevant factors at 
baseline.


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6.5.3
Exploratory 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 influence of patient characteristics 
(e.g., demographics, disease stage) and background medication on the 
pharmacokinetics of crenezumab will be explored using 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. 
CSF concentration data for crenezumab and the ratio between CSF and serum 
crenezumab will be tabulated and summarized as appropriate for the patients who
participated in the CSF substudy.
Additional PK analyses will be conducted as appropriate.
6.5.4
Exploratory Biomarker Analyses
An analysis will be performed to explore association of the treatment effect with patient 
genotypes to assess the influence of the APOE4 status, 
 on the crenezumab 
treatment effect, the primary efficacy variable, and selected safety parameters and 
summarized by each of the genotypes. 
Exploratory analyses of the relationship between crenezumab exposure and biomarker 
(imaging, plasma pharmacodynamics, or CSF pharmacodynamics), efficacy, or safety 
measures will be performed as appropriate. The results of these analyses may be 
reported separately from the Clinical Study Report.
6.6
CHINA SUBPOPULATION ANALYSIS
Following completion of the global enrollment phase of Study BN29553, additional 
patients will continue to be enrolled in a China extension phase (i.e., China extension
to the main Phase III study BN29553) to ensure a total enrollment sufficient to support 
registration in the People's Republic of China.  This China subpopulation may include 
patients enrolled at sites in China during both the global enrollment phase and the China 
extension phase and could be included in this OLE, if applicable.
The objective of the China extension phase and the China subpopulation analyses is to 
assess the long-term 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.  


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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.
6.7
INTERIM ANALYSIS
No formal interim analysis of the efficacy results is planned for the OLE study. In the 
event that an interim efficacy analysis is performed prior to the primary analysis, it will be 
described in the SAP and will include specifications for adjustment of the Type I error 
level at the time of the primary analysis.
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, ECG, and other 
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.
PRO and ObsRO data will be collected through the use of an electronic device provided 
by a vendor.  The device is designed for entry of data in a way that is attributable, secure, 
and accurate, in compliance with U.S. FDA regulations for electronic records (21 CFR 
Part 11).  The electronic data are available for view access only via secure access to a 
web server.  Only identified and trained users may view the data, and their actions 
become part of the audit trail.  The Sponsor will have view access only.  System 
backups for data stored by the Sponsor and records retention for the study data will be 
consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.


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At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.
7.3
ELECTRONIC PATIENT AND CLINICIAN REPORTED OUTCOME 
DATA
An electronic device will be used to capture PRO and clinically reported outcome data.  
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. FDA regulations for electronic records (21 CFR 
Part 11).  The data will be transmitted to a centralized database maintained by the 
electronic device vendor.
The electronic data will be available for view access only, via a secure method.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor’s standard procedures.
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which 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-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
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.


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


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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug Application (IND) will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Home Nursing Informed Consent Form) 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.
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.


Crenezumab—F. Hoffmann-La Roche Ltd
102/Protocol BN40031, Version 2
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 (HIPAA) of 1996.  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. 
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
or legally authorized representative, 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.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 


Crenezumab—F. Hoffmann-La Roche Ltd
103/Protocol BN40031, Version 2
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.3).
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, ICFs, 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.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, 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 


Crenezumab—F. Hoffmann-La Roche Ltd
104/Protocol BN40031, Version 2
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 4.3.3).  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:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in 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 
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.
 
 


Crenezumab—F. Hoffmann-La Roche Ltd
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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).


Crenezumab—F. Hoffmann-La Roche Ltd
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10.
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Appendix 1
Schedule of Activities: Open-Label Extension Study
Assessment/ 
Procedure
Open-Label Extension
Follow-Up for Pts 
Discontinuing OLE 
Treatment
Follow-Up for Pts 
Completing OLE 
Treatment a
OLE 
Scrn. b
Visit 1 
OLE 
Wk 1 c
OLE
Wk 5 
and Every
4 Wks 
thereafter
(7 days) c
Visit 4 
OLE 
Wk 13 
(7 
days) c,d
OLE 
Wk 25
(7 
days) c,d
OLE 
Wk 53
(7 
days) c,d
OLE 
Wk 77
(7 
days) c,d
OLE 
Wk 105 
and Every 
52 Wks 
thereafter
(7 days)
c,d
Last 
Dose in 
OLE 
+4 Wks 
(or ET)
Last 
Dose in 
OLE 
+16 
Wks
Final 
Annual 
Visit for 
OLE
Discon. 
before
Wk 
53/105 e
Last 
Dose in 
OLE
+4 Wks
Last 
Dose in 
OLE 
+16 Wks
Informed consent for 
OLE
x
Review of OLE 
eligibility criteria
x
Coagulation blood 
test
x f
Vital signs g
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis h
x
x
x
x
x
x
x
x
Urine pregnancy test i
x
x
x
x
x
x
x
x
x
PK serum sample j
x
x k
x k
x
x
x
x
x
x
Immunogenicity 
sample l
x
x
x
x
x
x
x
x
x
Amyloid-PET/tau-
PET/CSF m, n
x n
x n
PD plasma sample j, n
x n
x n
12-Lead ECG o
x
x
x
x
x


