Clinical trial NCT03114657
Conditions: Alzheimer's Disease
Sponsor: Hoffmann-La Roche
Start date: 2017-03-29; Completion date: 2019-06-11
Enrollment: 806 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized, double-blind, placebo-controlled, parallel-group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The primary efficacy assessment will be performed at 105 weeks. The participants who do not enter open-label extension will enter for a long term follow-up period for up to 52 weeks after the last crenezumab dose (Week 153).

Detailed description:

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

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND 
SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE 
NCT Number: 
NCT03114657 
Document Date: 
Protocol Version 2: 14-March-2018  
 
 
 


FINAL PROTOCOL 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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 BN29553, Version 2  
PROTOCOL 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, EFFICACY AND SAFETY 
STUDY OF CRENEZUMAB IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S 
DISEASE 
PROTOCOL NUMBER: 
BN29553 
VERSION NUMBER: 
2  
EUDRACT NUMBER: 
2016-003288-20 
IND NUMBER: 
100,839 
TEST PRODUCT: 
Crenezumab (RO5490245) 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1: 15 November 2016 
DATE AMENDED: 
Version 2:  See electronic date stamp below 
 
14-Mar-2018 17:35:22
Title
Approver's Name
Company Signatory
Date and Time (UTC)


 
Crenezumab—F. Hoffmann-La Roche Ltd 
2/Protocol BN29553, Version 2  
 
PROTOCOL AMENDMENT, VERSION BN29553: 
RATIONALE 
Protocol BN29553 has been amended to clarify the study’s secondary and exploratory 
objectives and planned statistical analysis.  Additional minor changes have been made 
to improve protocol clarity.   
The main changes to the protocol, along with a rationale for each change, are 
summarized below: 
• 
Secondary efficacy objectives in Table 1 have been restructured into the following 
categories: a) cognitive, functional, and behavioral outcomes and, b) caregiver and 
quality-of-life endpoints (Section 3.3.9).  Exploratory efficacy objectives have also 
been added, and endpoints have been amended, specifically:   
– 
The secondary endpoint, Alzheimer’s Disease Assessment Scale-Cognitive 
(ADAS-Cog 12) has been changed to ADAS-Cog 11 as it affords a more 
differentiated endpoint from the ADAS-Cog13 endpoint.  A Mini Mental State 
Examination (MMSE) change from baseline to Week 105 has been added to 
assess severity of dementia because this scale is a widely used instrument to 
approximate stage of disease.  
– 
The time-to-clinically-evident-decline endpoint has been removed since the 
complex scale-based composite endpoint originally proposed is no longer 
considered to have clinical validity.  Instead, a number of exploratory efficacy 
endpoints aiming to enable "time to clinically meaningful event"−type analyses 
have been added as they may be clinically useful yet rarer and not well studied 
event endpoints with which to assess and describe the drug’s potential efficacy. 
These event endpoints will be more clearly defined in the Statistical Analysis 
Plan. 
• 
The pharmacokinetic and biomarker objectives and endpoints in Table 1 have been 
restructured and updated for clarity. 
• 
The protocol statistical considerations and analysis plan have been revised as 
follows: 
– 
Sample size re-estimation text has been added to Section 6.1 (Determination 
of Sample Size) as is commonly done in pivotal studies.  In the event the 
variability of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) endpoint is 
observed to be greater than planned, the proposed sample size increase will 
reduce the risk of an underpowered study, thereby reducing the risk of having 
less than 80% power to reach significance when the true relative reduction in 
CDR-SB equals 30%. 
– 
Wording has been updated at the end of Section 6 to clarify the population that 
will not be part of the primary analyses. 
– 
Additional endpoints have been added to the type 1 error control hierarchy to 
reflect their importance for valid hypothesis testing in the secondary efficacy 
endpoints analysis (Section 6.4.2). 


 
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– 
Exploratory Efficacy Analyses (Section 6.4.3) and Interim Analyses (Section 
6.8) sections have been rewritten for greater clarity (Section 6.4.3). 
– 
The biomarker analyses section has been updated to reflect the biomarker 
objectives (Section 6.7). 
 
In addition, the following minor changes have been made and are summarized below 
with a rationale for each change: 
• 
Update to Background on Alzheimer’s disease section (Section 1.1) to reflect recent 
developments and current thinking in the field of Alzheimer’s disease.  
• 
Alignment of the following protocol sections with latest Crenezumab Investigator’s 
Brochure (Version 10) 
– 
Background on Crenezumab, Summary of Nonclinical Studies, and inclusion of 
recent preclinical data related to crenezumab’s preclinical profile and 
mechanism of action (Sections 1.2 and 1.2.1). 
– 
Summary of Clinical Studies (Section 1.2.2) 
– 
Safety Overview, Immunogenicity, and Pharmacokinetics (Sections 1.2.3–
1.2.5). 
– 
Study Rationale Background (Section 1.3.1) 
• 
Additional information describing the findings of previous studies has been added to 
Biomarkers section (Section 1.2.6.3).  
• 
The Overall Benefit-Risk Summary has been updated for greater clarity (Section 
1.3.6); the risk−benefit profile remains unchanged. 
• 
The Overview of Study Design (Section 3.1.1) has been updated to reflect the 
changes introduced elsewhere in this amendment.  The following updates have also 
been made to this section: 
– 
Clarification of the primary analysis period from the time of randomization 
through to Week 105. 
– 
Added guidance regarding long-term follow-up of patients who discontinue 
study drug early or complete study treatment but do not enter the open-label 
extension has been added.  
• 
Wording has been updated throughout the protocol to reflect the contribution of 
patients from Taiwan and Hong Kong to the China extension (according to 
applicable Chinese regulations).  
• 
Clarification is provided around use of medical food supplements for Alzheimer’s 
disease not limited to Souvenaid (Section 3.1.3).  
• 
Requirements for the removal of no planned changes of Alzheimer’s medications for 
6 months post-randomization (Section 3.1.3) have been changed.  Any such 
changes would still occur (even if unplanned) when medically indicated and have no 
impact on the patient’s participation in the study.  


 
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4/Protocol BN29553, Version 2  
• 
Clarification provided for the possible screening window duration to ensure patients 
are randomized within the protocol-defined screening window (Section 4.6.8.1). 
• 
Clarification of the following exclusion criteria (Section 4.2): 
– 
Patients with a history of seizures will be excluded if in the opinion of the 
investigator it is likely to result in cognitive impairment, which was not immediately 
clear in the original wording.  The protocol permitted therapy regarding 
anticonvulsants has also been aligned accordingly.  
– 
The version of Diagnostic and Statistical Manual of Mental Disorders has been 
corrected from Version 5 to Version 4 to accurately reflect the 
alcohol/substance abuse or dependence exclusion criteria. 
– 
The cancer criterion text has been updated.   
– 
Screening hemoglobin A1c text has been updated. 
– 
Significant respiratory diseases whether or not they are likely to result in 
cognitive impairment. 
• 
The exclusion criterion regarding sleep apnea has been updated on account of the 
relatively high prevalence of sleep apnea in this population and benefit of treatment 
(e.g., continues positive airway pressure).  Sleep apnea that is considered by the 
investigator to be adequately treated and not contributing to cognitive dysfunction is 
allowed (treatment compliance should be documented).  Patients with sleep apnea 
that may be contributing to cognitive impairment are excluded. 
• 
Addition of text to recognize country variability in designation of non−Investigational 
Medicinal Product (NIMP)/IMP status to positron emission tomography (PET) 
tracers (Section 4.3.2.2).  Adverse event reporting requirements for PET ligands 
administered in this study and associated substudies were also added 
(Sections 5.3.1 and 5.4.2). 
• 
There was an update to the Permitted Therapy section to provide additional clarity 
and removal of duplicate text regarding antihistamines (Section 4.5.1). 
• 
The restriction was removed of once only repeat testing of patient samples during 
screening (Section 4.6.7 and Appendix 1 Schedule of Activities). 
• 
The addition of text to permit other biomarkers associated with Alzheimer’s disease 
or study treatment to be analyzed in peripheral blood samples as 
pharmacodynamics markers (Section 4.6.7.2). 
• 
Amyloid-related imaging abnormalities (ARIA) text including management of ARIA 
and required dose adjustments has been updated and restructured for greater 
clarity.  New nonclinical information has also been provided (Sections 5.1.1 and 
5.1.2).  Additional information and guidance for the reporting of ARIA adverse 
events has also been included in the Selected Adverse Events section (Section 
5.2.4). 
• 
Medical Monitor contact information has been updated in the Emergency Medical 
Contacts to reflect the change in the secondary Medical Monitor (Section 5.4.1). 


 
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5/Protocol BN29553, Version 2  
• 
The Schedule of Activities (Appendix 1) has been updated to correct errors and 
provide additional guidance and clarity in the footnotes. 
• 
The Diagnostic Verification Form (Appendix 4) has been edited to reflect the correct 
process. 
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


 
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6/Protocol BN29553, Version 2  
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14 
PROTOCOL SYNOPSIS .................................................................................... 15 
1. 
BACKGROUND .......................................................................................... 31 
1.1 
Background on Alzheimer’s Disease ..................................... 31 
1.2 
Background on Crenezumab ................................................. 32 
1.2.1 
Summary of Nonclinical Studies ............................................ 33 
1.2.2 
Summary of Clinical Studies .................................................. 35 
1.2.2.1 
Study ABE4427g ................................................................... 36 
1.2.2.2 
Study ABE4662g ................................................................... 36 
1.2.2.3 
Study ABE4869g ................................................................... 36 
1.2.2.4 
Study ABE4955g ................................................................... 37 
1.2.2.5 
Study GN28525 ..................................................................... 37 
1.2.2.6 
Study GN29632 ..................................................................... 37 
1.2.2.7 
Study GP29172 ..................................................................... 39 
 
 ..................................................................... 39 
1.2.2.9 
Study GN28352 ..................................................................... 39 
1.2.2.10 
Study BN29552 ..................................................................... 39 
1.2.3 
Safety Overview .................................................................... 39 
1.2.3.1 
Overall Adverse Event Profile ................................................ 40 
1.2.3.2 
Deaths ................................................................................... 41 
1.2.3.3 
Pneumonia ............................................................................ 41 
1.2.3.4 
AmyloidRelated Imaging Abnormalities of 
Edema/Effusion and Hemosiderin Deposition ....................... 42 
1.2.3.5 
Summary ............................................................................... 42 
1.2.4 
Immunogenicity ..................................................................... 43 
1.2.5 
Pharmacokinetics .................................................................. 44 
1.2.6 
Biomarkers ............................................................................ 45 
1.2.6.1 
Summary ............................................................................... 45 
1.2.6.2 
Brain Imaging Pharmacodynamic Biomarkers ....................... 45 
1.2.6.3 
Plasma and Cerebrospinal Fluid 
Pharmacodynamic Biomarkers .............................................. 46 


 
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1.3 
Study Rationale and Benefit-Risk Assessment ...................... 47 
1.3.1 
Background ........................................................................... 47 
1.3.2 
Efficacy .................................................................................. 48 
1.3.3 
Dose ...................................................................................... 50 
1.3.4 
Biomarkers ............................................................................ 52 
1.3.5 
Risk to Patients without Alzheimer’s Disease 
Pathology ............................................................................... 52 
1.3.6 
Overall Benefit-Risk Summary ............................................... 53 
2. 
OBJECTIVES AND ENDPOINTS ............................................................... 54 
3. 
STUDY DESIGN ......................................................................................... 57 
3.1 
Description of the Study......................................................... 57 
3.1.1 
Overview of Study Design ..................................................... 57 
3.1.2 
Substudies ............................................................................. 60 
3.1.3 
Use of Symptomatic Treatments for Alzheimer’s 
Disease .................................................................................. 60 
3.1.4 
Data Monitoring Committee ................................................... 60 
3.2 
End of Study .......................................................................... 60 
3.2.1 
Long-Term Follow-Up ............................................................ 61 
3.3 
Rationale for Study Design .................................................... 61 
3.3.1 
Rationale for Treatment Duration .......................................... 61 
3.3.2 
Rationale for Long-Term Follow-Up ....................................... 61 
3.3.3 
Rationale for Crenezumab Dosage ....................................... 62 
3.3.4 
Rationale for Patient Population ............................................ 62 
3.3.5 
Rationale for Control Group ................................................... 64 
3.3.6 
Rationale for Rescue Strategy ............................................... 64 
3.3.7 
Rationale for Diagnostic Verification ...................................... 64 
3.3.8 
Rationale for Primary Outcome Measure............................... 65 
3.3.8.1 
Clinical Dementia Rating-Sum of Boxes ................................ 65 
3.3.9 
Rationale for Key Secondary Outcome Measures ................. 66 
3.3.9.1 
Alzheimer’s Disease Assessment 
Scale-Cognition ..................................................................... 66 
3.3.9.2 
ADCS-iADL and ADCS-ADL 7otal 6core .............................. 66 
3.3.10 
Rationale for Pharmacokinetic Sampling ............................... 67 


 
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3.3.11 
Rationale for Biomarker Assessments ................................... 67 
3.3.11.1 
Cerebrospinal Fluid Biomarkers ............................................ 67 
3.3.11.2 
Positron Emission Tomography Imaging 
Biomarker .............................................................................. 67 
3.3.11.3 
Brain Volumetry ..................................................................... 67 
4. 
MATERIALS AND METHODS .................................................................... 68 
4.1 
Inclusion Criteria .................................................................... 68 
4.2 
Exclusion Criteria ................................................................... 70 
4.3 
Method of Treatment Assignment and Blinding ..................... 74 
4.4 
Study Treatment .................................................................... 75 
4.4.1 
Formulation, Packaging, and Handling .................................. 76 
4.4.1.1 
Crenezumab and Placebo ..................................................... 76 
4.4.2 
Dosage, Administration, and Compliance .............................. 76 
4.4.2.1 
Crenezumab and Placebo ..................................................... 76 
4.4.2.2 
Non-Investigational Medicinal Products ................................. 77 
4.4.3 
Investigational Medicinal Product Accountability ................... 77 
4.4.4 
Post-Trial Access to Crenezumab ......................................... 77 
4.5 
Concomitant Therapy ............................................................ 78 
4.5.1 
Permitted Therapy ................................................................. 78 
4.5.2 
Prohibited Therapy ................................................................ 79 
4.6 
Study Assessments ............................................................... 79 
4.6.1 
Informed Consent Forms and Screening Log ........................ 80 
4.6.2 
Medical History and Demographic Data ................................ 80 
4.6.3 
Physical Examinations ........................................................... 81 
4.6.4 
Vital Signs .............................................................................. 81 
4.6.5 
Cognitive Assessments ......................................................... 82 
4.6.5.1 
Clinical Dementia Rating Scale ............................................. 82 
4.6.5.2 
Alzheimer’s Disease Assessment 
Scale-Cognition ..................................................................... 83 
4.6.5.3 
Alzheimer’s Disease Cooperative Study-Activities 
of Daily Living Inventory......................................................... 83 
4.6.5.4 
Mini-Mental State Examination .............................................. 83 
4.6.5.5 
Free and Cued Selective Reminding Test –
Immediate Recall ................................................................... 83 


 
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4.6.5.6 
Functional Activities Questionnaire ........................................ 83 
4.6.5.7 
Neuropsychiatric Inventory Questionnaire ............................. 84 
4.6.5.8 
Columbia−Suicide Severity Rating Scale .............................. 84 
4.6.5.9 
Zarit Caregiver Interview for Alzheimer’s Disease ................. 84 
4.6.5.10 
Quality of Life–Alzheimer’s Dementia .................................... 84 
4.6.5.11 
EQ-5D.................................................................................... 85 
4.6.6 
Electronic Assessment of Rating Scales ............................... 85 
4.6.7 
Laboratory, Biomarker, and Other Biological 
Samples ................................................................................. 85 
4.6.7.1 
Standard Laboratory Samples ............................................... 85 
4.6.7.2 
Biomarker Sampling .............................................................. 86 
4.6.7.3 
Immunogenicity Sampling ...................................................... 87 
4.6.7.4 
Pharmacokinetic Sampling (Serum Crenezumab) ................. 88 
4.6.8 
Timing of Study Assessments ............................................... 88 
4.6.8.1 
Screening and Pretreatment Assessments............................ 88 
4.6.8.2 
Study Assessments ............................................................... 90 
4.6.9 
Confidentiality ........................................................................ 91 
4.6.10 
Brain Magnetic Resonance Imaging ...................................... 91 
4.6.11 
Electrocardiograms ................................................................ 92 
4.6.12 
Samples for Research Biosample Repository ....................... 93 
4.6.12.1 
Overview of the Research Biosample Repository .................. 93 
4.6.12.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 93 
4.6.12.3 
Sample Collection .................................................................. 94 
4.6.12.4 
Confidentiality ........................................................................ 95 
4.6.12.5 
Consent to Participate in the Research 
Biosample Repository ............................................................ 95 
4.6.12.6 
Withdrawal from the Research Biosample 
Repository ............................................................................. 95 
4.6.12.7 
Monitoring and Oversight ....................................................... 96 
4.7 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 96 
4.7.1 
Patient Discontinuation .......................................................... 96 
4.7.2 
Study Treatment Discontinuation ........................................... 96 


 
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4.7.3 
Study and Site Discontinuation .............................................. 97 
5. 
ASSESSMENT OF SAFETY ....................................................................... 98 
5.1 
Safety Plan ............................................................................ 98 
5.1.1 
Amyloid-Related Imaging 
Abnormalities-Edema/Effusion and Amyloid-
Related Imaging Abnormalities-Hemosiderin 
Deposition .............................................................................. 98 
5.1.2 
Management of Amyloid-Related Imaging 
Abnormalities including Required Dose 
Adjustments ......................................................................... 101 
5.1.2.1 
AmyloidRelated Imaging 
Abnormalities-Edema/Effusion (ARIA-E) ............................. 101 
5.1.2.2 
AmyloidRelated Imaging 
Abnormalities-Hemosiderin Deposition (ARIA-H) ................ 102 
5.1.3 
Prevention and Management of Hypersensitivity 
and Infusion Reactions ........................................................ 103 
5.1.4 
Additional Safety Monitoring ................................................ 103 
5.2 
Safety Parameters and Definitions ...................................... 103 
5.2.1 
Adverse Events ................................................................... 103 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) .................................................................... 104 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) .................................................. 105 
5.2.4 
Selected Adverse Events ..................................................... 105 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .............................................. 106 
5.3.1 
Adverse Event Reporting Period ......................................... 106 
5.3.2 
Eliciting Adverse Event Information ..................................... 107 
5.3.3 
Assessment of Severity of Adverse Events ......................... 107 
5.3.4 
Assessment of Causality of Adverse Events ....................... 107 
5.3.5 
Procedures for Recording Adverse Events .......................... 108 
5.3.5.1 
Infusion-Related Reactions .................................................. 108 
5.3.5.2 
Diagnosis versus Signs and Symptoms............................... 108 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................. 109 
5.3.5.4 
Persistent or Recurrent Adverse Events .............................. 109 


 
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5.3.5.5 
Abnormal Laboratory Values ............................................... 109 
5.3.5.6 
Abnormal Vital Sign Values ................................................. 110 
5.3.5.7 
Abnormal Liver Function Tests ............................................ 111 
5.3.5.8 
Deaths ................................................................................. 111 
5.3.5.9 
Preexisting Medical Conditions ............................................ 111 
5.3.5.10 
Lack of Efficacy or Worsening of Alzheimer’s 
Disease ................................................................................ 112 
5.3.5.11 
Hospitalization or Prolonged Hospitalization ........................ 112 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration ................................................ 112 
5.3.5.13 
Patient-Reported Outcome Data ......................................... 113 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor ........................................................ 113 
5.4.1 
Emergency Medical Contacts .............................................. 113 
5.4.2 
Reporting Requirements for Serious Adverse 
Events, Adverse Events of Special Interest, and 
PET Ligand Adverse Events ................................................ 114 
5.4.2.1 
Events That Occur prior to Study Drug Initiation .................. 114 
5.4.2.2 
Events That Occur after Study Drug Initiation ...................... 114 
5.4.3 
Reporting Requirements for Pregnancies ............................ 114 
5.4.3.1 
Pregnancies in Female Patients .......................................... 114 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ............... 115 
5.4.3.3 
Abortions ............................................................................. 115 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 115 
5.5 
Follow-Up of Patients after Adverse Events ........................ 116 
5.5.1 
Investigator Follow-Up ......................................................... 116 
5.5.2 
Sponsor Follow-Up .............................................................. 116 
5.6 
Adverse Events That Occur after the Adverse 
Event Reporting Period........................................................ 116 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ............................................................... 116 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ..................... 117 
6.1 
Determination of Sample Size ............................................. 117 
6.2 
Summaries of Conduct of Study .......................................... 118 


 
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6.3 
Summaries of Treatment Group Comparability ................... 118 
6.4 
Efficacy Analyses ................................................................ 118 
6.4.1 
Primary Efficacy Endpoint .................................................... 118 
6.4.2 
Secondary Efficacy Endpoints ............................................. 119 
6.4.3 
Exploratory Efficacy Analyses ............................................. 120 
6.5 
Safety Analyses ................................................................... 120 
6.6 
Pharmacokinetic Analyses ................................................... 121 
6.7 
Biomarker Analyses ............................................................. 121 
6.8 
Interim Analysis ................................................................... 122 
6.9 
China Subpopulation Analysis ............................................. 123 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 123 
7.1 
Data Quality Assurance ....................................................... 123 
7.2 
Electronic Case Report Forms ............................................. 124 
7.3 
Source Data Documentation ................................................ 124 
7.4 
Use of Computerized Systems ............................................ 125 
7.5 
Retention of Records ........................................................... 125 
8. 
ETHICAL CONSIDERATIONS .................................................................. 125 
8.1 
Compliance with Laws and Regulations .............................. 125 
8.2 
Informed Consent ................................................................ 125 
8.3 
Institutional Review Board or Ethics Committee .................. 127 
8.4 
Confidentiality ...................................................................... 127 
8.5 
Financial Disclosure ............................................................ 128 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 128 
9.1 
Study Documentation .......................................................... 128 
9.2 
Protocol Deviations .............................................................. 128 
9.3 
Site Inspections ................................................................... 128 
9.4 
Administrative Structure....................................................... 128 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 129 
9.6 
Protocol Amendments ......................................................... 129 
10. REFERENCES ......................................................................................... 131 


 
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LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 55 
Table 2 
Adverse Event Severity Grading Scale ..................................... 107 
 
 
LIST OF FIGURES 
Figure 1 
Pharmacokinetic Profile Based on Modelling and Simulation 
Data for 60 mg/kg of Crenezumab Administered 
Intravenously Every 4 Weeks Compared with 15 mg/kg 
Crenezumab Administered Intravenously Every 4 Weeks .......... 51 
Figure 2 
Overall Study Design .................................................................. 59 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments ......................................................... 138 
Appendix 2 
National Institute on Aging/Alzheimer’s Association Criteria 
for Dementia due to Alzheimer’s Disease ................................. 145 
Appendix 3 
National Institute on Aging/Alzheimer’s Association Criteria 
for Prodromal Alzheimer’s Disease (Mild Cognitive 
Impairment due to Alzheimer’s Disease) .................................. 147 
Appendix 4 
Diagnostic Verification Form ..................................................... 148 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, 
DOUBLE BLIND, PLACEBO CONTROLLED, 
PARALLEL GROUP, EFFICACY AND SAFETY 
STUDY OF CRENEZUMAB IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE  
PROTOCOL NUMBER: BN29553 
VERSION NUMBER: 
2  
EUDRACT NUMBER: 
2016-003288-20 
IND NUMBER: 
100,839 
TEST PRODUCT: 
Crenezumab (RO5490245) 
MEDICAL MONITOR: 
 M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
this form to your local study monitor.  
 


 
Crenezumab—F. Hoffmann-La Roche Ltd 
15/Protocol BN29553, Version 2  
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE BLIND, 
PLACEBO CONTROLLED, PARALLEL GROUP, EFFICACY AND 
SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: 
BN29553 
VERSION NUMBER: 
2  
EUDRACT NUMBER: 
2016-003288-20 
IND NUMBER: 
100,839 
TEST PRODUCT: 
Crenezumab (RO5490245) 
PHASE: 
III 
INDICATION: 
Alzheimer’s disease 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives and Endpoints 
This study will evaluate the efficacy, safety, and pharmacokinetics of crenezumab compared 
with placebo in patients with prodromal to mild Alzheimer’s disease (AD).  Specific objectives 
and corresponding endpoints for the study are outlined in the table below. 






 
Crenezumab—F. Hoffmann-La Roche Ltd 
18/Protocol BN29553, Version 2  
Objectives and Corresponding Endpoints (cont.)  
AD = Alzheimer’s disease; ADAS-Cog-11 = Alzheimer’s Disease Assessment Scale-Cognition 11; 
ADAS-Cog (subscale) 13 = Alzheimer’s Disease Assessment Scale-Cognition (subscale) 13; 
ADCS-ADL = Alzheimer’s Disease Cooperative Study−Activities of Daily Living Inventory; 
ADCS-iADL = Alzheimer’s Disease Cooperative Study−Activities of Daily Living Inventory 
Instrumental Subscale; ADL = activity of daily living; ARIA-E = Amyloid−related imaging 
abnormalities-edema/effusion; ARIA-H = Amyloid−related imaging abnormalities-hemosiderin 
deposition; CDR-SB = Clinical Dementia Rating–Sum of Boxes; CDR-GS = Global Score; 
C-SSRS = Columbia Suicide Severity Rating Scale; FAQ = Functional Activities Questionnaire; 
HRQOL = health−related quality of life; IV = intravenous; MMSE = Mini Mental State Exam; 
MRI = magnetic resonance imaging; NPI-Q = Neuropsychiatric Inventory Questionnaire; 
PD = pharmacodynamic; PET=positron emission tomography; PK = pharmacokinetic; 
QOL-AD = Quality of Life-Alzheimer’s Disease Scale; ZCI-AD = Zarit Caregiver Interview for 
Alzheimer’s Disease. 
 
Study Design 
Description of Study 
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study to evaluate the safety and efficacy of crenezumab in patients with prodromal AD (pAD) to 
mild AD (mAD).  
To maintain a balanced number of patients enrolled in each treatment arm, randomization will 
be stratified by dementia status (pAD vs. mAD), APOE status (presence or absence of ε4 allele), 
anti-dementia medications (present of absent) at baseline, and geographic region.  
Approximately 250 centers in approximately 30 countries worldwide will participate in this study.  
Patients will be selected on the basis of clinical diagnosis of probable AD (according to the 
National Institute on Aging/Alzheimer’s Association [NIAAA] Diagnostic Criteria and Guidelines 
for AD) OR pAD (according to the NIAAA Diagnostic Criteria and Guidelines for AD).  
Eligible patients will be 50−85 years old and must have increased brain amyloid as indicated by 
reduced cerebrospinal fluid (CSF) amyloid beta (Aβ)1-42 concentration (i.e., CSF-enrolled 
patients) or positive amyloid positron emission tomography PET scan by qualitative read 
(i.e., PET-enrolled patients). 
At the time of screening, patients must have a Mini-Mental State Examination (MMSE) score 
of ≥ 22 points and a Clinical Dementia Rating Global Score (CDR-GS) of 0.5 or 1.0.  To confirm 
objective memory impairment, patients must have a Free and Cued Selective Reminding 
Test−Immediate Recall (FCSRT-IR) Cueing Index * of ≤ 0.67 and a total free recall score of ≤ 27. 
 
* FCSRT cueing index is calculated as follows:  
[Free recall score − total score achieved] / [Free recall score − 48] 
Neuroradiologic evaluation will use a standard magnetic resonance imaging (MRI) protocol 
(including T2* weighted gradient−recalled echo [GRE] and fluid−attenuated inversion recovery 
[FLAIR]).  Screening MRIs will be read by a central reader who will exclude patients with other 
structural causes of dementia, significant cerebral vascular pathology, and other relevant 
exclusion criteria.  
Patients will be eligible for the study whether or not they are receiving standard of care 
symptomatic medications for AD (i.e., cholinesterase inhibitors or memantine, or combination), 
or medical food supplements (e.g., Axona or Souvenaid).  These medications must have been 
stable for ≥ 3 months prior to screening.  
The study will consist of a screening period of up to 12 weeks for each patient who agrees to 
participate, signs the informed consent form, and is eligible for the study.  Eligible patients will 
then undergo the baseline visit (Week 1), when they will receive the first dose following 
completion of all relevant assessments.  Patients will be enrolled in a double-blind treatment 
period of 100 weeks (26 doses; 60 mg/kg crenezumab or placebo by IV infusion every 4 weeks 
[q4w]), and a final efficacy and safety assessment 4 weeks following the patient’s last dose 
(Week 105).  Patients will then have the option to enter the open-label extension (OLE) study if 
eligible.  Patients who do not enter the OLE will have additional follow up visits at 16 and 52 




 
Cr e n e z u m a b — F.  H off m a n n -L a R o c h e Lt d  
2 0 /Pr ot o c ol B N 2 9 5 5 3, V er si o n 2  
n e c e s s ar y c o n s e nt f or m, a n d h a s s uffi ci e nt c o g niti v e c a p a cit y t o a c c ur at el y r e p ort u p o n 
t h e p ati e nt’ s b e h a vi or a n d c o g niti v e a n d f u n cti o n al a biliti e s. 
–  
I s i n s uffi ci e ntl y g o o d g e n er al h e alt h t o h a v e a hi g h li k eli h o o d of m ai nt ai ni n g t h e s am e 
l e v el of i nt er a cti o n wit h t h e p ati e nt a n d p arti ci p ati o n i n st u d y pr o c e d ur e s t hr o u g h o ut t h e 
st u d y d ur ati o n.  
E v er y eff ort s h o ul d b e m a d e t o h a v e s a m e c ar e gi v er p arti ci p at e t hr o u g h o ut t h e d ur ati o n of 
t h e st u d y.  
•  
Fl u e n c y i n t h e l a n g u a g e u s e d at t h e st u d y sit e  
•  
Willi n g n e s s a n d a bilit y t o c o m pl et e all a s p e ct s of t h e st u d y (i n cl u di n g M RI, l u m b ar p u n ct ur e 
[if a p pli c a bl e], cli ni c al g e n ot y pi n g, a n d P E T i m a gi n g [if a p pli c a bl e]); t h e p ati e nt s h o ul d b e 
c a p a bl e of c o m pl eti n g a s s e s s m e nt s eit h er al o n e or wit h t h e h el p of t h e c ar e gi v er  
•  
A d e q u at e vi s u al a n d a u dit or y a c uit y, i n t h e i n v e sti g at or’ s j u d g m e nt, s uffi ci e nt t o p erf or m t h e 
n e ur o p s y c h ol o gi c al t e sti n g ( e y e gl a s s e s a n d h e ari n g ai d s ar e p er mitt e d)  
•  
F or w o m e n of c hil d b e ari n g p ot e nti al:  a gr e e m e nt t o r e m ai n a b sti n e nt (r efr ai n fr o m 
h et er o s e x u al i nt er c o ur s e) or u s e c o ntr a c e pti v e m et h o d s t h at r e s ult i n a f ail ur e r at e of  <  1 % 
p er y e ar d uri n g t h e tr e at m e nt p eri o d a n d f or at l e a st 8 w e e k s aft er t h e l a st d o s e of st u d y 
dr u g.  
–  
A w o m a n i s c o n si d er e d t o b e of c hil d b e ari n g p ot e nti al if  s h e i s p o st m e n ar c h e al, h a s n ot 
r e a c h e d a p o st m e n o p a u s al st at e (≥ 1 2  c o nti n u o u s m o nt h s of a m e n orr h e a wit h n o i d e ntifi e d 
c a u s e ot h er t h a n m e n o p a u s e), a n d h a s n ot u n d er g o n e s ur gi c al st erili z ati o n (r e m o v al of 
o v ari e s a n d/ or ut er u s).  
–  
E x a m pl e s of c o ntr a c e pti v e m et h o d s wit h a f ail ur e r at e of 
 1 %  p er y e ar i n cl u d e bil at er al 
t u b al li g ati o n, m al e st erili z ati o n, e st a bli s h e d pr o p er u s e of h or m o n al c o ntr a c e pti v e s t h at 
i n hi bit o v ul ati o n, h or m o n e-r el e a si n g i ntr a ut eri n e d e vi c e s, a n d c o p p er i ntr a ut eri n e 
d e vi c e s.  
–  
T h e r eli a bilit y of s e x u al a b sti n e n c e s h o ul d b e e v al u at e d i n r el ati o n t o t h e d ur ati o n of t h e 
cli ni c al tri al a n d t h e pr ef err e d a n d u s u al lif e st yl e of t h e p ati e nt.  P eri o di c a b sti n e n c e 
( e. g., c al e n d ar, o v ul ati o n, s y m pt ot h er m al, or p o st o v ul ati o n m et h o d s) a n d wit h dr a w al ar e 
n ot a c c e pt a bl e m et h o d s of c o ntr a c e pti o n.  
•  
F or m e n:  a gr e e m e nt t o r e m ai n a b sti n e nt (r efr ai n fr o m h et er o s e x u al i nt er c o ur s e) or u s e 
c o ntr a c e pti v e m e a s ur e s, a n d a gr e e m e nt t o r efr ai n fr o m d o n ati n g s p er m, a s d efi n e d b el o w:  
–  
Wit h f e m al e p art n er s of c hil d b e ari n g  p ot e nti al or pr e g n a nt f e m al e p art n er s, m e n m u st r e m ai n 
a b sti n e nt or u s e a c o n d o m d uri n g t h e tr e at m e nt p eri o d a n d f or at l e a st 8 w e e k s aft er t h e l a st 
d o s e of st u d y dr u g t o a v oi d e x p o si n g t h e e m br y o.  M e n m u st r efr ai n fr o m d o n ati n g s p er m 
d uri n g t hi s s a m e p e ri o d. 
–  
T h e r eli a bilit y of s e x u al a b sti n e n c e s h o ul d b e e v al u at e d i n r el ati o n t o t h e d ur ati o n of t h e 
cli ni c al tri al a n d t h e pr ef err e d a n d u s u al lif e st yl e of t h e p ati e nt.  P eri o di c a b sti n e n c e ( e. g., 
c al e n d ar, o v ul ati o n, s y m pt ot h er m al, or p o st o v ul ati o n m et h o d s)  a n d wit h dr a w al ar e n ot 
a c c e pt a bl e m et h o d s of c o ntr a c e pti o n.  
•  
E vi d e n c e of t h e A D p at h ol o gi c al pr o c e s s, b y a p o siti v e a m yl oi d a s s e s s m e nt eit h er o n C S F 
A β 1 −4 2  l e v el s a s m e a s ur e d o n t h e El e c s y s β-A m yl oi d( 1 -4 2) T e st S y st e m O R a m yl oi d P E T 
s c a n b y q u alit ati v e r e a d b y t h e c or e/ c e ntr al P E T l a b or at or y.  
•  
D e m o n str at e d a b n or m al m e m or y f u n cti o n at F C S R T/ M M S E c o nse nt  or at  m ai n  s cr e e ni n g 
[ F C S R T c u ei n g i n d e x  ≤ 0. 6 7  A N D fr e e r e c all  ≤ 2 7]  
•  
E vi d e n c e of r etr o s p e cti v e d e cli n e c o nfir m e d b y a di a g n o si s v erifi c ati o n f or m  
•  
Mil d s y m pt o m at ol o g y, a s d efi n e d b y a s cr e e ni n g M M S E s c or e of  ≥ 2 2 p oi nt s a n d C D R -G S of 
0. 5 or 1. 0.  M M S E m a y b e p erf or m e d at F C S R T/ M M S E c o nse nt or m ai n  s cr e e ni n g.  
•  
M e et s NI A A A c or e cli ni c al crit eri a f or pr o b a bl e A D d e m e nti a or p A D (c o n si st e nt wit h t h e 
NI A A A di a g n o sti c crit eri a a n d g ui d eli n e s f or M CI )  


 
Crenezumab—F. Hoffmann-La Roche Ltd 
21/Protocol BN29553, Version 2  
• 
If the patient is receiving symptomatic AD medications, the dosing regimen must have been 
stable for 3 months prior to screening.  If the patient is taking medical food supplements 
(e.g., Axona or Souvenaid), these must also have been stable for 3 months prior to 
screening.   
• 
Inclusion is subject to review of clinical criteria at screening (diagnostic verification form) 
• 
Patient must have completed at least 6 years of formal education after the age of 5 years  
• 
For enrollment into the China Extension Phase, patients must have residence in mainland 
China, Hong Kong, or Taiwan and be of Chinese ancestry. 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any evidence of a condition other than AD that may affect cognition, including but not 
limited to, frontotemporal dementia, dementia with Lewy bodies, vascular dementia, 
Parkinson’s disease, corticobasal degeneration, Creutzfeldt-Jakob disease, progressive 
supranuclear palsy, frontotemporal degeneration, Huntington’s disease, normal pressure 
hydrocephalus, or hypoxia. 
• 
Seizure history that, in the opinion of the investigator, is likely to result in cognitive 
impairment 
• 
History or presence of clinically evident vascular disease that could potentially affect the 
brain (e.g., clinically significant carotid, vertebral stenosis or plaque; aortic aneurysm; 
intracranial aneurysm; cerebral hemorrhage; arterio-venous malformation. 
• 
History or presence of any stroke with clinical symptoms within the past 2 years, or 
documented history within the last 6 months of an acute event consistent, in the opinion of 
the investigator, with a transient ischemic attack.  
• 
History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) CNS trauma (e.g., cerebral contusion) 
• 
History or presence of intracranial tumor (e.g., glioma).  History or presence of meningioma 
that in the opinion of the investigator is not clinically significant and is unlikely to result in 
cognitive impairment is not excluded. 
• 
Presence of infections that affect brain function or history of infections that resulted in 
neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, viral or bacterial 
meningitis/encephalitis) 
• 
History or presence of systemic autoimmune disorders that potentially cause progressive 
neurologic disease with associated cognitive deficits (e.g., multiple sclerosis, lupus 
erythematosus, anti-phospholipid antibody syndrome, Behçet disease) 
• 
History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder  
– 
A history of major depression is acceptable if patient had no episode within the past 
year or is considered in remission or depression is controlled by treatment. 
• 
At risk of suicide in the opinion of the investigator 
• 
Alcohol and/or substance abuse or dependence (according to Diagnostic and Statistical 
Manual of Mental Disorders v4 criteria) within the past 2 years  
– 
Nicotine use is allowed. 
– 
Marijuana use is not allowed and must be discontinued 3 months before screening. 
• 
According to the MRI central reader, MRI evidence of a) > 2 lacunar infarcts, b) any 
territorial infarct > 1 cm3, or c) any white matter lesion that corresponds to an overall 
Fazekas score of 3 that requires at least 1 confluent hyperintense lesion on the FLAIR 
sequence, which is ≥20 mm in any dimension. 
• 
Evidence of more than 4 microbleeds and/or areas of leptomeningeal hemosiderosis 
(ARIA-H) as assessed by central review of T2* GRE MRI  
• 
Presence of significant cerebral vascular pathology as assessed by MRI central reader  


 
Crenezumab—F. Hoffmann-La Roche Ltd 
22/Protocol BN29553, Version 2  
• 
Presence on MRI of any cortical stroke regardless of age. 
• 
Inability to tolerate MRI procedures or contraindication to MRI, including, but not limited to, 
presence of pacemakers not compatible with MRI, aneurysm clips, artificial heart valves, 
ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an 
MRI scan; or any other clinical history or examination finding that, in the judgment of the 
investigator, would pose a potential hazard in combination with MRI 
 
The following cardiovascular disorders: 
• 
History or presence of atrial fibrillation except if only one episode that resolved > 1 year ago 
and for which treatment is no longer indicated 
• 
Within the last 2 years, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction, angina pectoris, or New York Heart Association Class II or 
higher cardiac failure) 
• 
Uncontrolled hypertension (e.g., blood pressure generally > 160 mmHg systolic or 
> 95 mmHg diastolic) 
 
The following hepatic/renal disorders: 
• 
Chronic kidney disease of Stage ≥ 4, according to the National Kidney Foundation Kidney 
Disease Outcomes Quality Initiative guidelines for chronic kidney disease 
• 
Confirmed and unexplained impaired hepatic function as indicated by screening AST or 
ALT ≥ 3 the upper limit of normal (ULN) or total bilirubin ≥ 2 ULN  
 
The following infections and immune disorders: 
• 
History of or known to currently have hepatitis B or hepatitis C infection that has not been 
adequately treated in the opinion of the investigator 
• 
Systemically, clinically significantly immunocompromised patients, owing to continuing 
effects of immune-suppressing medication 
• 
Corticosteroids are permitted as long as the dose is < 7.5 mg/day prednisolone equivalent 
and the condition being treated is not expected to deteriorate significantly during the study 
period. 
 
The following metabolic/endocrine disorders: 
• 
Abnormal thyroid function as indicated by abnormal screening tests that are judged to be 
clinically significant by the investigator, or abnormal thyroid function that requires a new 
treatment or an adjustment of current treatment 
– 
A patient may be rescreened if there is no improvement in cognition in the investigator's 
judgment after 3 months of adequate treatment for thyroid function. 
 
History of cancer except: 
• 
If considered to be cured  
OR 
• 
If not being actively treated with anti-cancer therapy or radiotherapy and, in the opinion of 
the investigator, not likely to require treatment in the ensuing 5 years 
• 
For prostate cancer or basal cell carcinoma, no significant progression over the previous 
2 years  
 
Other exclusion criteria: 
• 
Screening folic acid or vitamin B12 levels that are sufficiently low or remain low on retest 
such that deficiency may be contributing to cognitive impairment 
– 
A patient may be rescreened if there is no improvement in cognition after 3 months of 
adequate treatment for folic acid or vitamin B12 deficiency. 


 
Crenezumab—F. Hoffmann-La Roche Ltd 
23/Protocol BN29553, Version 2  
• 
Screening hemoglobin A1c > 8% (retesting is permitted if slightly elevated) or poorly 
controlled insulin-dependent diabetes (past hypoglycemic episodes are considered one 
example of poor control). 
– 
A patient may be rescreened after 3 months to allow optimization of diabetic control. 
• 
Pregnant or lactating, or intending to become pregnant during the study  
• 
Poor peripheral venous access  
• 
Other causes of intellectual disability that may account for cognitive deficits observed at 
screening (e.g., static encephalopathy, closed brain injury, mental retardation). 
– 
This may be based on, for example, patient’s sufficient education or work experience. 
• 
Clinically significant sleep apnea that may be contributing to cognitive impairment.  
Sleep apnea, which in the clinical judgment of the investigator is adequately treated, 
(e.g., continuous positive airway pressure-adequate patient treatment compliance should be 
documented) is allowed. 
• 
Significant respiratory diseases (e.g., severe chronic obstructive pulmonary disease – 
Global Initiative for Obstructive Lung Disease criteria Stage IV. 
• 
Deformity of the lumbosacral region of the spine that in the opinion of the investigator would 
contraindicate lumbar puncture in those who can only be CSF-eligible due to regional lack 
of availability of PET ligands. 
• 
Clinically significantly abnormal screening blood or urine that remain abnormal at retest 
• 
Impaired coagulation (screening PT > 1.2 × the ULN that remains abnormal on retest). 
• 
Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins 
• 
Any other severe or unstable medical condition that, in the opinion of the investigator or 
Sponsor, could be expected to progress, recur, or change to such an extent that it could put 
the patient at special risk, bias the assessment of the clinical or mental status of the patient 
to a significant degree, interfere with the patient’s ability to complete the study assessments, 
or would require the equivalent of institutional or hospital care 
• 
Residence in a skilled nursing facility such as a convalescent home or long-term care 
facility:  Patients who subsequently require residence in these facilities during the study 
may continue in the study and be followed for efficacy and safety provided that they have a 
caregiver who meets the minimum requirement. 
 