Appendix 1
Schedule of Activities: Open-Label Extension Study (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
112/Protocol BN40031, Version 2
Assessment/ 
Procedure
Open-Label Extension
Follow-Up for Pts 
Discontinuing OLE 
Treatment
Follow-Up for Pts 
Completing OLE 
Treatment a
OLE 
Scrn. b
Visit 1 
OLE 
Wk 1 c
OLE
Wk 5 
and Every
4 Wks 
thereafter
(7 days) c
Visit 4 
OLE 
Wk 13 
(7 
days) c,d
OLE 
Wk 25
(7 
days) c,d
OLE 
Wk 53
(7 
days) c,d
OLE 
Wk 77
(7 
days) c,d
OLE 
Wk 105 
and Every 
52 Wks 
thereafter
(7 days)
c,d
Last 
Dose in 
OLE 
+4 Wks 
(or ET)
Last 
Dose in 
OLE 
+16 
Wks
Final 
Annual 
Visit for 
OLE
Discon. 
before
Wk 
53/105 e
Last 
Dose in 
OLE
+4 Wks
Last 
Dose in 
OLE 
+16 Wks
Physical and 
neurologic exams p
x
x
x
x
Serum chemistry and 
hematology q, r
x
x
x
x
x
x
MRI s
x
x
x
x
x
x
CDR
x
x
x
x
x
x
x
ADAS-Cog-13
x
x
x
x
x
x
x
ADCS-ADL/FAQ t
x
x
x
x
x
x
x
MMSE
x
x
x
x
x
x
x
NPI-Q
x
x
x
x
x
x
x
FCSRT-IR
x
x
x
x
x
EQ-5D-5L
x
x
x
x
x
x
x
QoL-AD
x
x
x
x
x
x
x
ZCI-AD
x
x
x
x
x
x
x
C-SSRS SLV 
x
x
x
x
x
x


Appendix 1
Schedule of Activities: Open-Label Extension Study (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
113/Protocol BN40031, Version 2
Assessment/ 
Procedure
Open-Label Extension
Follow-Up for Pts 
Discontinuing OLE 
Treatment
Follow-Up for Pts 
Completing OLE 
Treatment a
OLE 
Scrn. b
Visit 1 
OLE 
Wk 1 c
OLE
Wk 5 
and Every
4 Wks 
thereafter
(7 days) c
Visit 4 
OLE 
Wk 13 
(7 
days) c,d
OLE 
Wk 25
(7 
days) c,d
OLE 
Wk 53
(7 
days) c,d
OLE 
Wk 77
(7 
days) c,d
OLE 
Wk 105 
and Every 
52 Wks 
thereafter
(7 days)
c,d
Last 
Dose in 
OLE 
+4 Wks 
(or ET)
Last 
Dose in 
OLE 
+16 
Wks
Final 
Annual 
Visit for 
OLE
Discon. 
before
Wk 
53/105 e
Last 
Dose in 
OLE
+4 Wks
Last 
Dose in 
OLE 
+16 Wks
Concomitant 
medications
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events 
x
x
x
x
x
x
x
x
x
x u
x
x
Study drug 
administration c
x
x
x
x
x
x
x
ADAanti-drug antibody; ADAS-Cog13Alzheimer’s Disease Activity Scale Cognition 13; ADCS-ADLAlzheimer’s Disease Cooperative Study–Activities 
of Daily Living; CDRClinical Dementia Rating; CSFcerebrospinal fluid; C-SSRSColumbia Suicide Severity Rating Scale; DBTPDouble-Blind 
Treatment Period; Discon.Discontinuation; eCRFelectronic Case Report Form; EQ-5D-5LEuroQOL 5-Dimension, 5-Level questionnaire; ETearly 
termination; FAQ=Functional Activities Questionnaire; FCSRT-IRFree and Cued Selective Reminding TestImmediate Recall; MMSEMini Mental State 
Examination; MRImagnetic resonance imaging; NPI-QNeuropsychiatric Inventory-Questionnaire; OLEopen-label extension; PDpharmacodynamic; 
PETpositron emission tomography; PKpharmacokinetic; Ptspatients; QOL-ADQuality of LifeAlzheimer’s Disease; Scrn. screening; SLVsince last 
visit; Wk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.  For patients who terminate early, assessments listed in the visit "Last 
Dose in OLE +4 weeks [or ET visit]" should be completed.
a Patients who continue treatment with crenezumab after completing of the study will not have any follow-up visits.
b Assessments performed at Week 105 of the parent studies BN29552 and BN29553 will be used as screening assessments for the OLE study as well 
as an OLE protocol-specific pre-infusion coagulation assessment (which can be done any time after consent).  If needed to complete assessments for 
OLE eligibility, an extra unscheduled visit can be done after consent and before Week 1, Visit 1 of the OLE.