The following medications are prohibited for a pre-specified duration prior to study start, as 
indicated, and during the entire period of study participation (patients who start these 
medications during the study may be withdrawn from study treatment): 
• 
Any previous administration of crenezumab or any other therapeutic that targets Aβ 
• 
Any investigational active immunotherapy (vaccine) that is under evaluation to prevent or 
postpone cognitive decline 
• 
Any passive immunotherapy (immunoglobulin) or other long−acting biologic agent that is 
under evaluation to prevent or postpone cognitive decline within 1 year of screening 
• 
Any other investigational treatment within 5 half-lives or 3 months of screening, whichever is 
longer 
• 
Any previous treatment with medications specifically intended to treat Parkinsonian 
symptoms or any other neurodegenerative disorder within 1 year of screening  
– 
Certain medications are acceptable if the patient is taking the medicine for a 
non-neurodegenerative disorder, such as restless leg disorder (e.g., pramipexole) 
• 
Typical antipsychotic or neuroleptic medication within 6 months of screening except as brief 
treatment for a non-psychiatric indication (e.g., emesis) 
• 
Atypical antipsychotics except with intermittent short-term use which is permitted except 
within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive assessment 


 
Crenezumab—F. Hoffmann-La Roche Ltd 
24/Protocol BN29553, Version 2  
• 
Anti-coagulation medications within 3 months of screening 
– 
Anti-platelet treatments (e.g., aspirin, clopidigrel, dipyridamol) are permitted. 
Short-term, peri-operative use of anti-coagulants will not result in discontinuation from 
the study; however, any such use must be discussed with the Sponsor. 
• 
Chronic use of opiates or opioids (including long-acting opioid medication) within 3 months 
of screening  
• 
Intermittent short-term use of short−acting opioid medications for pain is permitted except 
within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive assessment  
• 
Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) within 
1 month of screening and throughout the study 
• 
Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before screening 
– 
Intermittent short-term use of benzodiazepines, buspirone, or short−acting hypnotic 
medication for sleep or anxiety is allowed except within 2 days or 5 half-lives (whichever is 
longer) prior to any neurocognitive assessment.  However, intermittent use of barbiturates is 
not permitted.   
End of Study 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for safety analyses or safety follow-up is received for 
the last patient, whichever occurs later.   
Patients who discontinue from the study drug or who complete the study treatment and do not 
enter the OLE will be asked to return for the collection of safety and efficacy data 4, 16, and 
52 weeks after administration of the last dose of study treatment.  
Additionally, all patients who discontinue from study drug early will be encouraged to return 
for subsequent visits, especially the Week 105 visit (early discontinuation of study treatment 
does not imply study discontinuation). 
 
Length of Study 
LPLV for the double-blind treatment period is expected to occur 153 weeks after the last patient 
is enrolled (i.e., 52 weeks after the last dosing visit at Week 101) for those patients who do not 
enter the OLE. 
Investigational Medicinal Products 
The investigational medicinal product (IMP) for this study is crenezumab. 
Crenezumab will be administered via IV infusion to all patients.  Those randomized to the active 
arm will receive crenezumab at a dose of 60 mg/kg q4w for 26 doses.   
For all infusions (crenezumab and placebo), IV infusions will be administered by appropriately 
trained staff in the clinic or other agreed environment (e.g., the patient’s home); the first 
four infusions of study drug must be administered at the clinic.   
Comparator  
The comparator for this study is placebo. 
Placebo will be administered via IV infusion to all patients.     
IV infusions will be administered by appropriately trained staff in the clinic or other agreed 
environment (e.g., the patient’s home); the first four infusions of study drug must be 
administered at the clinic.   
Non-Investigational Medicinal Products 
Adding a new medication or changing the dose of a medication after randomization should 
occur only for the treatment of an adverse event or as medically indicated.  
The following medications are permitted if the dose and dose regimen have been stable for 
3 months prior to screening and are expected to remain stable after screening or if required for 
treatment of an adverse event after randomization:  


 
Crenezumab—F. Hoffmann-La Roche Ltd 
25/Protocol BN29553, Version 2  
• 
Prescription medications that might affect cognitive function (e.g., antidepressants, 
anticonvulsants) 
• 
Over-the-counter and/or herbal medications, food additive or any other agent or supplement 
intended to improve cognition or reduce cognitive decline 
• 
Medications used to treat a mood or anxiety disorder given as maintenance treatment 
• 
Medications with anticholinergic activity that may impair cognition or attention (e.g., centrally 
acting antihistamines, including brompheiramine, chlorpheniramine, dimenhydrinate, 
diphenhydramine, and doxylamine, or anti spasmodic medicines) 
• 
Intermittent use of centrally acting antihistamines is permitted, but 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)  
• 
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.  However, intermittent use of barbiturates is 
not permitted. 
• 
Dose of benzodiazepine for presurgical and pre-imaging sedation at appropriate visits if 
allowed by Ethics Committee or IRB 
• 
Anti-platelet therapies are permitted during study conduct 
Under certain circumstances, anticoagulation therapy (e.g., temporary usage during surgery, 
or for treatment of deep vein thrombosis) may be permitted.  In these circumstances, 
appropriate safety assessments should be made, e.g., prior to a lumbar puncture.  The 
investigator should discuss with the Sponsor all individual patient cases that require 
anticoagulant therapy proactively whenever possible. 
 
Patients who use oral contraceptives, hormone-replacement therapy, or other maintenance 
therapy should continue their use. 
Statistical Methods 
Primary Analysis 
The primary efficacy outcome measure is the change in CDR-SB from baseline (Week 1) to 
Week 105.  For this primary outcome measure, the difference in mean change from baseline to 
Week 105 between crenezumab- and placebo-treated patients will be estimated using mixed 
model repeated measures (MMRMs) adjusting for disease severity, APOEε4 status, geographic 
region, and the use or non-use of anti-dementia medications at baseline will be used to estimate 
the mean change from baseline for the primary endpoint.  The analysis will include randomized 
patients during the Global Enrollment Phase, with patients grouped according to the treatment 
assigned at randomization.  Data from patients enrolled after the close of Global Enrollment will be 
included in analyses separate from the primary analyses. 
The MMRM model will be used to estimate the mean change from baseline for the primary 
endpoint.  The model will include the change from baseline in CDR-SB as the dependent 
variable.  The effects in the model will include baseline score, treatment group, visit, 
treatment-by-visit interaction and baseline score-by-visit interaction.  Visit week will be treated 
as the repeated variable within a patient.  Patient, treatment, and visit week will be treated as 
class variables.  An unstructured variance−covariance structure will be applied to model the 
within-patient errors; in case of non-convergence, compound symmetry will be used.  
The difference in the changes from baseline of each dose group from placebo will be estimated 
at each time point.  The 95% CI and p-value for treatment difference will be presented. 
All efforts will be made to minimize missing data.  The Sponsor plans to request patients who 
discontinued early from study treatment to return for collection of safety and limited efficacy 
data until Week 105.  To explore the robustness of MMRM results for the primary efficacy 
conclusions, sensitivity analyses (for example, using multiple imputation and pattern mixture 
models) will be performed.  Descriptive summaries of the number of patients with missing data 




 
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determine the critical value for stopping for positive efficacy at the interim analysis.  If the study 
continues beyond the interim analysis, the critical value at the final analysis would be adjusted 
accordingly to maintain the protocol-specified overall type I error rate, per standard Lan-DeMets 
methodology.  This interim analysis would also be reviewed by the iDMC, and the Sponsor 
would remain blinded.  Additional criteria for recommending that the study be stopped for 
positive efficacy may be added to the iDMC Charter.   
Further details (e.g., timing, data to be reviewed by the iDMC, thresholds, etc.) will be 
documented in the interim SAP. The interim SAP will be submitted to relevant health 
authorities at least 2 months prior to the conduct of an interim analysis. 
As information external to the study (e.g., from other compounds) becomes available during the 
conduct of the study, the Sponsor may implement changes to the protocol to incorporate such 
learnings into the study, if possible.  Such learnings may be concerned with endpoints, 
biomarkers, and sample size reassessment due to the variability and size of treatment effect 
observed in other compounds, for example.  The Sponsor could implement such learnings 
through a protocol amendment while being blinded, but without consultation with the iDMC. 
 


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


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


 
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Abbreviation 
Definition 
PD 
pharmacodynamics 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PS1 
presenilin 1 
PS2 
presenilin 2 
q2w 
every 2 weeks 
q4w 
every 4 weeks 
QTcF 
QT interval corrected using Fridericia’s formula 
QoL 
quality of life 
QOL-AD 
Quality of Life-Alzheimer’s Disease scale 
RBR 
Research Biosample Repository 
RPCP 
randomized placebo−controlled period 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous 
SD 
standard deviation 
SMC 
Safety Monitoring Committee 
SUVR 
standardized uptake value ratio 
Tg 
transgenic 
TP 
therapeutic protein 
ULN 
upper limit of normal 
ZCI-AD 
Zarit Caregiver Interview for Alzheimer’s Disease 
 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON ALZHEIMER’S DISEASE 
Alzheimer’s disease (AD) is the most common form of dementia; it affects an estimated 
5.3 million individuals in the United States and 46.8 million people worldwide 
(Alzheimer’s Association 2015; Alzheimer’s Disease International 2015). The disease is 
characterized pathologically by the accumulation of extracellular β-amyloid (Aβ) plaques 
and intracellular neurofibrillary tangles in the brain.  Diagnosis is made through the 
clinical assessment of the neurologic and neuropsychiatric signs and symptoms of AD 
and the exclusion of other causes of dementia.  Approved medical therapies that inhibit 
acetylcholinesterase (AChE) activity or antagonize N-methyl-d-aspartate (NMDA) 
receptors in the brain may temporarily improve the symptoms of AD in some patients but 
do not modify progression of the disease (Cummings 2004).  See the crenezumab 
Investigator’s Brochure for further details on the pathology of AD. 
AD has until recently been diagnosed at the clinical dementia stage.  There is great 
variation in the course of the disease.  However, it has commonly been classified into 
stages by a brief cognitive screening examination, the Mini Mental State Examination 
(MMSE; Folstein et al. 1975) which ranges from a score of 30 (cognitively normal) to 0 
(fully impaired).  MMSE scores of around 20−26 are typically associated with mild AD, 
10−19 with moderate AD, and < 10 with severe AD (Dash and Villemarete-Pittman 2005). 
Although the progressive deterioration in AD is categorized into these three stages: 
mild, moderate, and severe, it more realistically resembles a continuum (Alzheimer’s 
Association 2015).  
AD is a slowly progressive disorder with no fixed events that define its onset 
(Albert et al. 2011).  Prior to a diagnosis of dementia, an individual may experience 
problems with memory, thinking, judgment, and language, but not to a degree sufficient 
to impact day-to-day life or normal functional activities.  This pre-dementia stage is 
commonly referred to as mild cognitive impairment (MCI); MCI alone is not sufficient to 
predict AD.  According to research criteria that have recently become available 
(Albert et al. 2011), the diagnosis of AD can be made with more certainty at the MCI 
stage with the help of biomarkers, and may then be called "MCI due to AD" or 
"prodromal AD (pAD)".   
Biomarker assessments (including positron emission tomography [PET] imaging of 
amyloid and cerebrospinal fluid [CSF] assessments) have confirmed that pAD 
represents a relatively early stage in the continuum of AD.  Mild AD (mAD) represents a 
stage of the disease where patients have not only cognitive, but also clear functional 
deficits.  The specificity of the clinical diagnosis of mild AD can also be increased by 
confirming biomarker changes associated with AD (McKhann et al. 2011).  
Classification schemes of AD are an area of ongoing research and are expected to evolve 
further (e.g., A/T/N; see Jack et al. 2016). 


 
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For potential patients for this clinical trial, evaluations include a thorough clinical 
assessment as well as measurement of disease relevant biomarkers, i.e., markers of 
amyloid accumulation in CSF or on brain PET scans.  Patients to be enrolled may be at 
the clinical stage of MCI (pAD) or mild dementia and will have positive biomarkers 
indicative of AD. (Albert et al. 2011; McKhann et al. 2011). 
The rate of AD progression shows great inter-individual variability with survival 
dependent on many factors, including age at onset.  Population studies 
(Brookmeyer et al. 2002; Larson et al. 2004) suggest a lag of approximately 5 years 
between symptom onset and diagnosis (Roberson et al. 2005; Waring et al. 2005).  
Thereafter, the median survival time following a diagnosis of AD depends strongly on the 
patient’s age at diagnosis.  The median survival time ranges from 8.3 years for persons 
diagnosed with AD at age 65 years to 3.4 years for persons diagnosed at age 90 years 
(Brookmeyer et al. 2002).  On average, individuals live for 3−9 years after diagnosis of 
AD (Helzner et al. 2008), and some survive as long as 20 years.  
1.2 
BACKGROUND ON CRENEZUMAB  
Crenezumab (RO5490245) is a fully humanized monoclonal antibody (mAb) based on a 
human IgG4 framework that contains heavy chain VHIII and light chain VκII subgroup 
sequences.  In vitro, crenezumab binds to Aβ peptides, Aβ1-40 and Aβ1-42, in 
multiple forms (monomers, oligomers, fibrils, and plaques).  Recent results suggest 
higher in vitro binding to oligomers over monomers (Ultsch et al. 2016) and in vivo 
crenezumab binding to brain areas postulated to be high in oligomers in AD Tg mice 
and no binding to the dense core of plaques (data on file).   
In vitro studies demonstrated the ability of crenezumab to block Aβ aggregation, 
promote Aβ disaggregation, and protect neurons from oligomer-induced cytotoxicity 
(Adolfsson et al. 2012).  Crenezumab’s IgG4 backbone confers reduced activation 
of Fcγ receptor (FcγRs) in comparison with IgG1 and was shown to minimize 
FcγR-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 FcγR-mediated microglial 
phagocytosis of oligomers (Adolfsson et al. 2012).  Following in vivo dosing in 
presenilin 2 (PS2) amyloid precursor protein (APP) Tg mice, crenezumab localizes to 
brain areas with putative high concentrations of Aβ 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 Aβ 
oligomers is a rational approach to modify disease progression in AD. 
Amyloid-related imaging abnormalities (ARIAs), indicative of vasogenic edema or 
effusions (ARIA-E) and microhemorrhages (mHs) or leptomeningeal hemosiderosis 
(ARIA-H), have been reported in recent AD trials involving mAbs that bind aggregated 
forms of Aβ and have IgG1 backbones with fully preserved FcγR-mediated effector 
function (Salloway et al. 2009; Ostrowitzki et al. 2012; Fuller et al. 2014; Sevigny et al. 


 
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2015).  As these molecules demonstrated increases in ARIA-E incidence with 
increasing dose and apolipoprotein E4 (APOE4) allele frequency, the dose levels 
administered in past trials have been constrained to limit these events (Salloway et al. 
2009; Sperling et al. 2012; Ostrowitzki et al. 2017).  Crenezumab was designed with an 
IgG4 backbone on the basis of the hypothesis that reducing effector functionshown to 
minimize FcγR-mediated activation of microglia and release of inflammatory cytokines 
upon oligomer engagementwould lower the risk of inducing ARIA-E and ARIA-H, 
possibly by minimizing inflammation at brain vasculature (Wilcock et al. 2006.  A lack 
of binding for crenezumab to vascular amyloid, noted following in vivo dosing in 
PS2APP Tg mice (GNE Study 15-2817B), may additionally reduce the risk of ARIA.   
The safety profile 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 ongoing Phase III program (i.e., 
60 mg/kg IV crenezumab). This dose selection is supported by the data from the 
Phase Ib GN29632 study that investigated higher doses than those in Phase II, 
including 60 mg/kg and 120 mg/kg IV Q4W.  The aim of the high dose is to achieve 
higher systemic exposure and therefore higher brain concentrations, which are predicted 
to result in greater efficacy than 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 CSF following a single IV dose.  Administration of two weekly 
doses of 5 mg/kg crenezumab to hAPP-Tg mice decreased total Aβ levels in soluble 
fractions of brain homogenates and increased plasma total Aβ 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 Aβ 
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. Because of the 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 Aβ levels were observed and 


 
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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). 
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 Aβ1-40 and Aβ1-42).  
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-Aβ 
antibodies in the AD population (i.e., ARIA-E and –H), additional studies were 
performed in Tg-mouse models of AD (hAPP or hAPP/presenilin 1 [PS1]) to evaluate for 
vascular injury (e.g., cerebral mH).  These studies were performed with PRO300491, a 
human/mouse chimeric anti-Aβ mAb that shares a humanized variable domain with 
crenezumab but has the murine IgG2a constant domain with D265A and N297A 
mutations.  This reverse chimera antibody (PRO300491) and crenezumab demonstrate 
comparable binding affinity to human Aβ1-40 and Aβ1-42 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 FcγR 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 


 
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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 Aβ1-40).  These 
findings support the hypothesis that Aβ 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 Aβ 
antibodies. 
Overall, the nonclinical studies demonstrated that crenezumab has an acceptable 
pharmacokinetic (PK) and safety profile to support long-term SC or IV dosing in patients. 
1.2.2 
Summary of Clinical Studies 
As of 27 May 2017, crenezumab has been or is being investigated in a total of 
11 completed or ongoing Phase I, Phase II, and Phase III clinical trials.  Approximately 
1051 subjects have been exposed to crenezumab in these studies (exposure in blinded 
studies is estimated using patient enrollment and study randomization scheme). 
Four Phase I studies (Studies ABE4427g, AB4662g, GP29172, 
) have 
been completed.  Study ABE4427g studied the safety, tolerability, and pharmacokinetics 
of single- and multiple-ascending doses of IV crenezumab in patients with mild to 
moderate AD who were 50−86 years of age.  Study ABE4662g studied the 
pharmacokinetics of IV and SC dosing and the relative bioavailability of crenezumab (SC 
dosing) in healthy volunteers who were 18−50 years of age.  Study GP29172 evaluated 
the pharmacokinetics of SC dosing and the bioequivalence of two formulations of 
crenezumab (SC dosing) in healthy volunteers who were 18-65 years of age.  
 
 
Two Phase I studies GN29632 and 
 are ongoing.  Study GN29632 is a 
dose-escalation study designed to assess safety and tolerability of multiple doses of 
crenezumab (30, 45, 60, and 120 mg/kg IV Q4W) in patients with mild to moderate AD 
followed by an open-label extension (OLE) phase.  
 
 
 
 
 
The Phase II program (ABE4869g, ABE4955g, GN28525, and GN28352), including an 
OLE study (GN28525), was designed to study safety and tolerability, and to initially 
assess the clinical and biomarker effects of crenezumab in two populations within the 
AD spectrum:  an AD dementia population (50−80 years of age) with mild to moderate 
disease severity (MMSE, 18−26); and an at-risk population for AD (30−60 years of age) 
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(autosomal dominant AD [ADAD] population).  The OLE study (GN28525) in patients 
who previously participated in either Study ABE4869g or ABE4955g is complete.  The 
Phase II Study GN28352 is ongoing in an ADAD population.   
The Phase III studies BN29552 and BN29553, which evaluate the efficacy, safety, and 
tolerability of crenezumab in pAD to mAD population (MMSE, 22−30), are ongoing. 
Sections 1.2.2.1−1.2.2.10 summarize the crenezumab clinical studies to date.  Refer to 
the Crenezumab Investigator’s Brochure for further information.   
1.2.2.1 
Study ABE4427g 
Study ABE4427g was a randomized, placebo-controlled, double-blind, Phase I study.  
The study had a single-dose dose−escalation stage followed by a randomized, 
placebo-controlled, double-blind, parallel, multiple-dose stage in patients 50−86 years of 
age who had been diagnosed with mild to moderate AD.  This study assessed four IV 
single dose levels with a range of 0.3−10 mg/kg and three IV multiple dose levels 
(four weekly doses each) with a range of 0.5−5 mg/kg. 
No patients died, discontinued treatment, or withdrew from the study because of an 
adverse event.  The incidence of adverse events was comparable across cohorts, with 
no evidence of a dose-related effect.  No cases of ARIA-E or infusion-related toxicities 
were reported.  Overall, crenezumab appeared to be well tolerated at the doses 
investigated.  The maximum dose administered was 10 mg/kg IV; a maximum-tolerated 
dose was not achieved.  Full details are provided in the crenezumab Investigator’s 
Brochure. 
1.2.2.2 
Study ABE4662g 
Study ABE4662g was a Phase I, single-dose, randomized, parallel-group, open-label 
study that evaluated the safety, tolerability, pharmacokinetics, and bioavailability of 
crenezumab following SC and IV administration in healthy volunteers.  Subjects were 
randomized in a 1:1 ratio to receive a single dose of approximately 1.8 mg/kg 
crenezumab by either SC injection or IV infusion.  Subjects were followed for 85 days 
post-dose.  The study has been completed.  
All subjects received a single dose of crenezumab IV (n = 11) or SC (n = 11).  
Crenezumab was well tolerated, and no deaths, discontinuations due to adverse events, 
or serious adverse events were reported.  Full details are provided in the crenezumab 
Investigator’s Brochure. 
1.2.2.3 
Study ABE4869g 
Study ABE4869g was a Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study designed to evaluate the safety and efficacy of 68 weeks of 
crenezumab treatment in patients 50−80 years of age who had been diagnosed with 
mild to moderate AD (MMSE, 18−26).  A total of 444 patients were enrolled and dosed in 


 
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the study:  184 patients in an SC cohort, 247 patients in the IV cohort, and 13 patients in 
a safety run-in cohort. 
The study was conducted in two parts.  In Part 1, the SC cohort, 184 patients were 
randomized and dosed in a 2:1 ratio (active: placebo) to receive either crenezumab 
300 mg or matching placebo administered via SC injection q2w.  In Part 2, the IV cohort, 
247 patients were randomized and dosed in a 2:1 ratio (active: placebo) to receive either 
crenezumab or matching placebo administered via IV infusion q4w.  Since the highest 
single dose assessed during the Phase I study (10 mg/kg IV) did not elicit any 
dose-limiting toxicities (DLTs), a run-in assessment of the safety and tolerability of 
multiple monthly IV administrations of 15 mg/kg crenezumab was conducted in a limited 
number of patients at selected sites prior to initiating full enrollment in the IV cohort in 
Part 2.  On the basis of the outcome of the safety run-in assessment, the dose of 
crenezumab of 15 mg/kg IV was selected for Part 2.  Safety information is provided in 
Section 1.2.3; full details are provided in the crenezumab Investigator’s Brochure.  
1.2.2.4 
Study ABE4955g 
Study ABE4955g, a Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study, was designed to evaluate the effects of crenezumab on brain 
amyloid burden as assessed by florbetapir-PET and other biomarkers in patients 
50−80 years of age who had been diagnosed with mild to moderate AD (MMSE, 18−26).  
This was a companion study to Study ABE4869g (see Section 1.2.2.3).  The 15 mg/kg 
dose was selected on the basis of the outcome of the safety run-in assessment during 
Study ABE4869g.  Thirty-nine patients were enrolled and dosed in Part 1 (SC cohort) of 
the study; 52 patients were enrolled and dosed in Part 2 (IV cohort).  Patients were 
randomized to receive crenezumab or placebo in a 2:1 ratio.  Safety information is 
provided in Section 1.2.3; full details are provided in the crenezumab Investigator’s 
Brochure.  
1.2.2.5 
Study GN28525 
Study GN28525 was an OLE study to the Phase II Studies ABE4869g and ABE4955g.  
The primary objective of Study GN28525 was to further evaluate the long-term safety 
and tolerability of crenezumab administered via IV or SC doses in patients with AD for 
up to 144 weeks.  Safety information is provided in Section 1.2.3; full details are 
provided in the Crenezumab Investigator’s Brochure. 
1.2.2.6 
Study GN29632 
Study GN29632 is an ongoing, randomized, double-blind, placebo-controlled Phase Ib 
study to evaluate crenezumab in patients with mild to moderate AD (see the 
crenezumab Investigator’s Brochure for further details).  The primary objective is to 
evaluate the safety and tolerability of doses higher than that used in the Phase II studies 
(15 mg/kg IV Q4W), including 60 mg/kg IV Q4W (the dose selected for Phase III) and 
higher.  


 
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Study GN29632 is designed to assess increasing doses of crenezumab in separate 
cohorts.  Dose escalation in new cohorts is governed by dose-limiting criteria and 
reviewed by an unblinded internal safety monitoring committee (SMC).  The purpose of 
the study is to identify early onset and high frequency adverse events, such as ARIA-E.  
If a patient experiences a dose-limiting event (defined below), he or she will not receive 
additional study drug.  If ≥ 2 patients on active treatment in a dose cohort experience a 
dose-limiting event as assessed by the SMC, then an evaluation of all available safety 
data will be performed to determine whether further dosing may continue at that dose or 
the dose reduced to a dose level not associated with DLT. 
The dose-limiting definitions are as follows: 
• 
DLT:  One National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 4.0 (NCI CTCAE v4.0) Grade ≥ 3 adverse event; or Grade ≥ 2 
adverse event falling in specific neurological categories or any infusion-related 
toxicity that occurs within 24 hours after study drug administration that is severe or 
serious or does not resolve promptly with a reduced infusion rate and/or supportive 
care. 
• 
Dose-limiting criteria related to ARIA-E:  A patient who exhibits ARIA-E will not 
receive any additional study drug until the ARIA-E has resolved.  Upon resolution, 
the patient may resume study drug administration at the same dose level; however, 
upon the first recurrence of ARIA-E, the patient will be discontinued from the study. 
• 
Dose-limiting criteria relating to ARIA-H:  A patient who exhibits ARIA-H that 
meets the criteria for superficial siderosis of the CNS; exhibits one new cerebral 
macrohemorrhage; has an increase of ≥ 1 in the number of symptomatic cerebral 
mH compared with screening; or has an increase of ≥ 6 in the number of 
asymptomatic cerebral mH compared with screening will be discontinued from 
treatment. 
 
Patients received double-blind treatment for 13 weeks followed by an OLE.  The initial 
cohort received placebo or crenezumab 30 or 45 mg/kg IV q4w.  There was a specified 
SMC meeting after all patients on the 30 and 45 mg/kg doses reached 13 weeks of 
treatment.  No stopping criteria were met (including no ARIA-E), and no serious adverse 
events related to study drug were observed; no DLTs have been reported.   
A second cohort included 26 patients on a crenezumab dose of 60 mg/kg IV Q4W or 
placebo (randomized in a 5:1 ratio).  There was a specified SMC meeting after all 
patients on the 60 mg/kg dose reached 13 weeks of treatment.  No stopping criteria 
were met (including no ARIA-E), and no serious adverse events related to study drug 
were observed.   
A third cohort included 23 patients on a crenezumab dose of 120 mg/kg IV Q4W or 
placebo (randomized in a 5:1 ratio), with a specified SMC meeting after all patients 


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reached 13 weeks of treatment.  No stopping criteria were met (including no ARIA-E), 
and no serious adverse events related to study drug were observed.     
The majority of patients entered the OLE phase which is ongoing.  Patients in the OLE 
continued on the same dose as per cohort assignment, except for those in the third 
cohort, who by design received a dose of 60 mg/kg IV Q4W.  Additionally, the protocol 
was subsequently amended so that patients in the first cohort are given the option to 
increase to 60 mg/kg IV Q4W.  
Safety data review for all dose groups is regularly conducted.  Safety information is 
provided in Section 1.2.3; full details are provided in the crenezumab Investigator’s 
Brochure. 
1.2.2.7 
Study GP29172 
Study GP29172 was a Phase I, single-dose, randomized, open-label, parallel-group 
study to assess the relative bioavailability of two formulations of crenezumab in healthy 
subjects following SC administration of a single 720 mg dose.  This study has been 
completed. 
 
 
 
 
 
1.2.2.9 
Study GN28352 
Study GN28352 is an ongoing Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study designed to evaluate the safety and efficacy of crenezumab in 
patients 30−60 years of age who are carriers of the PSEN 1 E280A mutation and who do 
not meet criteria for MCI or dementia because of AD.  Safety data are reviewed 
approximately every 6 months by an independent Data Safety Monitoring Board 
(DSMB). 
1.2.2.10 
Study BN29552 
Study BN29552 is an ongoing Phase III, randomized, double-blind, parallel-group, 
placebo-controlled trial designed to evaluate the safety and efficacy of crenezumab in 
patients aged 50−85 years who meet protocol-specified criteria for pAD to mAD.  
Patients are receiving a crenezumab dose of 60 mg/kg IV Q4W vs. placebo; 750 patients 
were planned to be enrolled into this study.  This study is fully enrolled. 
Data are reviewed approximately every quarter by an independent Data Monitoring 
Committee (iDMC). 
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, 
 


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), three completed Phase II studies (ABE4869g,ABE4955g, and GN28525), 
one ongoing Phase II study (GN28352), and two ongoing Phase I studies (
 and 
GN29632).  
The safety and tolerability profile of crenezumab to date supports its continued 
development in both sporadic (idiopathic) AD and ADAD. 
In the Phase II studies in mild to moderate AD, more fatal events and events of 
pneumonia were reported in crenezumab-treated patients versus placebo-treated 
patients.  However, the rates of death and pneumonia in the crenezumab arms were 
within the expected rates for the enrolled population.  Please refer to Sections 1.2.3.2 
and , 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 Aβ; specifically, ARIA-E events have been dose 
limiting for several anti-Aβ antibodies (see Section 1.2.3.4).   
Injection and infusion site reactions have been reported at similar rates in patients 
receiving crenezumab SC or IV and placebo in the Phase II studies. 
No clinically relevant changes have been observed in laboratory parameters, physical 
and neurologic examinations, vital signs, and ECG parameters.  
A Phase Ib study (GN29632) to evaluate doses higher than those used in the 
Phase II studies, including 60 mg/kg IV Q4W and 120 mg/kg IV Q4W, is ongoing.  As of 
the date of protocol release, no new or unexpected safety findings have been 
documented. Specifically, no DLTs, drug−related serious adverse events, and ARIA-E 
events have been reported (see Section 1.2.2.6).   
Detailed safety data from all studies are reported in the crenezumab Investigator’s 
Brochure.   
The Sponsor performs regular review of blinded data from the ongoing studies and, to 
date, has not identified unexpected safety findings.  Furthermore, Study GN29632 is 
overseen by an internal SMC, while an iDMC regularly reviews unblinded data from 
Study BN29552 (and Study BN29553) and a DSMB from study GN28352. 
1.2.3.1 
Overall Adverse Event Profile 
The Phase II program in mild to moderate AD (Studies ABE4869g and ABE4955g) 
comprises the largest completed studies conducted to date with crenezumab. 
The RPCP of the Phase II program in mild to moderate AD was defined as the 
protocol−specified reporting period of the 2:1 randomization IV and SC dose arms of 
Studies ABE4869g and ABE4955g.  The RPCP excluded the safety run-in arm of 
Study ABE4869g.  


 
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In the RPCP, patients were treated over a 68-week period and monitored for safety for 
4 additional weeks if they rolled over into Study GN28525 or for 16 weeks if they did not 
enter Study GN28525 or they discontinued treatment prematurely.  The observation 
period included the 68−week treatment period and the safety follow-up period.  
The safety evaluable database for the Phase II program included 535 patients with mild 
to moderate AD who received at least one dose of study drug.  Of these, 522 patients 
had been randomized to receive crenezumab at either 300 mg q2w SC (n = 148) or 
15 mg/kg q4w IV (n = 198) or to receive placebo (n = 176).  During the RPCP of the 
Phase II program, 9 patients (2.6%) who received crenezumab and 9 patients (5.1%) 
who received placebo withdrew due to adverse events.  There were no imbalances in 
the overall rates of adverse events between patients who received crenezumab and 
patients who receive placebo (91.1% [n = 318] vs. 90.8% [n = 157], respectively).  Serious 
adverse events were reported in 57 patients (16.3%) who received SC or IV crenezumab 
and in 21 patients (12.1%) who received SC or IV placebo.  The imbalance in the rate of 
serious adverse events was mainly due to reports of pneumonia (see Section 1.2.3.3). 
In the completed OLE study of the Phase II studies (Study GN28525), a total of 93.2% of 
patients from the original SC cohort and 87.7% of patients from the original IV cohort 
experienced at least one adverse event.  Reported adverse events were as expected in 
an elderly population with AD, with fall and urinary tract infection being the most 
frequently recorded adverse events.   
1.2.3.2 
Deaths 
During the RPCP of the Phase II program, there were five deaths.  All five deaths 
occurred in patients treated with crenezumab; none was assessed as related to study 
drug by the investigator.  This represents 1.4% of patients who received crenezumab 
compared with 0% of patients who received placebo.  The rate of death in the 
crenezumab arms was within the expected rates of death in the AD clinical trial 
population treated with placebo (0%−1.9%) or with Aβ−directed passive immunotherapy 
(2.1%−2.4%; Salloway et al. 2009, 2014; Doody et al. 2014).   
During the OLE part of the Phase II program, 15 patients died.  Ten of the 15 patients 
had received active crenezumab, and 5 had received placebo during RPCP of the 
Phase II study.  All deaths were assessed as not related to study drug by the 
investigator.   
1.2.3.3 
Pneumonia 
An imbalance in the rates of serious adverse events of pneumonia was observed in the 
RPCP of the Phase II program, with 6 cases (1.7%) in the crenezumab arms and 1 case 
(0.6%) in the placebo arms.  All serious pneumonia cases occurred 7−13 months after 
the first study dose.  Individual cases were confounded by age, smoking history, 
diabetes, obesity, some by previous pneumonia events, and tuberculosis, which are 
known risk factors for developing pneumonia.  An imbalance in non-serious adverse 


 
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events of total lower respiratory tract infection, also driven by pneumonia, was observed 
in the RPCP of the Phase II program, with 5 cases versus 0 cases (1.4% vs. 0%) of 
non-serious pneumonia observed in the crenezumab and placebo arms, respectively. 
The diagnosis of pneumonia was confirmed by chest radiology in 5 of the 11 cases 
reported in crenezumab-treated patients.  The vast majority of cases resolved upon 
standard treatment with antibiotics and in the absence of modification of the study drug 
regimen.  
Overall, the pneumonia rates observed in the RPCP of Studies ABE4869g and 
ABE4955g (3.2% total and 1.7% serious) were slightly higher than those observed 
among Phase III AD clinical trial populations (Henley et al. 2012; Doody et al. 2014; 
Henley et al. 2014; Salloway et al. 2014).  The pneumonia rates in the placebo-treated 
population were slightly lower (0.6%; Henley et al. 2012; Doody et al. 2014; Henley et al. 
2014; Salloway et al. 2014).  However, the precision of these estimates is limited by the 
relatively smaller sample size in crenezumab Phase II data compared to Phase III safety 
populations in bapineuzumab, solanezumab, and semagacestat studies.  The rate of 
pneumonia in crenezumab-treated patients (3.2%) is within the reported incidence of 
pneumonia in the elderly population (2.5%−4.4%; Vila-Corcoles et al. 2009). 
The rate observed during the OLE part of the Phase II program was similar to that 
observed in the RPCP. 
1.2.3.4 
Amyloid−Related Imaging Abnormalities of Edema/Effusion 
and Hemosiderin Deposition 
In the RPCP of the Phase II program in mild to moderate AD, a single case of 
asymptomatic ARIA-E was reported in a patient who received crenezumab.  This patient 
experienced asymptomatic recurrences during the OLE phase.  The proportion of 
patients with ARIA-H was similar in the crenezumab and placebo arms:  new (incident) 
mHs were documented in 11.5% (N = 40) of crenezumab-treated patients versus 12.7% 
(N = 22) of placebo-treated patients.   
1.2.3.5 
Summary 
The safety and tolerability profile of crenezumab to date supports its continued 
development in AD.   
More fatal events and pneumonia cases have been observed during the RPCP 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 deaths and pneumonia in 
crenezumab-treated patients were within the expected ranges for the elderly AD 
population. 


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




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


 
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Florbetapir-Positron Emission Tomography  
An evaluation of the effect of crenezumab on amyloid accumulation was conducted in 
Study ABE4955g.  Overall, there was no evidence of a treatment effect in either the SC 
or IV cohorts on changes from baseline to Week 69 in fibrillary brain amyloid using 
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 mild AD subpopulation (MMSE, 20−26).  There was no 
evidence of a treatment effect in the SC cohort.  In the IV cohort, an overall increase in 
the mean change in Florbetapir-PET standardized uptake value ratio (SUVR) was 
observed for patients in both the placebo and crenezumab treatment arms.  
The estimated mean change in florbetapir-PET SUVR from baseline was less for the 
crenezumab arm than the placebo arm at Weeks 47 and 69.  The treatment difference at 
Week 69 was 0.015 (95% CI, -0.005, 0.035; p = 0.131).  This difference represents a 
58.8% reduction in the rate of amyloid accumulation relative to placebo at Week 69.  
In the mild AD subpopulation, the difference in SUVR increased to 
0.018 (95% CI, -0.006, 0.041; p = 0.135).  This difference represents a 60.4% reduction 
in the rate of amyloid accumulation relative to placebo at Week 69. 
18F-fluordeoxyglucose Positron Emission Tomography 
There was no evidence of a treatment difference between crenezumab and placebo 
mean changes from baseline for either the SC or IV cohorts. 
1.2.6.3 
Plasma and Cerebrospinal Fluid Pharmacodynamic 
Biomarkers 
Plasma and CSF biomarker measurements were evaluated in Study ABE4955g.  
Concentrations of Aβ42, total tau, and phosphorylated tau (p-tau) in CSF were assessed 
in 55 patients with mild to moderate AD (MMSE, 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 
indicated an overall increase in CSF Aβ42 concentrations in patients given crenezumab. 
There was no evidence of a treatment difference between crenezumab and placebo 
mean changes from baseline for either the SC or IV cohorts on either CSF total tau or on 
p-tau. 
Preliminary data from Phase I study ABE4427g (Adolfsson et al. 2012), Phase II 
studies ABE4869g and ABE4955g, and Phase I study GN29632 show that total plasma 
Aβ42 and Aβ40 significantly increased following administration of crenezumab, 
demonstrating peripheral target engagement.  The increase in plasma 
pharmacodynamics is expected on the basis that when the Aβ42 and Aβ40 binds to 


 
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crenezumab it takes on the slow half-life of the antibody and therefore stays in the 
circulation longer.  Please refer to the Investigator Brochure for further information. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Background 
Current therapies for AD focus on symptomatic approaches that target synaptic function 
and cognitive enhancement (Cummings 2004).  Genetic evidence (e.g., Hardy and 
Selkoe 2002; Jonsson et al.2012) has linked the accumulation of Aβ peptides to 
progression of AD (i.e., the amyloid hypothesis).  This hypothesis suggests that 
overproduction of Aβ or failure to effectively clear this peptide leads to AD.  Thus, the 
targeting of Aβ and subsequent displacement of Aβ from the brain is a rational approach 
to modify AD progression. 
After nearly a decade of research on immunologic approaches to treating AD, including 
both active and passive immunization programs, much has been learned about selection 
criteria for antibodies that may maximize efficacy and minimize safety concerns.  
Consequently, the key efficacy considerations for the selection of an appropriate 
molecule to target Aβ included the selection of a mAb that 1) binds potentially toxic 
forms of Aβ, 2) reduces CNS Aβ 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 Aβ that 
binds to Aβ peptides in multiple forms, but notably with high affinity to oligomers 
(Adolfsson et al. 2012; Ultsch et al. 2016).  Crenezumab’s IgG4 backbone confers 
reduced activation of Fcγ receptor (FcγRs) in comparison to IgG1 and was shown to 
minimize FcγR-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 FcγR-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-Aβ 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 (see Section 1.2.2.6), 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 to obtain greater 


 
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efficacy while maintaining a favorable benefit-risk profile (see Section 1.3.3 for further 
details). 
Furthermore, recent advances in the fieldnotably data from the mAb against Aβ 
aducanumab (Sevigny et al. 2015) are supportive of the notion that higher doses than 
perhaps originally postulated (Ostrowitzki et al. 2017) may be needed in this field of 
anti-amyloid antibodies. 
Thus, in this study a dose of 60 mg/kg will be used to potentially enable better efficacy 
to be demonstrated (see Section 1.3.3 for further information on dose).  
1.3.2 
Efficacy 
Study ABE4869g did not meet its co-primary efficacy objectives.  In the higher dose 
cohort, a 16.8% treatment effect in the Alzheimer’s Disease Assessment 
Scale-Cognition, 12 questions (ADAS-Cog-12) change score was seen in the mild to 
moderate AD population (defined as an MMSE score, 18−26) at Week 73 relative to 
placebo (1.78 point difference; 95% CI, -0.89,4.44; p = 0.190) (Cummings et al. 2014; 
Mackey et al. 2016).  The observed treatment effect increased to 23.8% in a 
prespecified analysis in the mAD population (MMSE score, 20−26; 2.24 point difference; 
95% CI, -0.66, 5.15; p = 0.128) and to 35.4% in a subsequent analysis in patients with an 
MMSE of 22−26 (3.44 point difference; 95% CI, 0.24, 6.64).  
No treatment effect was observed in the Clinical Dementia Rating-Sum of Boxes 
(CDR-SB) in either the mild to moderate AD population (3.1%; 0.08 point difference; 
95% CI, -0.77, 0.92; p = 0.853) or mild AD population (-1.0%; -0.02 point difference; 
95% CI, -1.0, 0.96; p = 0.964).  In an exploratory analysis of a subset of patients with 
milder AD (MMSE, 22−26), the treatment effects for CDR-SB change from baseline to 
Week 73 scores relative to placebo increased to 19.6% (1.8 point difference favoring 
crenezumab; 95% CI, -0.65, 1.52).   
In the lower dose (300 mg q2w) SC crenezumab cohort, no treatment effect was 
observed on the ADAS-Cog-12 in any analysis.  A treatment effect toward benefit was 
observed with crenezumab on the CDR-SB at Week 73.  However, in the exploratory 
analysis (MMSE, 22−26), the treatment effect was in the direction of greater decline.  
A treatment effect was also observed on the Alzheimer’s Disease Cooperative 
Study−Activities of Daily Living Inventory (ADCS-ADL); however, it was not 
accompanied by a clear effect on cognition, particularly in the mildest patients.  More 
detail on Phase II results can be found in the crenezumab Investigator’s Brochure.  
When taken together, these data showed a consistent treatment effect only when a 
2.5-fold higher exposure of crenezumab was attained (see Section 1.2.5 for further 
information on the pharmacokinetics of crenezumab). 
Data from the Phase II program also showed that patients with milder disease (i.e., 
MMSE, 22−26) received greater treatment benefit.  Similar findings were observed in the 


 
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biomarker Study ABE4955g.  In the more recent 18-month Phase III global program with 
anti-amyloid antibodies in mild to moderate AD, solanezumab failed to meet primary 
endpoints on cognition and function.  However, treatment effects were observed in a 
prespecified secondary analysis of pooled data from patients with mild AD data from the 
EXPEDITION1 and EXPEDITION 2 studies (Doody et al. 2014), which showed a 
statistically significant effect on cognition (ADAS-Cog subscales 11 and 14) and a trend 
on function (ADCS-ADL).  No clinical benefit was observed in patients with moderate AD 
on any clinical scale, which supported the hypothesis that intervention is needed early in 
the course of disease.  
AD is a slow, progressive disorder with no fixed events that define its onset 
(Albert et al. 2011).  As AD is symptomatic long before dementia is diagnosed, pAD is 
recognized as an intermediate stage between normalcy and dementia.  According to this 
approach, Dubois et al. (2014) proposed the diagnosis of early AD on the objective 
evidence of significantly impaired memory and the presence of hippocampal atrophy on 
MRI, an abnormal pattern of CSF biomarkers, or a specific pattern on PET neuroimaging.  
This approach includes pAD and mAD, irrespective of the dementia diagnosis.  Because 
the accumulation of brain amyloid begins before the onset of AD dementia, it is 
reasonable to postulate that the benefit of anti-amyloid therapy may be greater if initiated 
at this earlier stage of the disease while neuronal damage is more limited.  This supports 
enrollment of patients who have detectable but more subtle cognitive deficits but have 
confirmed pathophysiology.   
The use of a single endpoint across both subpopulations of pAD and mAD is consistent 
with the current understanding of AD.  Use of the CDR-SB as the primary outcome 
measure for studies of prodromal to mild AD enables simultaneous demonstration of 
benefit on primary symptoms (e.g., cognition, function) and clinical relevance 
(Aisen 2009; Aisen et al. 2011) while also ensuring use of a clinical outcome 
assessment with adequate measurement properties (U.S. Food and Drug Administration 
[FDA] 2013). 
The approach to population and appropriate primary endpoint is used by others and 
many clinical programs now target the prodromal to mild AD continuum and use the 
CDR-SB to measure treatment benefit (see AMARANTH [NCT02245737] and PRIME 
[NCT02477800]). 
Collectively, the data support the rationale and strategy for conducting Phase III efficacy 
and safety studies with crenezumab in patients with prodromal to mild AD who have 
biomarker (CSF or PET) evidence of amyloid pathology. 
The purpose of this study is to establish efficacy and safety of crenezumab in patients 
with prodromal to mild AD who may or may not be treated concurrently with approved 
treatments for AD. 