Appendix 1
Schedule of Activities: Open-Label Extension Study (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
114/Protocol BN40031, Version 2
c Study drug administration should be performed only after all assessments/rating scales have been completed (unless indicated otherwise).  Study drug 
will be administered to patients by infusion (full details in the pharmacy manual).  Patients must 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.  There should be a telephone call to the patient 
following the first infusion.
d 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.  
e A final annual assessment (Week 53 or Week 105) will be obtained for patients who discontinue study treatment prior to Week 105.  If the next annual 
visit (Week 53 or Week 105) is expected within 3 months of the discontinuation, the final annual visit may be combined with the 4-week postdose 
safety visit.
f
The coagulation test can be done as soon as the OLE main Informed Consent Form has been signed.
g 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.  Pulse 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 vital signs should be recorded in the eCRF.  
h Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and pH.  Microscopic examination should be 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.
i
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.
j
Predose PK samples and plasma pharmacodynamics should be obtained prior to study drug administration on the same day of dosing.  Accurate 
recording of the time of study drug administration and pharmacokinetics is critical. Unscheduled PK samples should be taken in the event of 
anaphylaxis, anaphylactoid, or serious or severe hypersensitivity reactions.  For any patient suspected of developing anaphylaxis, or anaphylactoid or 
serious or severe hypersensitivity reactions warranting discontinuation of dosing, collect a wash-out ADA sample (16 weeks postdose) and concurrent 
PK sample.
k An additional PK sample should be collected 6090 minutes after end of infusion.
l
Immunogenicity samples should be obtained prior to study drug administration on the same day of dosing; samples should be 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 or severe hypersensitivity reactions at the time of the event.  For any patient suspected of developing 
anaphylaxis, or anaphylactoid or serious or severe hypersensitivity reactions warranting discontinuation of dosing, collect a wash-out ADA sample 
(16 weeks postdose) and concurrent PK sample.


Appendix 1
Schedule of Activities: Open-Label Extension Study (cont.)
Crenezumab—F. Hoffmann-La Roche Ltd
115/Protocol BN40031, Version 2
m CSF PK and biomarker samples, amyloid-PET, and tau-PET should be taken for patients who were in the respective longitudinal substudies of 
Studies BN29552 or BN29553 and have consented to additional sampling in the OLE.  Florbetapir F 18 must be used for the amyloid-PET 
assessment. The same scanner should be used as used in the substudy associated with Study BN29552 or BN29553.  Any scanner changes must be 
approved by the Sponsor.  See Section 4.5.7 for details of sampling.  CSF samples should be collected prior to dosing at the same day of dosing or 
the day prior to dosing. It is critical that the actual date and the time of sample collection is recorded.
n Plasma PD, CSF, and/or PET assessment to be performed at Week 53.  In the event that a patient terminates participation in the study prior to the 
Week 53 visit, the assessment should be performed at the early termination visit.  CSF and/or PET assessments will not be performed at early 
termination if less than 6 months have elapsed since the previous CSF and/or PET assessment.
o 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 other assessments (e.g., weight, pulse rate, systolic and diastolic blood pressure, respiratory rate, oxygen 
saturation, and body temperature).
p Complete physical and neurologic examinations should include an evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, and neurologic systems.  Neurologic examinations should include assessment of 
mental status, level of consciousness, cranial nerve function (including fundoscopic examination), motor function, sensory function, reflexes, 
coordination, and assessment of gait.  Other examination components or systems may be assessed as clinically indicated.  Symptom-directed 
physical and neurologic examinations may be done at any other visit as needed to assess the safety of the participant.
q Serum chemistry includes AST, ALT, ALP, total protein, total bilirubin, serum albumin, CPK, sodium, potassium, calcium, BUN or urea, and serum 
creatinine (and creatinine clearance calculated by the central laboratory). 
r
Hematology includes hemoglobin, hematocrit, RBC (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil,
and WBC other total counts). In the event of pneumonia, immunophenotyping analysis of peripheral blood cells should be done.
s MRIs should be done at Weeks 13, 25, 53, 105, and yearly thereafter.  MRI central read results must be available for review by site staff before dosing 
can proceed.  The patient will be called in advance of the MRI to check for any CNS-related symptoms. 
t
FAQ for caregivers of patients from Study BN29553.
u Only study-related serious adverse events will be collected (see also Section 5.6).