 
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As anti-amyloid therapy is not expected to provide acute improvement of symptoms, a 
minimum of a 100-week, 26−dose treatment period was selected to demonstrate 
enduring clinical benefit on the basis of the mechanism of action of crenezumab that is 
expected to delay disease progression rather than provide symptomatic improvement 
over baseline.  The proposed trial duration is supported by data from Study ABE4869g, 
which demonstrated that the difference in decline between placebo- and 
crenezumab-treated patients’ increased over time.  Placebo decline is expected to be 
greater at 24 months relative to 18 months; this greater decline allows greater potential 
to demonstrate treatment effect. 
The use of the OLE enables a longer assessment of benefit-risk in the target population 
among a large proportion of patients who enter the study and enables those who 
received placebo in the double-blind portion of the trial to obtain the potential benefit of 
active treatment. 
1.3.3 
Dose 
Given the very limited brain penetration observed for IgGs in general (0.2%−0.3% of 
levels in serum; Reiber and Felgenhauer 1987), high-serum drug concentrations will be 
required to increase exposure to the site of action.  
 
 
 
  
The Phase II studies demonstrated consistent treatment effects in the high-dose 
(15 mg/kg q4w IV) arm without eliciting dose-limiting events.  The therapeutic window for 
crenezumab has not been fully explored; increasing the dose in this study has the 
potential to increase efficacy while maintaining a favorable safety profile. 
Higher doses of crenezumab are predicted to increase concentrations in the brain 
compared with the 15 mg/kg IV dose and therefore maintain drug concentrations above 
the in vitro EC50 in the brain throughout the treatment period.  In vitro, the EC50 for 
crenezumab binding to Aβ1-42 monomers and aggregates was approximately 0.2 µg/mL 
and higher target engagement of soluble Aβ was observed with higher crenezumab 
concentrations (Adolfsson et al. 2012).  Crenezumab binds both Aβ1-40 and Aβ1-42 with 
high affinity (7.3 ± 0.6 nM and 11.1 ± 1.2 nM, respectively), inhibits Aβ aggregation, and 
promotes Aβ  disaggregation.  The dose of 60 mg/kg results in a 4-fold increase in 
exposure in all PK parameters compared with 15 mg/kg (see Figure 1). 
 
 
 


 
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Figure 1 Pharmacokinetic Profile Based on Modelling and Simulation Data 
for 60 mg/kg of Crenezumab Administered Intravenously Every 
4 Weeks Compared with 15 mg/kg Crenezumab Administered 
Intravenously Every 4 Weeks 
 
Conc = concentration; Q4w = every 4 weeks; Dotted red line = EC50. 
 
Nonclinical safety data provide 2-, 6-, and 3-fold safety factors for the 60-mg/kg dose at 
steady state on the basis of human equivalent dose, average exposure (AUC), and Cmax, 
respectively, relative to the maximum tested dose of 100 mg/kg per week via SC 
administration in cynomolgus monkeys (see the crenezumab Investigator’s Brochure). 


 
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The dose used in this study, 60 mg/kg IV q4w, along with higher doses, is being 
evaluated in the ongoing Phase Ib Study GN29632 (see Section 1.2.2.6).  This study 
was designed to provide evidence of absence of early safety signals for higher doses of 
crenezumab than had been used in the completed Phase II program.  All patients in this 
study are able to continue into an OLE.  Up to the date of this protocol, no stopping 
criteria had been met (including no occurrences of ARIA-E), and no serious adverse 
events related to study drug had been observed.  Patients who reached 13 weeks of 
treatment all transitioned to an OLE. 
In this Phase III study, use of a higher dose (60 mg/kg) q4w than previously used in the 
Phase II program has been selected as it provides the opportunity to determine the 
optimal benefit-risk for patients. 
1.3.4 
Biomarkers 
In AD, core biomarkers that have been developed that reflect amyloid and neurofibrillary 
tangle pathology, and neuronal degeneration.  Additional biomarkers that reflect other 
aspects of Alzheimer’s pathology are also being developed. 
Two imaging modalities are mainly used as secondary or exploratory endpoints in 
clinical trials of AD:  structural MRI and amyloid PET.  The change in volumes of specific 
brain regions as measured by structural MRI is thought to reflect neuronal loss and 
atrophy.  PET tracers that bind to fibrillar Aβ in the brain (e.g., florbetapir, approved for 
use by the FDA in 2011) are thought to represent accumulation of the Aβ plaques 
(Joshi et al. 2012).   
The CSF is in direct contact with the extracellular space of the brain and biomarkers 
measured in CSF can reflect biochemical changes in the brain.  Low CSF Aβ42  is well 
established as a biomarker of Alzheimer’s pathology (Shaw et al. 2009; 
Le Bastard et al. 2013).  Thus, CSF Aβ levels may provide information on diagnosis and 
disease progression and act as a biomarker for target engagement and for the impact of 
crenezumab on Aβ retention and aggregation.  Changes in CSF total 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.  
1.3.5 
Risk to Patients without Alzheimer’s Disease Pathology 
Due to rigorous screening procedures in this study, including the measurement of CSF 
Aβ1-42 and amyloid-PET scan, it is expected that only patients with AD pathology will be 
enrolled.  In the event that a patient without amyloid pathology is enrolled, no additional 
risk is expected.  However, such a patient may experience other side effects related to 
the product (e.g., infusion reactions, development of ADAs). 


 
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1.3.6 
Overall Benefit-Risk Summary 
The benefit-risk profile of investigation of crenezumab at a dose of 60 mg/kg IV q4w in a 
population of prodromal to mild AD patients is favorable. 
Overall, the benefit-risk assessment of crenezumab is based on the following: 
• 
In Phase II studies in patients with AD: 
– 
In prespecified subanalyses, a consistent effect on ADAS-Cog-12 was 
observed in the subset of patients with mAD (MMSE, 22−26) who were treated 
with crenezumab 15 mg IV q4w versus placebo.  
– 
Treatment with crenezumab was associated with an increase in CSF-Aβ42 
relative to placebo, which was suggestive of target engagement in the CNS. 
– 
ARIA events were within the range of background events in this population.   
A single patient experienced three events of asymptomatic ARIA-E, all of which 
were Grade 1 in severity.  
– 
ARIA appears to be manageable with MRI monitoring and dose-intervention 
algorithms and do not appear to lead to significant adverse outcomes  
(e.g., Sperling et al. 2012a) 
– 
While more deaths and pneumonia cases were observed with crenezumab 
versus placebo, there was no pattern seen in the causes of death, and no 
obvious common mechanism observed for pneumonia 
(e.g., immunosuppression).  In addition, death rates are in line with background 
rates for the placebo-treated or untreated AD population (Henley et al. 2014) 
and in the variability range reported in clinical trials for compounds of this class 
with similar patient populations and durations of treatment (Doody et al. 2014; 
Salloway et al. 2014).  The rate of pneumonia in crenezumab-treated patients 
(3.2%) is within the reported incidence of pneumonia in the elderly population 
(2.5%−4.4%; Chong and Street 2008), and slightly higher than the rate of 
pneumonia cases reported in the active and placebo arms of the solanezumab 
Phase III trials (2.0% and 2.1%, respectively; Doody et al. 2014).  This may be 
attributable to the small patient numbers in the Phase II studies. 
• 
Until January 2018, in the ongoing clinical development program two additional 
ARIA-E (one symptomatic] have been observed.  The benefit−risk profile remains 
unchanged by these adverse events. 
• 
Patients will undergo regular brain MRI monitoring, and discontinuation rules are in 
place in case of ARIA. 
• 
Patients will be asked about prior respiratory history and any risk factors for 
pneumonia at screening.  Those with significant respiratory disease (such as severe 
chronic obstructive pulmonary disease [COPD]) will be excluded.  Pneumonia 
cases, other serious respiratory infections, and deaths will be closely monitored in 
the study, through the requirement to report these cases to the Sponsor within 
24 hours with a full description of the case (see Section 5.4).  


 
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• 
An unblinded iDMC is in place to review adverse events, serious adverse events, 
ARIA-E and ARIA-H findings, and adverse events of special interest (including 
pneumonia) as well as laboratory and ECG data.  Review will occur regularly (e.g., 
quarterly).  Details of the iDMC will be provided in the iDMC Charter (available on 
request). 
2. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of crenezumab 
compared with placebo in patients with prodromal to mild AD.  Specific objectives and 
corresponding endpoints for the study are outlined in Table 1. 






 
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Table 1 Objectives and Corresponding Endpoints (cont.)  
AD = Alzheimer’s disease; ADAS-Cog-11 = Alzheimer’s Disease Assessment Scale-Cognition 11; 
ADAS-Cog (subscale) 13 = Alzheimer’s Disease Assessment Scale-Cognition (subscale) 13; 
ADCS-ADL = Alzheimer’s Disease Cooperative Study−Activities of Daily Living Inventory; 
ADCS-iADL = Alzheimer’s Disease Cooperative Study−Activities of Daily Living Inventory 
Instrumental Subscale; ADL = activity of daily living; ARIA-E = Amyloid−related imaging 
abnormalities-edema/effusion; ARIA-H = Amyloid−related imaging abnormalities-hemosiderin 
deposition; CDR-SB = Clinical Dementia Rating–Sum of Boxes; CDR-GS = Global Score; 
C-SSRS = Columbia Suicide Severity Rating Scale; FAQ = Functional Activities Questionnaire; 
HRQOL = health−related quality of life; IV = intravenous; MMSE = Mini Mental State Exam; 
MRI = magnetic resonance imaging; NPI-Q = Neuropsychiatric Inventory Questionnaire; 
PD = pharmacodynamic; PET=positron emission tomography; PK = pharmacokinetic; 
QOL-AD = Quality of Life-Alzheimer’s Disease Scale; ZCI-AD = Zarit Caregiver Interview for 
Alzheimer’s Disease. 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overview of Study Design 
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to evaluate the safety and efficacy of crenezumab in patients with 
prodromal to mild AD.  
The planned number of patients in the Global Enrollment Phase for this study is 
approximately 750 (375 randomized to crenezumab 60 mg/kg IV and 375 randomized to 
placebo).  
 
 
 
  This China subpopulation may 
include patients enrolled at sites in mainland China, Hong Kong, and/or Taiwan 
(according to applicable Chinese regulations) during both the Global Enrollment Phase 
and the China Extension Phase. 
To maintain a balanced number of patients enrolled in each treatment arm, 
randomization will be stratified by dementia status (pAD vs. mAD), APOE status 
(presence or absence of ε4 allele), anti-dementia medications (present of absent) at 
baseline, and geographic region.  Approximately 250 centers in approximately 
30 countries worldwide will participate in this study.  
Patients will be selected on the basis of clinical diagnosis of probable AD (according to 
the National Institute on Aging/Alzheimer’s Association [NIAAA] Diagnostic Criteria and 
Guidelines for AD; see Appendix 2; McKhann et al. 2011) OR pAD (according to the 
NIAAA Diagnostic Criteria and Guidelines for AD; see Appendix 3; Albert et al. 2011).  


 
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Eligible patients will be 50−85 years old and must have increased brain amyloid as 
indicated by reduced CSF Aβ1-42 concentration (i.e., CSF-enrolled patients) or positive 
amyloid PET scan by qualitative read (i.e., PET-enrolled patients). 
At the time of screening, patients must have a MMSE score of ≥ 22 points and a Clinical 
Dementia Rating-Global Score (CDR-GS) of 0.5 or 1.0.  To confirm objective memory 
impairment, patients must have a Free and Cued Selective Reminding Test−Immediate 
Recall (FCSRT-IR) Cueing Index * of ≤ 0.67 and a total free recall score of ≤ 27. 
 
* FCSRT cueing index is calculated as follows:  
[Free recall score − total score achieved] / [Free recall score − 48] 
Neuroradiologic evaluation will use a standard MRI protocol (including T2*-weighted 
gradient−recalled echo [GRE] and fluid−attenuated inversion recovery [FLAIR]).  
Screening MRIs will be read by a central reader who will exclude patients with other 
structural causes of dementia, significant cerebral vascular pathology, and other relevant 
exclusion criteria (see Section 4.2).  
Patients will be eligible for the study whether or not they are receiving standard-of-care 
symptomatic medications for AD (i.e., ChEIs or memantine, or combination), or medical 
food supplements (e.g., Axonaor Souvenaid).  These medications or supplements 
must have been stable for ≥ 3 months prior to screening.  
The study will consist of a screening period of up to 12 weeks for each patient who 
agrees to participate, signs the informed consent form, and is eligible for the study.  
Eligible patients will then undergo the baseline visit (Week 1), when they will receive the 
first dose following completion of all relevant assessments.  Patients will be enrolled in a 
double−blind treatment period of 100 weeks (26 doses; 60 mg/kg crenezumab or placebo 
by IV infusion Q4W), and a final efficacy and safety assessment 4 weeks following the 
patient’s last dose (Week 105).  Patients will then have the option to enter the OLE study 
if eligible.  Patients who do not enter the OLE will have additional follow-up visits at 16 
and 52 weeks after the last dose, primarily for safety and also for limited efficacy 
assessments.  Assessments for patients who participate in the OLE will be documented 
in a specific OLE protocol.  
Patients who discontinue treatment before Week 105 should be encouraged to return for 
subsequent visits, for non-infusion related assessments, especially the Week 105 visit. 
Patients will undergo brain MRI examinations for monitoring of safety and as a 
biomarker to assess study drug activity.  Patients will also undergo tests to monitor 
safety (including standard safety blood tests, ECG, MRI), as well as tests for cognition, 
function, and quality-of-life (QOL) assessments.  Blood samples for assessment of 
pharmacokinetics, PD biomarkers, and for the measurement of antibodies directed 


 
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against crenezumab and other components of the drug product will be obtained from all 
patients.  
The incidence and nature of adverse events, serious adverse events, ARIA-E and 
ARIA-H abnormalities, adverse events of special interest, and laboratory abnormalities 
will be assessed on a regular basis by an unblinded iDMC.  
An overview of the study design is provided in Figure 2.  A schedule of assessments is 
provided in Appendix 1. 
Figure 2 Overall Study Design 
 
Q4W = every 4 weeks; W/w = week. 
Notes:  The 8-week screening period can be extended up to a total of 12 weeks.  Patients who 
discontinue treatment early will be encouraged to return for subsequent visits, for non-
infusion related assessments, especially the Week 105 visit. 
 
The study consists of four distinct periods: 
Screening:  Up to 12 weeks in length for each eligible patient. 
Double-Blind Treatment:  Double-blind treatment period of 100 weeks.  After screening, 
patients who meet all eligibility criteria will be randomly assigned to one of two arms 
(crenezumab 60 mg/kg or placebo) in a 1:1 ratio.  Starting on Week 1 after baseline 
assessments, each patient will receive 26 total IV infusions of study administered Q4W.  
Primary Analyses Period: Randomization through Week 105 


 
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Long-Term Treatment Follow-up:  Patients who discontinue from the study drug  or 
who complete the study treatment and do not enter the OLE will be asked to return for 
the collection of safety and efficacy data 4, 16, and 52 weeks after administration of the 
last dose of study treatment.  
Additionally all patients who discontinue from study drug early will be encouraged to 
return for subsequent visits, especially the Week 105 visit (early discontinuation of 
study treatment does not imply study discontinuation). 
Open-Label Extension:  All eligible patients will have the opportunity to enter an OLE 
(documented in a separate protocol). 
For the schedule of assessments at each visit, see Appendix 1. 
3.1.2 
Substudies 
Substudies associated with study BN29553 will be described in separate protocols with 
associated informed consents.  Substudy protocols may include data analysis plans that 
utilize assessments from the main study including, but not limited to demographic and 
efficacy assessments. 
3.1.3 
Use of Symptomatic Treatments for Alzheimer’s Disease 
Patients will be eligible for the study whether or not they are receiving symptomatic 
medications for AD (i.e., ChEIs or memantine, or combination, or medical food 
supplements (e.g., Axona or Souvenaid).  These medications and supplements must 
have been stable for ≥ 3 months prior to screening.  
3.1.4 
Data Monitoring Committee 
The incidence and nature of adverse events, serious adverse events, adverse events of 
special interest, ARIA-E and ARIA-H abnormalities, ECG findings, vital signs, laboratory 
abnormalities, and limited efficacy data will be assessed on a regular basis by an iDMC.  
It is anticipated that these assessments will occur approximately every 3 months 
(quarterly). 
The details of iDMC will be provided in the iDMC Charter. 
The iDMC will also undertake evaluation of any planned interim analyses for efficacy or 
futility (see Section 6.). 
3.2 
END OF STUDY 
The end of the study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for safety analyses or safety follow-up is 
received for the last patient, whichever occurs later.  LPLV for the double-blind treatment 
period is expected to occur 153 weeks after the last patient is enrolled (i.e., 52 weeks 
after the last dosing visit at Week 101) for those patients who do not enter the OLE. 


 
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3.2.1 
Long-Term Follow-Up 
Patients who discontinue from the study drug or who complete the study treatment and 
do not enter the OLE will be asked to return for the collection of safety and efficacy 
data 4, 16, and 52 weeks after administration of the last dose of study treatment.  
Additionally all patients who discontinue from study drug early will be encouraged to 
return for subsequent visits, especially the Week 105 visit (early discontinuation of 
study treatment does not imply study discontinuation). 
3.3 
RATIONALE FOR STUDY DESIGN 
This is a Phase III, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study of the efficacy and safety of crenezumab in patients with a diagnosis 
of prodromal to mild AD, as defined by clinically evident symptoms (consistent with the 
NIAAA updated diagnostic research criteria for AD dementia; Appendix 2 [mAD] and 
Appendix 3 [pAD]), increased amyloid burden (defined by CSF or PET criteria), and 
clinical symptoms.  
3.3.1 
Rationale for Treatment Duration 
The treatment duration of 100 weeks (26 doses) for assessment of the primary endpoint 
has been selected on the basis of the mechanism of action of crenezumab that is 
expected to delay disease progression rather than provide symptomatic improvement 
over baseline.  Any difference between treatment and control will be on the basis of a 
reduction in the progression of AD over time.  Ongoing trials in the AD area have used 
durations of at least 18 months.  
The proposed trial duration is supported by data from Study ABE4869g which 
demonstrated that the difference in decline between placebo- and crenezumab-treated 
patients’ increased over time until 18 months (the end of the trial).  Placebo decline is 
expected to be greater at 24 months relative to 18 months; this greater decline allows 
greater potential to demonstrate a treatment effect. 
To ensure that evidence relating to early efficacy is captured, assessments relevant to 
the study objectives will be obtained at 6, 12, and 18 months. 
3.3.2 
Rationale for Long-Term Follow-Up 
The primary objective of the long term follow-up is to estimate the long-term safety of 
crenezumab.  Assessments performed 16 and 52 weeks after the last dose of treatment 
will evaluate the effects of treatment on both efficacy and safety parameters over an 
extended period when no study drug is administered.  These assessments will be 
conducted in all patients who discontinue treatment early  or who complete the study but 
do not enter the OLE.  These assessments will allow for the exploration of the long-term 
effects of exposure to study drug given that continued cognitive decline is expected in 
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3.3.3 
Rationale for Crenezumab Dosage 
The goal of dose selection in this Phase III study is to select a safe treatment regimen 
that also efficiently removes amyloid species from the brains of patients with AD.  In the 
Phase II studies, 198 patients (163 in Study ABE4869g and 35 in Study ABE4955g) 
received the IV crenezumab dose of 15 mg/kg Q4W and demonstrated consistent 
treatment effects in prespecified subgroups without eliciting dose-limiting events.  
This suggested that the therapeutic window for crenezumab had not been fully explored. 
A higher dose than that used in the Phase II program will result in increased brain 
exposure and thus result in increased target engagement and the potential for better 
efficacy (see Section 1.3.3 for further details).  
3.3.4 
Rationale for Patient Population 
The patient selection approach is consistent with the NIAAA research diagnostic criteria  
and guidelines for AD as well as with the Qualification Opinion from the European 
Medicines Agency’s Committee for Medicinal Products for Human Use on the use of 
CSF biomarkers for enrichment of trials in mild to moderate AD dementia (2012), and 
FDA draft guidance for early AD (2013).  The FDA guidance refers to the early stage of 
AD in which individuals present with MCI; however, there is consensus in the field that 
biomarkers of amyloid pathology are expected to also add value to patient selection in 
mAD studies. 
To adequately determine the safety and tolerability of crenezumab, an antibody that 
targets Aβ, the study population should have documented evidence of amyloid pathology.  
Therefore, the study will enroll patients with prodromal to mild AD with evidence of an 
abnormal brain amyloid load.  The rationale for selecting amyloid-positive patients in this 
study is to ensure that patients are enrolled with the pathology targeted by crenezumab.  
The crenezumab Phase III prodromal to mild AD study will enroll patients who have 
biomarker evidence for β-amyloid deposition.  Biomarker enrichment may be important 
for anti-amyloid therapy clinical trials because recent results have demonstrated that 
approximately 20% patients who are enrolled in trials based on a clinical diagnosis of AD 
may not have underlying amyloid pathology as assessed by amyloid-PET 
(Doody et al. 2014; Sperling et al. 2012b).  These results are consistent with screening 
results in Study ABE4995g, in which 16.5% (18/109) of screened patients with a clinical 
diagnosis of AD subsequently screen-failed due to a negative florbetapir amyloid-PET 
scan (visual read).  Lastly, biomarker evidence of amyloid pathology is consistent with 
recently proposed revised diagnostic criteria for AD (McKhann et al. 2011; 
Dubois et al. 2014). 
For enrollment, biomarker evidence of β-amyloid deposition will be assessed either by 
decreased CSF Aβ1−42 levels (using a prespecified cutpoint and the Roche Diagnostics 
Elecsys β amyloid [1−42] immunoassay) or a centralized visual assessment of PET 
brain amyloid imaging.  The Sponsor is proposing to enroll patients on the basis of a 


 
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positive CSF test or PET scan because both approaches have been shown to correlate 
with the “gold standard” of β-amyloid pathology at autopsy (Shaw et al. 2009; 
Clark et al. 2011; Le Bastard et al. 2013).  Both methods have been widely used in the 
research community, and patients or physicians in the trial and in clinical practice 
generally may not have access to both methods.  
This approach is in line with emerging evidence that indicates consistency between 
PET-amyloid imaging and CSF biomarkers.  Low CSF Aβ1-42 shows an inverse 
relationship with in vivo β−amyloid cortical load as measured with Pittsburgh 
Compound B amyloid PET imaging (Fagan et al. 2006; Forsberg et al. 2008; 
Tolboom et al. 2009).  There is concordance on the information obtained via PET 
amyloid imaging and low CSF Aβ1-42 in broad populations across a range of severity of 
AD (pre-dementia through mild to moderate AD; Jagust et al. 2009; Fagan et al. 2011; 
Landau et al. 2013; Zwan et al. 2014).  
As the accumulation of Aβ brain amyloid begins before the onset of AD dementia, it is 
reasonable to postulate that the benefit of anti-amyloid therapy may be greater if initiated 
at an early stage of the disease.  This hypothesis is supported by the Phase II data from 
crenezumab (see the crenezumab Investigator’s Brochure for further details) and 
Phase III data from solanezumab in mild to moderate AD, where the treatment effects 
were observed in patients with mAD, but not in patients with moderate AD 
(Doody et al. 2014).  For this reason, Roche has focused clinical development of 
crenezumab on the prodromal to mild segment of AD.  
Patients in this study are required to meet standard research criteria for AD (according 
to the NIAAA research criteria and guidelines for AD dementia; Appendix 2) in the mild 
dementia stage, or pAD (according to the NIAAA research criteria and guidelines for MCI; 
Appendix 3).  Patients with pAD will present with documented objective evidence of 
deficit in one cognitive domain.  Patients with mAD will present with documented deficits 
in at least two cognitive domains and functional decline.  Overall, the population will 
have an MMSE of ≥ 22 points and a CDR-GS of between 0.5 and 1.0.  The MMSE score 
provides evidence of mild disease severity and the CDR-GS score indicates that the 
patients have noticeable amnestic (pAD) or cognitive and functional (mAD) deficits.  
To ensure that the patients selected are likely to decline over the 2-year trial, 
two approaches have been included.  The first is that all patients have to demonstrate 
amnestic deficits as measured by the cueing index of the FCSRT (e.g., 
Sarazin et al. 2007) and the total free recall score.  The FCSRT Cueing Index of ≤ 0.67 
AND a free recall score of ≤ 27 have been selected.  The cueing index measures the 
ability of the patient to benefit from being reminded by the use of specific cue words in 
order to recall the target word.  To prevent patients who have a high free recall who don’t 
appear to further benefit from reminding from being included simply due to an apparent 
low cueing index, a free recall score of ≤ 27 has also been included.  The cueing index 
cut-off has been generated from internal data sets (prior to the start of this study) in 


 
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which patients with cueing index of ≤ 0.67 had a greater likelihood of decline over the 
proposed time frame.  The FCSRT index is consistent with those published by Sarazin et 
al. (2007) and Auriacombe et al. (2010). 
The second approach to ensure decline is to verify that there is evidence of prior decline 
through observations made by clinician or caregiver and recorded on the diagnostic 
verification form (see Appendix 4).  A caregiver is defined as a person who in the 
investigator’s judgment has frequent and sufficient contact with the patient so as to be 
able to provide accurate information as to the patient’s cognitive and functional abilities, 
who agrees to provide information at clinic visits that require partner input for scale 
completion, and who signs the necessary consent form.  This person should not be a 
caregiver in a paid position (e.g., a healthcare professional). 
To minimize the effects of confounding the cognitive assessments, anyone with a current 
untreated depressive episode (i.e., presence of depressive symptoms) will be excluded 
from the study.  Current treatment for depression will be documented in the electronic 
Case Report Form (eCRF). 
3.3.5 
Rationale for Control Group 
This is a placebo-controlled trial in which patients will be eligible for study participation 
whether or not they are receiving standard of care medications for AD (i.e., ChEIs, 
memantine, or combinations thereof) and/or medical supplements (e.g., Axona or 
Souvenaid).  Given that there are currently no approved disease-modifying compounds 
that could serve as an active control, patients will be randomized to crenezumab or 
placebo.  
3.3.6 
Rationale for Rescue Strategy 
A rescue strategy may be recommended by the iDMC based on their unblinded 
assessment of the benefit-risk profile (see Section 3.1.4).  In the event that this strategy 
is recommended, all ongoing patients will be switched to a lower dose of IV crenezumab.  
In the event that this occurs, the sample size will be adjusted so that all existing patients 
are replaced by new patients at the revised study dose (see Section 6.1). 
3.3.7 
Rationale for Diagnostic Verification 
Enrollment into this trial is subject to adjudication by the Medical Monitor or designated 
staff.  The objective of the adjudication process is to ensure that patients are enrolled on 
the basis of objectively ascertained and well-documented diagnosis of AD 
(McKhann et al. 2011) or pAD symptomatology sufficient to meet the appropriate criteria 
specified in Albert et al. (2011).  The Medical Monitor or assignee may review 
anonymized source documents and may solicit advice from other qualified Sponsor staff 
or external, independent experts to support this adjudication process.  The scope and 
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documents and documented for review on the diagnostic verification form (see 
Appendix 4). 
3.3.8 
Rationale for Primary Outcome Measure 
AD is considered a continuous disease that passes through consecutive stages without 
discrete transition points.  Thus, the use of a single endpoint across both subpopulations 
of prodromal and mild AD is consistent with the current understanding of AD. 
Showing the benefit of new therapies for patients in the early stages of AD is challenging, 
owing to the lack of sensitive assessment tools.  Use of the CDR-SB as the primary 
outcome measure for studies of prodromal to mild AD enables simultaneous 
demonstration of benefit on primary symptoms (e.g., cognition, function) and clinical 
relevance (Aisen 2009; Aisen et al. 2011) while also ensuring use of a clinical outcome 
assessment with adequate measurement properties (FDA 2013). 
Assessments in clinical trials for AD should be obtained across several domains of 
neurologic function, including cognitionmeasured directly by objective tests (cognitive 
endpoints)and functioning.  Improved clinical outcomes in both cognitive and 
functional domains should translate to an overall benefit measured by global 
improvement score, which would demonstrate that a proportion of patients achieved a 
clinically meaningful benefit from this therapy.  
3.3.8.1 
Clinical Dementia Rating-Sum of Boxes 
The Washington University CDR is a global assessment instrument that yields Global 
(GS) and Sum of Boxes (SB) scores.  The CDR is derived from a semi-structured 
interview with the patient and an appropriate informant, and it rates impairment in 
six categories (memory, orientation, judgment and problem solving, community affairs, 
home and hobbies, and personal care) on a 5-point scale in which no impairment = 0, 
questionable impairment = 0.5, and mild, moderate, and severe impairment = 1, 2, and 3, 
respectively.  From the six individual category ratings or box scores the CDR-GS is 
established by clinical scoring rules where CDR 0 = no dementia and CDR of 0.5, 1, 2, or 
3 = questionable, mild, moderate, or severe dementia, respectively (Morris 1993).  
The CDR-SB score is a detailed quantitative general index that provides more 
information than the CDR-GS in patients with prodromal to mild dementia 
(O'Bryant et al. 2010).  In particular, the CDR-SB has been proposed for use in 
longitudinal assessment of dementia and is widely used in AD studies as a global 
measure of disease progression (Lynch et al. 2006).  Furthermore, as proposed in the 
FDA’s draft guidance for developing drugs for the early stages of disease, the use of a 
composite scale, validated in early stage patients to assess both cognition and function 
as a single primary efficacy outcome measure, is appropriate.  The CDR-SB score fulfills 
these criteria (FDA 2013) and is now being utilized as the sole primary endpoint in 
studies of patient populations that encompass prodromal to mild AD including 
AMARANTH (https://clinicaltrials.gov/ct2/show/NCT02245737) and PRIME 
(https://clinicaltrials.gov/ct2/show/NCT02477800). 


 
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The proposal for the Phase III program is to employ the CDR-SB as a primary endpoint 
for an integrated functional/global assessment, and the ADAS-Cog-13 and 
ADAS-Cog-11, ADCS-iADL and ADCS-ADL as key secondary endpoints to 
additionally support assessment of cognition as a core symptom of this disease (ADAS-
Cog) and function (ADCS-ADL instrumental function subscore and total score), 
separately (see Section 3.3.9). 
3.3.9 
Rationale for Key Secondary Outcome Measures 
The key secondary endpoints for studies in prodromal to mild AD have been chosen to 
reflect the treatment benefit on cognitive and functional endpoints.  The rationale for 
selection of key secondary endpoints is provided in Sections 3.3.9.1 (ADAS-Cog) and 
3.3.9.2 (ADCS-iADL and ADCS-ADL total score). 
3.3.9.1 
Alzheimer’s Disease Assessment Scale-Cognition 
The ADAS-Cog is an examiner-administered battery that assesses multiple cognitive 
domains, including memory, comprehension, praxis, orientation, and spontaneous 
speech (Rosen et al. 1984; Mohs et al. 1997).  The ADAS-Cog is considered the 
standard primary endpoint in AD treatment studies (Mani 2004) and is generally 
considered the gold standard for assessing cognitive function in AD clinical studies 
(Cano et al. 2010; Sevigny et al. 2010).  The 12-item version of the scale does not 
include adequate assessment of executive function particularly for patients in the early 
stages of AD.  In the crenezumab Phase II program, the 12-item version (ADAS-Cog-12) 
was used in patients with mild to moderate AD (defined as screening MMSE score of 
18−26), and a treatment effect was detected in a subpopulation of patients with mAD 
(MMSE, 22−26).  Because of the expected increased sensitivity to detect a treatment 
effect in patients on the milder part of the AD continuum, the Sponsor proposes to use 
the 13-item version (ADAS-Cog-13), which is supplemented with executive measures 
sensitive to change in patients at the milder end of the disease spectrum 
(Mohs et al. 1997) as the key secondary endpoints.  
3.3.9.2 
ADCS-iADL and ADCS-ADL Total Score (Vellas et al. 2008)  
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in patients with AD.  The ADCS-ADL covers both basic ADL (e.g., eating and 
toileting) and more complex "instrumental" ADL or iADL (e.g., using the telephone, 
managing finances, preparing a meal).  The ADCS-ADL scale with its  resulting total 
score is considered a standard (co-)primary endpoint in treatment trials in patients in 
the mild to moderate dementia stage of AD.  Because of the expected increased 
sensitivity to detect a treatment effect in patients on the milder part of the AD 
continuum, the Sponsor will use both the ADCS-ADL total score and also the 
ADCS-iADL subscore as a key secondary endpoint in order to capture meaningful 
clinically evident decline on functional abilities. 


 
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3.3.10 
Rationale for Pharmacokinetic Sampling 
A sparse sampling schedule is being utilized to minimize patient burden and still provide 
an adequate characterization of the population PK profile of crenezumab.  The PK data 
may be compared with available data from other crenezumab studies and may be used 
to assess exposure-response relationships for relevant imaging,  plasma PD biomarkers, 
ECG, and efficacy and safety outcomes in patients with prodromal to mild AD, as 
appropriate. 
3.3.11 
Rationale for Biomarker Assessments 
The biomarker assessments described in Section 3.3.11.1 (CSF), Section 3.3.11.2 (PET 
imaging), and Section 3.3.11.3 (brain volumetry) will be used to investigate the effect of 
crenezumab on the underlying pathology of AD in the clinical trial population. 
3.3.11.1 
Cerebrospinal Fluid Biomarkers 
Amyloid plaque deposition, neurofibrillary tangle formation, and neuronal degeneration 
are known pathologic features of AD.  Decreased CSF Aβ1−42 and elevated CSF total-tau 
(t-tau) and p-tau are considered a biochemical signature of AD.  Accumulating evidence 
suggests that low CSF Aβ1−42 reflects underlying amyloid plaque pathology, whereas 
increased t-tau and p-tau levels may be reflective of neurodegeneration and/or tau 
pathology. CSF assessment will be utilized as a screening biomarker for BN29553.  
3.3.11.2 
Positron Emission Tomography Imaging Biomarker 
The definitive postmortem diagnosis of AD requires the presence of progressive 
dementia during life and the presence of neuropathological lesions (i.e., neuritic plaques 
composed of β-amyloid aggregates and neurofibrillary tangles formed from 
hyperphosphorylated tau protein).  However, imaging approaches using ligands that 
demonstrate high affinity for aggregated amyloid and tau are able to provide an 
assessment of deposition in vivo, which can be evaluated over time (Clark et al. 2011).  
PET imaging assessment will be utilized as a screening biomarker for BN29553. 
3.3.11.3 
Brain Volumetry 
A characteristic feature of AD is neuronal destruction.  Such neuronal loss is 
demonstrated at a macroscopic level by progressive cerebral atrophy, which can be 
tracked on MRI (Fox and Kennedy 2009).  Multiple changes in brain anatomy beyond 
those associated with normal aging have been reported in patients with AD 
(e.g., enlarged ventricles, decreased cortical thickness, decreased total brain volume, 
and hippocampal atrophy), and there is evidence for strong correlations between these 
imaging biomarkers and functional cognitive measures (Li and Wahlund 2011).  Based 
on volumetric MRI measurements, the 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. 


 
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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 reader. 
4. 
MATERIALS AND METHODS  
This study will include approximately 750 male and female patients with increased 
amyloid burden (defined by CSF or PET criteria), objective memory impairment indicated 
by cognitive assessment, and a diagnosis of probable AD or pAD based on diagnostic 
verification (and relevant NIAAA criteria; see Appendix 2 [probable AD] and Appendix 3 
[pAD]) enrolled during the Global Enrollment Phase.  Additional criteria are defined in 
Section 4.1. 
 
 
 
 
If the patient is currently receiving medications for AD, doses must have been stable for 
at least 3 months prior to screening. 
Patients who discontinue from this study are not permitted to be enrolled and 
re-randomized for a second course of treatment. 
4.1 
INCLUSION CRITERIA 
Patients must meet the following criteria for study entry: 
• 
Able to provide written consent signed by the patient (co-signed by the patient’s 
legally authorized representative, if required by the local regulations, guidelines, and 
independent ethics committee or institutional review board [IRB]) 
• 
Aged between 50 and 85 years at screening, inclusive 
• 
Weight between 40 and 120 kg, inclusive 
• 
Availability of a person (referred to as the “caregiver” throughout this protocol) who 
in the investigator's judgment: 
– 
Has frequent and sufficient contact with the patient to be able to provide 
accurate information regarding the patient’s cognitive and functional abilities, 
agrees to provide information at clinic visits (which require partner input for 
scale completion), signs the necessary consent form, and has sufficient 
cognitive capacity to accurately report upon the patient’s behavior and cognitive 
and functional abilities. 
– 
Is in sufficiently good general health to have a high likelihood of maintaining the 
same level of interaction with the patient and participation in study procedures 
throughout the study duration. 
Every effort should be made to have same caregiver participate throughout the 
duration of the study.  
• 
Fluency in the language used at the study site 


 
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• 
Willingness and ability to complete all aspects of the study (including MRI, lumbar 
puncture [if applicable], clinical genotyping, and PET imaging [if applicable]); the 
patient should be capable of completing assessments either alone or with the help 
of the caregiver 
• 
Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to 
perform the neuropsychological testing (eye glasses and hearing aids are permitted) 
• 
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive methods that result in a failure rate 
of < 1% per year during the treatment period and for at least 8 weeks after the last 
dose of study drug. 
– 
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (≥ 12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus). 
– 
Examples of contraceptive methods with a failure rate of  < 1% per year include 
bilateral tubal ligation, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, 
and copper intrauterine devices. 
– 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception. 
• 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use contraceptive measures, and agreement to refrain from donating sperm, as 
defined below: 
– 
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at least 
8 weeks after the last dose of study drug to avoid exposing the embryo.  Men must 
refrain from donating sperm during this same period. 
– 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and 
withdrawal are not acceptable methods of contraception.  
• 
Evidence of the AD pathological process, by a positive amyloid assessment either 
on CSF Aβ1−42 levels as measured on the Elecsys β-Amyloid(1-42) Test System OR 
amyloid PET scan by qualitative read by the core/central PET laboratory.  
• 
Demonstrated abnormal memory function at FCSRT/MMSE consent or at main 
screening [FCSRT cueing index  ≤ 0.67 AND free recall ≤ 27] 
• 
Evidence of retrospective decline confirmed by a diagnosis verification form (see 
Appendix 4) 


 
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• 
Mild symptomatology, as defined by a screening MMSE score of ≥ 22 points and 
CDR-GS of 0.5 or 1.0.  MMSE may be performed at FCSRT/MMSE consent or 
main screening. 
• 
Meets NIAAA core clinical criteria for probable AD dementia (see Appendix 2; 
McKhann et al. 2011) or pAD (consistent with the NIAAA diagnostic criteria and 
guidelines for MCI; Appendix 3; Albert et al. 2011)  
• 
If the patient is receiving symptomatic AD medications, the dosing regimen must 
have been stable for 3 months prior to screening.  If the patient is taking medical 
food supplements (e.g., Axona® or Souvenaid®), these must also have been stable 
for 3 months prior to screening. 
• 
Inclusion is subject to review of clinical criteria at screening (diagnostic verification 
form; see Appendix 4). 
• 
Patient must have completed at least 6 years of formal education after the age of 
5 years  
• 
For enrollment into the China Extension Phase, patients must have residence in 
mainland China, Hong Kong, or Taiwan and be of Chinese ancestry. 
 
4.2 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Any evidence of a condition other than AD that may affect cognition, including but 
not limited to, frontotemporal dementia, dementia with Lewy bodies, vascular 
dementia, Parkinson’s disease, corticobasal degeneration, Creutzfeldt-Jakob 
disease, progressive supranuclear palsy, frontotemporal degeneration, Huntington’s 
disease, normal pressure hydrocephalus, or hypoxia. 
• 
Seizure history that, in the opinion of the investigator, is likely to result in 
cognitive impairment 
• 
History or presence of clinically evident vascular disease that could potentially affect 
the brain (e.g., clinically significant carotid, vertebral stenosis or plaque; aortic 
aneurysm; intracranial aneurysm; cerebral hemorrhage; arterio-venous 
malformation). 
• 
History or presence of any stroke with clinical symptoms within the past 2 years, or 
documented history within the last 6 months of an acute event consistent, in the 
opinion of the investigator, with a transient ischemic attack.  
• 
History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) CNS trauma (e.g., cerebral contusion) 
• 
History or presence of intracranial tumor (e.g., glioma).  History or presence of 
meningioma that, in the opinion of the investigator, is not clinically significant and is 
unlikely to result in cognitive impairment is not excluded. 
• 
Presence of infections that affect brain function or history of infections that resulted 
in neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, viral or bacterial 
meningitis/encephalitis) 


 
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• 
History or presence of systemic autoimmune disorders that potentially cause 
progressive neurologic disease with associated cognitive deficits (e.g., multiple 
sclerosis, lupus erythematosus, anti-phospholipid antibody syndrome, Behçet 
disease) 
• 
History of schizophrenia, schizoaffective disorder, major depression, or bipolar 
disorder  
– 
A history of major depression is acceptable if patient had no episode within the 
past year or is considered in remission or depression is controlled by treatment. 
• 
At risk of suicide in the opinion of the investigator 
• 
Alcohol and/or substance abuse or dependence (according to Diagnostic and 
Statistical Manual of Mental Disorders v4 criteria) within the past 2 years  
– 
Nicotine use is allowed. 
– 
Marijuana use is not allowed and must be discontinued 3 months before 
screening. 
• 
According to the MRI central reader, MRI evidence of a) > 2 lacunar infarcts, b) any 
territorial infarct > 1 cm3, or c) any white matter lesion that corresponds to an overall 
Fazekas score of 3 that requires at least 1 confluent hyperintense lesion on the 
FLAIR sequence, which is ≥ 20 mm in any dimension. 
• 
Evidence of more than 4 microbleeds and/or areas of leptomeningeal hemosiderosis 
(ARIA-H) as assessed by central review of T2* GRE MRI (see MRI Charter for 
further details).  
• 
Presence of significant cerebral vascular pathology as assessed by MRI central 
reader (see MRI Charter for further details). 
• 
Presence on MRI of any cortical stroke regardless of age. 
• 
Inability to tolerate MRI procedures or contraindication to MRI, including, but not 
limited to, presence of pacemakers not compatible with MRI, aneurysm clips, 
artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or 
body that would contraindicate an MRI scan; or any other clinical history or 
examination finding that, in the judgment of the investigator, would pose a potential 
hazard in combination with MRI 
 
The following cardiovascular disorders: 
• 
History or presence of atrial fibrillation except if only one episode that resolved 
> 1 year ago and for which treatment is no longer indicated 
• 
Within the last 2 years, unstable or clinically significant cardiovascular disease 
(e.g., myocardial infarction, angina pectoris, or New York Heart Association Class II 
or higher cardiac failure) 
• 
Uncontrolled hypertension (e.g., blood pressure generally > 160 mmHg systolic or 
> 95 mmHg diastolic) 
 


 
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The following hepatic/renal disorders: 
• 
Chronic kidney disease of Stage ≥ 4, according to the National Kidney Foundation 
Kidney Disease Outcomes Quality Initiative guidelines for chronic kidney disease 
• 
Confirmed and unexplained impaired hepatic function as indicated by screening 
AST or ALT ≥ 3 the upper limit of normal (ULN) or total bilirubin ≥ 2 ULN  
 
The following infections and immune disorders: 
• 
History of or known to currently have hepatitis B or hepatitis C infection that has not 
been adequately treated in the opinion of the investigator 
• 
Systemically, clinically significantly immunocompromised patients, owing to 
continuing effects of immune-suppressing medication 
• 
Corticosteroids are permitted as long as the dose is < 7.5 mg/day prednisolone 
equivalent and the condition being treated is not expected to deteriorate significantly 
during the study period. 
 
The following metabolic/endocrine disorders: 
• 
Abnormal thyroid function as indicated by abnormal screening tests that are judged 
to be clinically significant by the investigator, or abnormal thyroid function that 
requires a new treatment or an adjustment of current treatment 
– 
A patient may be rescreened if there is no improvement in cognition in the 
investigator's judgment after 3 months of adequate treatment for thyroid 
function. 
 
History of cancer except: 
• 
If considered to be cured  
OR 
• 
If not being actively treated with anti-cancer therapy or radiotherapy and, in the 
opinion of the investigator, not likely to require treatment in the ensuing 5 years 
• 
For prostate cancer or basal cell carcinoma, no significant progression over the 
previous 2 years  
 
Other exclusion criteria: 
• 
Screening folic acid or vitamin B12 levels that are sufficiently low or remain low on 
retest such that deficiency may be contributing to cognitive impairment 
– 
A patient may be rescreened if there is no improvement in cognition after 
3 months of adequate treatment for folic acid or vitamin B12 deficiency. 
• 
Screening hemoglobin A1c (HbA1C) > 8% (retesting is permitted if slightly elevated) 
or poorly controlled insulin-dependent diabetes (past hypoglycemic episodes are 
considered one example of poor control). 
– 
A patient may be rescreened after 3 months to allow optimization of diabetic 
control. 


 
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• 
Pregnant or lactating, or intending to become pregnant during the study  
• 
Poor peripheral venous access  
• 
Other causes of intellectual disability that may account for cognitive deficits 
observed at screening (e.g., static encephalopathy, closed brain injury, mental 
retardation). 
– 
This may be based on, for example, patient’s sufficient education or work 
experience. 
• 
Clinically significant sleep apnea that may be contributing to cognitive impairment. 
Sleep apnea, which in the clinical judgment of the investigator is adequately 
treated, (e.g., continuous positive airway pressure−adequate patient treatment 
compliance should be documented) is allowed.  
• 
Significant respiratory diseases (e.g., severe COPD – Global Initiative for 
Obstructive Lung Disease criteria Stage IV). 
• 
Deformity of the lumbosacral region of the spine that in the opinion of the 
investigator would contraindicate lumbar puncture in those who can only be 
CSF-eligible due to regional lack of availability of PET ligands. 
• 
Clinically significantly abnormal screening blood or urine that remain abnormal at 
retest 
• 
Impaired coagulation (screening PT > 1.2 × the ULN that remains abnormal on retest). 
• 
Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins 
• 
Any other severe or unstable medical condition that, in the opinion of the 
investigator or Sponsor, could be expected to progress, recur, or change to such an 
extent that it could put the patient at special risk, bias the assessment of the clinical 
or mental status of the patient to a significant degree, interfere with the patient’s 
ability to complete the study assessments, or would require the equivalent of 
institutional or hospital care 
• 
Residence in a skilled nursing facility such as a convalescent home or long-term 
care facility:  Patients who subsequently require residence in these facilities during 
the study may continue in the study and be followed for efficacy and safety provided 
that they have a caregiver who meets the minimum requirement (refer to 
Section 4.1). 
 
The following medications are prohibited for a pre-specified duration prior to study start, 
as indicated, and during the entire period of study participation (patients who start these 
medications during the study may be withdrawn from study treatment): 
• 
Any previous administration of crenezumab or any other therapeutic that targets Aβ 
• 
Any investigational active immunotherapy (vaccine) that is under evaluation to 
prevent or postpone cognitive decline 


 
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• 
Any passive immunotherapy (immunoglobulin) or other long−acting biologic agent 
that is under evaluation to prevent or postpone cognitive decline within 1 year of 
screening 
• 
Any other investigational treatment within 5 half-lives or 3 months of screening, 
whichever is longer 
• 
Any previous treatment with medications specifically intended to treat Parkinsonian 
symptoms or any other neurodegenerative disorder within 1 year of screening  
– 
Certain medications are acceptable if the patient is taking the medicine for a 
non-neurodegenerative disorder, such as restless leg disorder (e.g., pramipexole) 
• 
Typical antipsychotic or neuroleptic medication within 6 months of screening except 
as brief treatment for a non-psychiatric indication (e.g., emesis) 
• 
Atypical antipsychotics except with intermittent short-term use which is permitted 
except within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive 
assessment 
• 
Anti-coagulation medications within 3 months of screening 
– 
Anti-platelet treatments (e.g., aspirin, clopidigrel, dipyridamol) are permitted. 
Short-term, peri-operative use of anti-coagulants will not result in 
discontinuation from the study; however, any such use must be discussed with 
the Sponsor (see section 4.5.1 for further details). 
• 
Chronic use of opiates or opioids (including long-acting opioid medication) within 
3 months of screening  
• 
Intermittent short-term use of short−acting opioid medications for pain is permitted 
except within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive 
assessment  
• 
Stimulant medications (amphetamine, methylphenidate preparations, or modafinil) 
within 1 month of screening and throughout the study 
• 
Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before 
screening 
– 
Intermittent short-term use of benzodiazepines, buspirone, or short−acting hypnotic 
medication for sleep or anxiety is allowed except within 2 days or 5 half-lives 
(whichever is longer) prior to any neurocognitive assessment.  However, intermittent 
use of barbiturates is not permitted.   
• 
Permitted medications are described in Section 4.5.1  
4.3 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
Randomization will be performed centrally using an interactive voice/Web response 
system (IxRS) that uses stratified block randomization.  After screening, patients who 
meet all eligibility criteria will be randomly assigned to 1 of 2 treatment groups 
(crenezumab or placebo).  Patients will be randomized in a drug to placebo ratio of 1:1.  


 
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Randomization to treatment allocation will also be stratified by dementia status (pAD vs. 
mAD), patient APOEε4 status (presence or absence of ε4 allele), background 
medication at baseline (present, absent) and geographic region.  Stratification factors 
will ensure balance of these strong prognostic factors across treatment arms and 
facilitate unbiased estimate of treatment effect in subgroups based on disease severity 
and geographic regions.  
Except in circumstances in which a health authority, Ethics Committee (EC), or IRB 
requires the patient be told of his or her APOE status, patients, investigators, central 
MRI reader, and the cognitive test rater as well as the Sponsor will be blinded to 
individual patient APOE genotype results. APOE status information will be supplied 
directly to the IxRS vendor by the central testing laboratory so that the information can 
be incorporated at the time of randomization.  In cases where APOE status is already 
known, these prior results will be blinded to the Sponsor and as much as possible to the 
site and central MRI reader.  
The study is to be conducted in a double-blind manner to minimize potential bias from 
investigators and patients.  The Sponsor will be blinded to study treatment.  The Master 
Randomization or Master Medication List will not be available at the study center, to 
Roche monitors, project statisticians, or to the project team at Roche with the exception 
of those responsible for performing PK, PD, and ADA assessments.  Personnel 
responsible for performing PK, PD and ADA assessments will be unblinded to patients’ 
treatment assignments to identify appropriate samples to be analyzed.  Samples from 
patients assigned to the placebo group will not be analyzed except by request (e.g., to 
evaluate a possible error in dosing).   
If unblinding is necessary for patient management (e.g., in the case of a serious adverse 
event for which patient care might be affected by knowledge of treatment assignment), 
the investigator will be able to break the treatment code by contacting the IxRS.  
Treatment codes should not be broken except in emergency situations.  If the 
investigator wishes to know the identity of the study treatment for any other reason, he 
or she should contact the Medical Monitor directly.  The investigator should document 
and provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a serious adverse event). 
For regulatory reporting purposes, and if required by local health authorities, the 
Sponsor will break the treatment code for all serious, unexpected suspected adverse 
reactions that are considered by the investigator or Sponsor to be related to study drug. 
4.4 
STUDY TREATMENT  
The investigational medicinal product (IMP) for this study is crenezumab. 


 
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4.4.1 
Formulation, Packaging, and Handling 
4.4.1.1 
Crenezumab and Placebo 
Crenezumab and placebo will be supplied by the Sponsor as a solution buffered at 
pH 5.5 (using arginine succinate solution that contains polysorbate 20 and water for 
injection) in 6.0 mL glass vials.  For information on formulation and handling of 
crenezumab, see the pharmacy manual and crenezumab Investigator’s Brochure. 
4.4.2 
Dosage, Administration, and Compliance 
4.4.2.1 
Crenezumab and Placebo 
Crenezumab or placebo will be administered via IV infusion to all patients.  Those 
randomized to the active arm will receive crenezumab at a dose of 60 mg/kg q4w for 
26 doses.   
For all infusions (crenezumab and placebo), IV infusions will be administered by 
appropriately trained staff in the clinic or other agreed environment (e.g., the patient’s 
home); the first four infusions of study drug must be administered at the clinic.   
The IV drug will be prepared and infused from the IV bag by infusion pump.  The bag 
size, drug preparation, and infusion rates are all described in the pharmacy manual 
guidance.  All patients will be monitored for a minimum of 1 hour after dosing, and vital 
signs will be measured immediately following completion of the infusion and ≥ 60 minutes 
after the end of the infusion as described in the pharmacy manual. 
For the IV dose calculation, the patient’s screening weight (reference weight) should be 
used.  If the current weight changes by ≥ 10%, the current weight should become the 
new reference weight for subsequent dosing.  If the patient’s weight changes again by 
≥ 10% from the reference weight, the IV dose should again be recalculated.  See the 
pharmacy manual for further information. 
Crenezumab will be administered to patients under close medical supervision in a 
setting with access to 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.  In any patient who 
develops anaphylaxis, anaphylactoid, or serious hypersensitivity reactions, a blood 
sample will be collected for analyses of antibodies to crenezumab and/or other 
components of the drug product. In addition, for any patient suspected of developing 
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discontinuation of dosing, a washout ADA sample (16 weeks post-dose) and concurrent 
PK sample must be collected. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF.  Adverse events associated with an overdose or 
incorrect administration of study drug should be recorded on the Adverse Event eCRF. 
At applicable sites, following the first 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 (please refer 
to Section 4.6 for details).  
4.4.2.2 
Non-Investigational Medicinal Products 
All patients who are enrolled using PET amyloid evaluation at baseline and those in any 
relevant substudies will be assessed by PET imaging using an appropriate PET ligand.  
Details of substudies are described in separate protocols. 
According to EU guidance, the PET ligands used in the context of this study (and 
associated substudies) 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 (and associated substudies) please refer to Section 5.7. 
4.4.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (crenezumab or placebo) will be provided 
by the Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of IMPs, using the IxRS to confirm the shipment condition and 
content.  Any damaged shipments will be replaced. 
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site's method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log. 
4.4.4 
Post-Trial Access to Crenezumab 
The Sponsor will offer post-trial access to the study drug (crenezumab) free of charge to 
eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 


 
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A patient will be eligible to receive study drug after completing the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being  
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 
A patient will not be eligible to receive study drug after completing the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient's country and is reasonably 
accessible to the patient (e.g., is covered by the patient's insurance or wouldn't 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for AD 
• 
The Sponsor has reasonable safety concerns regarding the study drug as treatment 
for AD 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient's country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
4.5 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, nutritional supplements) used by a patient 
3 months prior to screening through the study completion/early termination visit.  
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF page. 
4.5.1 
Permitted Therapy  
Adding a new medication or changing the dose of a medication after randomization 
should occur only for the treatment of an adverse event or as medically indicated. 
The following medications are permitted if the dose and dose regimen have been stable 
for 3 months prior to screening and are expected to remain stable after screening or if 
required for treatment of an adverse event after randomization:  
• 
Prescription medications that might affect cognitive function (e.g., antidepressants, 
anticonvulsants) 
• 
Over-the-counter and/or herbal medications, food additive or any other agent or 
supplement intended to improve cognition or reduce cognitive decline 


 
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• 
Medications used to treat a mood or anxiety disorder given as maintenance 
treatment 
• 
Medications with anticholinergic activity that may impair cognition or attention 
(e.g., centrally acting antihistamines, including brompheiramine, chlorpheniramine, 
dimenhydrinate, diphenhydramine, and doxylamine, or anti spasmodic medicines) 
• 
Intermittent use of centrally acting antihistamines is permitted, but 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)  
• 
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.  However, intermittent 
use of barbiturates is not permitted. 
• 
Dose of benzodiazepine for presurgical and pre-imaging sedation at appropriate 
visits if allowed by EC or IRB 
• 
Anti-platelet therapies are permitted during study conduct 
Under certain circumstances, anticoagulation therapy (e.g., temporary usage during 
surgery, or for treatment of deep vein thrombosis) may be permitted.  In these 
circumstances, appropriate safety assessments should be made, e.g., prior to a 
lumbar puncture.  The investigator should discuss with the Sponsor all individual 
patient cases that require anticoagulant therapy proactively whenever possible. 
 
Concomitant and excluded therapies for determination of patient eligibility are described 
in Section 4.2. 
Patients who use oral contraceptives, hormone-replacement therapy, or other 
maintenance therapy should continue their use. 
4.5.2 
Prohibited Therapy 
Any medication that is prohibited before screening is also prohibited during conduct of 
the study (see Section 4.2).  If a patient receives any prohibited treatment during the 
study, the patient may be withdrawn from study treatment. 
4.6 
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.  


 
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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 4.6.8 and as specified in the schedule of assessments (see 
Appendix 1).  
At applicable sites, certain study assessments may be performed by an HN professional 
at the patient’s home or nursing center to improve access and convenience for patients 
who participate in the study.  The Sponsor will select a healthcare company that will be 
responsible for providing HN services for participating sites (the HN vendor).  The HN 
vendor is responsible for ensuring that all HN professionals are licensed, qualified, and 
in good standing, as per applicable regulations, and that appropriate background checks 
have been performed.  If the investigator at a participating site determines that HN 
services are appropriate for a patient and the patient gives written informed consent to 
participate in HN visits, the HN network will communicate with the patient and the 
patient’s site.  HN visits will be scheduled on specified visit days, to allow for relevant 
assessments to be performed by the HN professional.  The schedule of assessments 
(see Appendix 1) specifies the assessments and visits that may be performed by an HN 
professional. 
Rescue medications and equipment to treat anaphylactic and anaphylactoid reactions 
must be available for home nursing visits.  Patients and their caregivers will be alerted to 
watch for signs of anaphylactic/anaphylactoid reactions and to contact the study center 
as soon as possible if any such signs are noted. 
4.6.1 
Informed Consent Forms and Screening Log 
All patients and caregivers must review, sign and date the most current IRB-EC 
approved written informed consent for participation in the study before any 
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. 
4.6.2 
Medical History and Demographic Data 
Medical history status includes clinically significant diseases, respiratory diseases and 
risk factors, surgeries, cancer history (including prior cancer therapies and procedures), 
smoking history, use of alcohol and drugs of abuse, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, 
nutritional supplements) used by the patient within 3 months prior to the screening visit.  


 
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Demographic data will include age, sex, and self-reported race/ethnicity.  Medical history 
and demographic data will be collected at the screening visit only.  Demographics of 
caregiver will also be collected. 
As this study is being conducted in multiple geographic regions, it is likely that patients of 
different ethnic origins will be enrolled in the study.  Although there is currently no 
indication that crenezumab (RO5490245) is metabolized or eliminated differently or that 
the treatment effect would be different in patients with different ethnic origins, collecting 
this information is essential to adequately evaluate the results of this study 
(e.g., possible differences in PK exposure [concentration of the drug in the blood] or 
treatment effect). 
4.6.3 
Physical Examinations 
A physical examination should be performed and should include an evaluation of the 
head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 
musculoskeletal, respiratory, gastrointestinal, genitourinary, and neurological systems, 
as clinically indicated.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF.  At Week 105, this examination 
will be repeated. 
At intervening visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the Adverse Event eCRF. 
The schedule of assessments indicates when height and weight should be recorded. 
4.6.4 
Vital Signs 
Blood pressure and heart rate will be taken when the patient is at rest and should not be 
measured unless at least 15 minutes have elapsed since the last blood draw.  The same 
arm should be used for all blood pressure measurements.  
Body temperature will be taken at each visit. 
Respiratory rate and oxygen saturation will be taken at each visit. 
Heart rate will be determined by radial pulse and will be recorded as beats per minute. 
The pulse should be counted for a minimum of 20 seconds at each assessment. 
The schedule of assessments indicates when vital signs (blood pressure, heart rate, 
respiratory rate, oxygen saturation, and body temperature) are to be recorded (see 
Appendix 1). 


 
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4.6.5 
Cognitive Assessments 
Cognition will be assessed using the ADAS-Cog, FCSRT, CDR, and MMSE.  
The cognitive assessments described in this section will be performed in the 
recommended order specified in Section 4.6.8 and the schedule of assessments (see 
Appendix 1).  
The scales and assessments for this study will be provided unless otherwise specified.  
Whenever possible, the same rater and caregiver should complete the scales for a given 
patient throughout the study.  Potential raters will receive training and be approved by 
the rating scale contract research organization (CRO) prior to being allowed to 
administer any cognitive assessments/rating scales in the study.  
Raters who are rating secondary scales do not need approval but do need to have 
completed appropriate training.  In addition, given that the primary outcome measure in 
this trial involves subjective judgment, the adequacy of patient interviews and ratings will 
be monitored by an endpoint reliability program administered by the rating scale CRO; 
this is considered to be an essential part of good research methodology.  Prior studies 
have clearly demonstrated that the failure to adequately monitor such ratings can 
substantially increase the risks of failed trials (Becker and Greig 2008; Kobak 2010).  
4.6.5.1 
Clinical Dementia Rating Scale  
Washington University’s CDR is a global assessment instrument that yields global 
scores (i.e., CDR-GS).  The sum of boxes (i.e., CDR-SB) score is a detailed quantitative 
general index that provides more information than the CDR-GS in patients with mild 
dementia (O'Bryant et al. 2010).  The CDR characterizes 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 website:  
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, 
ADAS-Cog, or ADCS-ADL.  However, if in exceptional circumstances only this assessor 
is available to perform these other scales, then the CDR patient interview must be 
completed after the caregiver interview but before ADAS-COG, MMSE and other 
cognitive scales are completed.  
Raters who assess the CDR should not be involved in any other aspects of patient care 
for the person that they are rating, including assessment of adverse events and 
preparation or infusion of study drug. 


 
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4.6.5.2 
Alzheimer’s Disease Assessment Scale-Cognition  
The ADAS-Cog is the most frequently used scale to assess cognition in clinical trials for 
mild to moderate AD (Rozzini et al. 2007; Connor and Sabbagh 2008; Ihl et al. 2012).  
The modified version will be used; it has 13 items and includes the addition of 1) delayed 
word recall, and 2) number cancellation, as well as use of only 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 11-item version of ADAS-COG will also be analyzed. 
4.6.5.3 
Alzheimer’s Disease Cooperative Study-Activities of Daily 
Living Inventory 
The ADCS-ADL (Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in patients with AD (Vellas et al. 2008).  The ADCS-ADL covers both basic ADL 
(e.g., eating and toileting) and more complex ADL or iADL (e.g., using the telephone, 
managing finances, preparing a meal).  
4.6.5.4 
Mini-Mental State Examination  
The MMSE (v9.8 including serial 7s) is a set of standardized questions used to evaluate 
possible cognitive impairment and help stage the severity level of this impairment.  
The questions target six areas:  orientation, registration, attention, short-term recall, 
language, and constructional praxis/visuospatial abilities.  
4.6.5.5 
Free and Cued Selective Reminding Test –Immediate Recall  
The FCSRT-IR is a measure of memory under conditions that control attention and 
cognitive processing in order to obtain an assessment of memory.  Impairments in 
FCSRT-IR performance have been associated with preclinical and early dementia in 
several longitudinal epidemiological studies (Grober and Buschke 1987; 
Sarazin et al. 2007).  
Free and total recall are the two measures from this assessment.  Cued recall and the 
cueing index can be calculated from these two scores. Lower scores imply poorer 
performance on all aspects of the test. 
4.6.5.6 
Functional Activities Questionnaire  
Impairments in daily functioning is a key clinical feature of AD.  Early in AD, impairments 
are seen in so-called iADLs (e.g., handling of finances, using transportation).  This loss 
of iADLs leads to a loss in resulting in increased burden to caregivers and increased 
costs independence (Marshall et al. 2011). 
The Functional Activities Questionnaire (FAQ) is an informant-based assessment that 
presents a forced choice of four levels of functioning for 10 ADLs.  The FAQ total score 


 
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is calculated by adding together the scores of each item – higher scores indicate 
worsening function (Pfeffer et al. 1982). 
4.6.5.7 
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 distress is rated on a 6-point scale (no distress, minimal, mild, moderate, 
severe, extreme, or very severe).  
4.6.5.8 
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 the lifetime suicidality of a patient (C-SSRS at 
baseline) as well as any new instances of suicidality (C-SSRS since last visit).  
The structured interview prompts recollection of suicidal ideation, including the intensity 
of the ideation, behavior, and attempts with actual/potential lethality.  The baseline 
C-SSRS will be collected at baseline and the C-SSRS since last visit will be collected at 
subsequent visits as indicated in the schedule of assessments (Appendix 1).  
The assessment will be completed by a certified C-SSRS rater after he or she interviews 
the patient and if necessary, the patient’s caregiver during the study visit.  
4.6.5.9 
Zarit Caregiver Interview for Alzheimer’s Disease  
The Zarit Caregiver Interview for AD (ZCI-AD) is a modified version of the Zarit Burden 
Interview, which was originally designed to reflect the stresses experienced by 
caregivers of people with dementia (Zarit and Zarit 1990).  The modified version includes 
slight modifications in item and title wording (e.g., removal of “your relative” to refer 
directly to the patient, removal of “burden” from title) and the use of 11-point numerical 
rating scales.  The ZCI-AD scale consists of a total of 30 items and is completed by the 
caregiver without involvement from the site staff.  Total and domain scores will be 
calculated (higher scores indicate higher levels of distress).  Documentation of the 
questionnaire’s psychometric properties will be performed as exploratory analyses.  
If a patient’s caregiver is replaced during the study, the ZCI-AD will not be completed by 
his or her new caregiver.  
4.6.5.10 
Quality of Life–Alzheimer’s Dementia  
The Quality of Life-AD (QOL-AD) was developed to assess QOL in patients who have 
dementia (Logsdon et al. 1999, 2002).  The QOL-AD consists of 13 items that cover 


 
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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.  
4.6.5.11 
EQ-5D 
The EQ-5D is a standardized measure of health status designed to provide a simple 
generic measure of health for clinical and economic appraisal.  It is broadly applicable 
across a wide range of health conditions and treatment. 
The EQ-5D assesses five domains to provide a health state index.  These are 
anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. 
Two versions are used in this study:  EQ-5D-5L proxy v1, reported on behalf of the 
patient and the EQ-5D-5L patient version provided to caregivers to assess caregiver 
health status.  
4.6.6 
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, FAQ, FCSRT 
MMSE, NPI-Q, QOL-AD, ZCI-AD, and C-SSRS.  The diagnostic verification will also be 
included on the device used for scales and submitted electronically. 
4.6.7 
Laboratory, Biomarker, and Other Biological Samples  
4.6.7.1 
Standard Laboratory Samples 
Samples for the following laboratory tests will be sent to a central laboratory for analysis. 
Instruction manuals and supply kits will be provided for all central laboratory 
assessments.  
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual.  
• 
Serum chemistry:  AST, ALT, alkaline phosphatase, total protein, total bilirubin, 
serum albumin, CPK, sodium, potassium, calcium, BUN/UREA, and serum 
creatinine (and creatinine clearance calculated by the central laboratory)  
• 
HbA1c, folic acid, and vitamin B12, T4, free T4, and thyroid-stimulating hormone 
levels will also be assessed as per the schedule of assessments  


 
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• 
Hematology:  hemoglobin, hematocrit, RBC (with morphology), WBC counts, 
platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and WBC–other 
total counts  
• 
Screening serologies:  HIV, hepatitis B, hepatitis C 
• 
Coagulation:  PT  
• 
Immunophenotyping:  including CD4, CD8, CD3, CD19, CD16 + 56.   
• 
Urine for drugs of abuse:  At screening only, urine samples will be analyzed for the 
presence of the following drugs:  amphetamine, benzodiazepines, cannabinoids, 
opiates, cocaine, barbiturates, and methadone.   
• 
Results will be used to verify patient eligibility pertaining to drugs of abuse. 
Inconclusive results may be repeated during the screening period.  Investigators 
should use their best clinical judgment in cases where results may be erroneous 
(e.g., permitted use of opiates or ingestion of food/food supplements).  
• 
Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and 
pH.  Microscopic examination performed at the central laboratory if blood and/or 
protein results are positive or strongly positive.  Results do not need to be recorded 
on the eCRF. 
• 
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.  
 
4.6.7.2 
Biomarker Sampling 
Samples will be collected from all patients and will be used for research purposes to 
identify dynamic biomarkers that may be predictive of response to treatment with 
crenezumab (in terms of dose, safety, and tolerability) and will help to better understand 
the pathogenesis, course, and outcome of AD and related diseases.  
For patients who consent to the optional Research Biosample Repository (RBR), 
residual biomarker samples will be kept for future biomarker research (see 
Section 4.6.12). 
The procedures for the collection, handling, and shipping of biomarker samples are 
specified in the Sample Handling and Logistics Manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.6.12), biomarker samples will be destroyed 
no later than 5 years after the final Clinical Study Report has been completed.  However, 
the storage period will be in accordance with the IRB/EC-approved Informed Consent 
Form and applicable laws (e.g., health authority requirements). 


 
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Cerebrospinal Fluid Sampling  
CSF samples will be collected in those patients who chose this approach for 
confirmation of Aβ levels for eligibility purposes (CSF-enrolled patients). Samples will be 
collected according to the schedule of assessments (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 at screening from patients who are 
enrolled using CSF Aβ (see Appendix 1).  The sample will be divided into aliquots onsite 
and used for the following:  
• 
Biomarker analysis, including Aβ1−42, t-tau, and p-tau.  This sample may also be 
used to support the development of biomarker assays for diagnostic use.  
 
Clinical Genotyping 
During screening, three mandatory whole blood samples will be obtained for DNA 
extraction from every patient who has consented to participate in the study.  All patients 
will be evaluated for APOE 
, an exploratory diagnostic 
biomarker.  Except in circumstances in which a health authority, EC, or IRB requires the 
patient be told of his or her APOE status 
, results will be 
blinded to patients, investigators, and the Sponsor in order to maintain the blind in the 
event that dose reduction is implemented.  Data arising from these analyses will be 
subject to the same confidentiality as the rest of the study.  
RNA Sampling 
During screening, two whole blood samples will be obtained for RNA extraction from 
every patient who has consented to participate in the study.  
 
 
  
Plasma Sampling 
Plasma sampling will be conducted during screening, at baseline, and at subsequent 
visits as detailed in the schedule of assessments (see Appendix 1).  One whole blood 
sample will be obtained for plasma extraction from every patient who has consented to 
participate in the study.   
This sample will be used to evaluate plasma Aβ levels and other biomarkers associated 
with AD or study treatment in peripheral blood as pharmacodynamics markers.  
4.6.7.3 
Immunogenicity Sampling 
Blood samples will be collected to assess the possible development of ADAs in all 
patients as noted in the schedule of assessments (see Appendix 1) and in case of 


 
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anaphylaxis, anaphylactoid, or serious hypersensitivity reactions and at wash out in the 
case of discontinuation for anaphylaxis.  Serum samples will be analyzed for antibodies 
to crenezumab using a bridging ELISA.  Samples may be tested for antibodies against 
other drug product substances. 
The procedures for the collection, handling, and shipping of ADA samples are specified 
in the Sample Handling and Logistics Manual supplied to the site by the Sponsor.  
4.6.7.4 
Pharmacokinetic Sampling (Serum Crenezumab) 
Blood samples will be collected to evaluate the pharmacokinetics of crenezumab in 
serum as noted in the schedule of assessments (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 hypersensitivity reactions, and at 
wash out in the case of discontinuation for anaphylaxis. 
Processing, storage, and shipping instructions for these PK blood samples are 
presented in a separate laboratory manual provided by the Sponsor to the clinical 
research unit. 
Serum concentrations of crenezumab will be determined using validated analytical 
procedures. 
Samples from patients who receive placebo may not be measured initially but will be 
retained for subsequent analysis if appropriate.   
4.6.8 
Timing of Study Assessments 
4.6.8.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site. 
After giving written informed consent, patients who are willing to participate in the study 
will undergo thorough screening assessments within 12 weeks prior to the baseline visit, 
as detailed in the schedule of assessments (Appendix 1).  Patients must fulfill all the 
entry criteria for participation in the study and the results must be available prior to the 
baseline visit.  
If the FCSRT and MMSE are completed following FCSRT/MMSE consent, and the patient is not 
excluded, these assessments would not need to be repeated during the screening period.  If a 
patient completes the FCSRT following FCSRT/MMSE consent, the patient may be 
asked to perform the MMSE scale even if they do not meet FCSRT related eligibility 
criteria. 


 
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In case of an abnormal laboratory or ECG result at screening that may normalize upon 
retest, investigators have the option to repeat the tests (prior to baseline and within the 
screening window) to confirm the test results before randomizing a patient at baseline. 
Unexpected logistical or technical issues may necessitate an extension to the 8-week 
screening period.  However, all screening assessments, including the FCSRT/MMSE 
scales if done following the FCSRT/MMSE consent, should completed within a 
maximum of 12 weeks prior to baseline.  (Exception:  MRI scans must be conducted 
within 8 weeks prior to baseline.)  As careful scheduling must remain a priority, an 
assessment of progress through the screening period will be made at 8 weeks from first 
start of screening (inclusive of screening assessments related to the FCSRT/MMSE 
consent).  Any extension beyond 12 weeks requires review and approval by the Sponsor. 
The recommended order of clinical assessments/rating scales at screening is as follows: 
Patient 
Caregiver 
1. 
FCSRT/MMSE may be done following 
the FCSRT/MMSE consent) 
2. 
CDR (patient interview) 
3. 
MMSE (if not completed at 
FCSRT/MMSE consent) 
4. 
ADAS-Cog-13 
1. 1.  CDR (caregiver input) 
ADAS-Cog-13 = Alzheimer’s Disease Activity Scale-Cognitive (subscale) 13; CDR = Clinical 
Dementia Rating; FCSRT = Free and Cued Serial Recall Task; MMSE = Mini Mental State 
Examination.  
 
Following the patient assessments on the screening visit, the clinician should complete 
the diagnosis verification form (see Appendix 4) and submit this within 48 hours of visit.  
The patient may not continue through screening, including any further invasive screening 
procedures (e.g., new CSF, MRI, PET scan), until patient eligibility has been confirmed.  
If a patient does not qualify on the basis of eligibility tests, the patient may be rescreened 
again after at least 3 months have elapsed if recruitment for the study is still ongoing 
(see Sections 4.1 and 4.2). 
In the event that a patient has an alternative PET scan available (e.g., from a prior 
clinical investigation), this may be used for confirmation of eligibility, subject to meeting 
criteria as defined in the PET Imaging Charter. 
As noted in the exclusion criteria (see Section 4.2), patients may be rescreened after 
appropriate treatment if they were originally excluded for abnormal thyroid, folic acid, 
vitamin B12, or HbA1c results.  Other laboratory tests that would exclude the patient 
may be repeated (as an unscheduled laboratory assessment) if it is suspected that the 


 
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abnormal result is transient and likely to be normal at repeat.  The Sponsor will monitor 
the number of repeat laboratory tests during Screening. 
Patients may be rescreened if the protocol is amended such that they would satisfy the 
amended criteria and if recruitment for the study is still ongoing.  In this case, all 
screening assessments must be repeated other than the MRI (if performed within 
8 weeks of randomization), lumbar puncture and prior PET testing if within eligible 
ranges.  
Patients may be rescreened if there is a substantial change in the patient’s condition 
(e.g., a disallowed medication was stopped) and if recruitment for the study is still 
ongoing and all eligibility criteria are met. 
If FCSRT (and MMSE) are completed following FCSRT/MMSE consent, and the 
patient is not excluded, these assessments would not need to repeated during the 
screening period.  It is suggested that the remaining screening tests with the exception 
of the lumbar puncture and MRI and PET scan be done within 1 to 2 weeks of signing 
the main informed consent (to allow adequate time for the remaining tests).  As soon as 
all these results are available, and none exclude the patient from the trial, the CSF 
collection and/or PET scan and MRI scan should be done if required.  It will take several 
days to receive the results of the MRI or CSF, and, on occasion, the originally scheduled 
MRI or CSF collection day may need to be postponed and in the case of the MRI, it may 
need to be repeated.  Therefore, the scheduling of these tests needs to be done 
carefully and should begin as soon as possible. 
It is recommended that the MRI appointment should be scheduled to occur no more 
than 3 weeks after the beginning of the screening period.  This is to allow sufficient time 
for the amyloid assessment (PET or LP) to be performed and evaluated before the end 
of the screening period.  
A Patient Eligibility Checklist that documents the investigator’s assessment of each 
screened patient with regard to the study’s inclusion and exclusion criteria is to be 
completed by the investigator.  A screen failure log must be maintained by the 
investigator. 
4.6.8.2 
Study Assessments 
In order to be randomized to receive double-blind treatment, patients must have no 
significant change in medical, psychiatric or neurological conditions or change in 
medication since screening.  The recommended order of assessments and rating scales 
is as follows: 
• 
Clinical assessments (e.g., QoL-AD, ZCI-AD, MMSE; ADAS-Cog-13; ADCS-ADL; 
CDR), including all those that require caregiver input, should be completed before 
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• 
Vital signs; ECGs; blood draws for clinical laboratory assessments, 
pharmacokinetics, ADA, and plasma biomarkers; and urine samples are 
recommended to be collected following scale assessments and must be collected 
before study drug administration. 
 
The recommended order of clinical assessments/rating scales at baseline, on treatment, 
and at the Week 105 (or early termination) visit  is as follows: 
Patient 
Caregiver 
1. ADAS-Cog-13 
2. CDR (patient interview) 
3. MMSE 
4. FCSRT 
5. QoL-AD (if appropriate) 
6. C-SSRS 
1. CDR (caregiver input) 
2. ADCS-ADL 
3. FAQ 
4. EQ-5D 
5. ZCI-AD (if appropriate) 
6. QoL-AD(if appropriate) 
7. NPI-Q(if appropriate) 
ADAS-Cog-13 = Alzheimer’s Disease Activity Scale-Cognitive (subscale) 13; 
ADCS-ADL = Alzheimer’s Disease Cooperative Study-Activities of Daily Living; 
C-SSRS = Columbia-Suicide Severity Rating Scale; CDR = Clinical Dementia Rating; 
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-Alzheimer’s 
Disease. 
 
Vital signs, ECGs, blood draws for clinical laboratory assessments, pharmacokinetics, 
ADA, plasma biomarkers, and urine samples are recommended to be collected 
following scale assessments and must be collected before study drug administration. 
If assessments are split over 2 days, all safety assessments must be done on same day 
as the infusion. 
4.6.9 
Confidentiality  
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4. 
4.6.10 
Brain Magnetic Resonance Imaging  
The MRI should be performed using a scanner with a field strength of 1.5 T or higher 
and where practical the same scanner should be used for an individual patient for the 
entire duration of the study.  MRI will be conducted at patient screening to provide a 
baseline for future safety monitoring, as a baseline measure of structural brain volumes, 
and as baseline information for the PET substudy concordance analysis (for the 
schedule of assessments, see Appendix 1).  In addition, the screening MRI will be used 
to help determine whether the exclusion criteria have been met (number of microbleeds, 
presence of mass lesions, etc.).  MRI will be used during the study to help assess safety 
such as the occurrence of microbleeds or signs potentially indicative of inflammation or 
ARIA-E.  Additional unscheduled MRI scans may be utilized to better understand 


 
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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 are enrolled using CSF-amyloid criteria should either undergo lumbar 
puncture for CSF sample and then wait for 3 days before having MRI or, ideally, undergo 
MRI before the CSF sample is taken.   
During study conduct, within 3 days prior to the scheduled MRI visit, site staff should 
contact the patient or caregiver to prospectively determine whether the patient is 
experiencing any CNS-related symptoms. MRI results must be available for review by 
site staff before dosing can occur.   
Details regarding image acquisition and data transfer by the scanning facilities, and the 
procedures, clinical assessments, and quantitative measurements performed by the core 
laboratory can be found in the MRI Charter and Scanning Manuals. 
4.6.11 
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 assessments (see 
Appendix 1) and may be obtained at unscheduled timepoints as clinically indicated.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements. 
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 5 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws).  Circumstances that may induce changes 
in heart rate, including environmental distractions (e.g., television, radio, conversation) 
should be avoided during the pre-ECG resting period and during ECG recording. 
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  Digital recordings will be analyzed at the central ECG laboratory 
and data transmitted to Roche. 
The following should be recorded by the electrocardiograph machine:  heart rate, RR 
interval, QRS interval, PR duration, uncorrected QT interval, and QT interval corrected 
using Fridericia’s formula (QTcF) and Bazett’s formula based on the machine readings 
of the individual ECG tracings. 


 
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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.   
4.6.12 
Samples for Research Biosample Repository  
4.6.12.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
In this study, all specimens for the RBR will come from retaining the residual samples 
remaining after the protocol-specified analysis has been performed on protocol-specified 
mandatory samples, including those collected in the associated substudy protocols.  
These residual samples will be retained from patients who give specific consent to 
participate in this optional research.   
RBR specimens will be used to achieve the following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.6.12.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.6.12) will not be applicable at that site. 


 
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4.6.12.3 
Sample Collection 
Three types of residual samples will be retained by the RBR for identification of dynamic 
(non-inherited) biomarkers:  CSF, plasma, and RNA.  
• 
Plasma and CSF samples may be used for exploratory biomarker assays, including 
but not limited to determination of markers of amyloid deposition and/or clearance, 
markers of oxidative stress, neurodegeneration, inflammation, or other processes 
implicated in the pathogenesis of AD.  These samples will be used to further the 
Sponsor’s understanding of AD and the response to treatment and may also be 
used to support the development of biomarker and diagnostic assays. 
• 
RNA samples may be tested using techniques such as RNAseq, microarray profiling 
and/or quantitative reverse transcription polymerase chain reaction to study the 
expression profile of genes known to be involved in AD.  These samples will be 
used to further our understanding of AD and the response to treatment and may 
also be used to support the development of biomarker and diagnostic assays.  
 
The following sample type will be retained by the RBR for identification of inherited 
genetic biomarkers:  
• 
DNA extracted from whole blood:  DNA samples may be used to explore the 
associations of specific variants of genes implicated in susceptibility and 
pathogenesis of AD with therapy response.   DNA samples in the RBR may also be 
used for whole genome sequencing to explore how genetic changes affect diseases 
or response to treatment. 
 
Whole blood samples may be sent to one or more laboratories for DNA extraction to 
enable analysis of germline mutations, somatic mutations via whole genome sequencing 
(WGS), next-generation sequencing (NGS), or other genomic analysis methods.   
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents. 
RBR specimens 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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4.6.12.4 
Confidentiality 
Specimens and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses, data derived from RBR 
specimens 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 specimens must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
 
 
 
4.6.12.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each 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, specific signature will be 
required to document a patient's agreement to provide optional RBR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research. 
 
4.6.12.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR specimens have the right to withdraw their 
specimens from the RBR at any time for any reason.  If a patient wishes to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 


 
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RBR Research Sample Withdrawal of Informed Consent eCRF.  The patient will be 
provided with instructions on how to withdraw consent after the trial is closed.  A 
patient's withdrawal from Study BN29553 does not, by itself, constitute withdrawal of 
specimens from the RBR.  Likewise, a patient's withdrawal from the RBR does not 
constitute withdrawal from Study BN29553. 
4.6.12.7 
Monitoring and Oversight 
RBR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to 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. 
4.7 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.7.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 
Study treatment discontinuation does not imply discontinuation from the study as 
described in Section 4.7.2.  Reasons for withdrawal from the study may include, but are 
not limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
 
Patients should be informed of circumstances under which their participation may be 
terminated by the investigator without the patient’s consent.  Any administrative or other 
reasons for withdrawal must be explained to the patient. 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  However, patients will not be followed for any reason after consent 
has been withdrawn.  Patients who withdraw from the study will not be replaced. 
4.7.2 
Study Treatment Discontinuation 
Patients must discontinue study treatment permanently if they experience any of the 
following:  
• 
Pregnancy 


 
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• 
Evidence of more than 10 microbleeds and/or areas of leptomeningeal 
hemosiderosis (ARIA-H), including any present at baseline, as assessed by central 
review of MRI.  
• 
Diagnosed with three recurrent, symptomatic ARIA-E events or exacerbations of 
previous events. 
 
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
Patients who discontinue from the study drug or who complete the study treatment and 
do not enter the OLE will be asked to return for the collection of safety and efficacy data 
4, 16, and 52 weeks after administration of the last dose of study treatment.  
Additionally all patients who discontinue from study drug early will be encouraged to 
return for subsequent visits, especially the Week 105 visit (early discontinuation of 
study treatment does not imply study discontinuation). 
4.7.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Futility analyses from this or other studies with crenezumab suggest that treatment 
with crenezumab is likely not effective 
• 
Sponsor determines it is in the best interest of the patients. 
 
The Sponsor will notify the investigator if the study is placed on hold, or if the Sponsor 
decides to discontinue the study or development program.   
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 


 
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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.  Please 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 52 weeks after the last dose of 
study drug.  
An iDMC will review unblinded safety and limited efficacy data at regular intervals (see 
Section 3.1.4 and the iDMC charter for further details). 
5.1.1 
Amyloid-Related Imaging Abnormalities-Edema/Effusion and 
Amyloid-Related Imaging Abnormalities-Hemosiderin 
Deposition 
The occurrence of imaging abnormalities believed to represent amyloid−related imaging 
abnormalities-edema/effusion has been reported in association with the investigational 
use of compounds that are intended to treat Alzheimer’s disease through the reduction 
of amyloid β in the brain.  These imaging abnormalities have, in the majority of instances, 
been asymptomatic, and their presence has been detected by brain magnetic resonance 
imaging (Salloway et al. 2009; Sperling et al. 2011).   
These magnetic resonance imaging signal hyperintensities seen in the parenchyma and 
leptomeninges are named amyloid−related imaging abnormalities-edema/effusion to 
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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 microhemorrhages in Alzheimer’s disease have a point prevalence of 
23% (Vernooij et al. 2008).  One longitudinal study found that in patients with 
Alzheimer’s disease the incidence of ≥ 1 microhemorrhage after a mean follow-up of 
2 years was 12% (Goos et al. 2010).  Recently, the occurrence of microhemorrhage has 
also been identified as an adverse event in anti-amyloid vaccination trials, and together 
with superficial siderosis, these events have been termed amyloid−related imaging 
abnormalities-hemosiderin deposition (Sperling et al. 2011).  Limited data on 
amyloid−related imaging abnormalities-hemosiderin deposition occurrence are available, 
but a retrospective analysis in patients with Alzheimer’s disease who were treated with 
anti-amyloid β antibodies with full effector function reported that 24 out of 207 patients 
(11.6%) developed amyloid−related imaging abnormalities-hemosiderin deposition 
(Sperling et al. 2012a).  Acute occurrence of cerebral microhemorrhage is not always 
considered clinically significant (Greenberg et al. 2009).  Study patients who received 
bapineuzamab and developed amyloid−related imaging abnormalities-hemosiderin 
deposition without amyloid−related imaging abnormalities-edema/effusion were clinically 
asymptomatic (Sperling et al. 2012a).  However, the clinical significance of cerebral 
microhemorrhage is not yet fully understood.   
Recent population-based studies have shown that cerebral microhemorrhages 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 microhemorrhages (Cordonnier et al. 2011) and high 
numbers of cerebral microhemorrhages 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 microhemorrhages 
(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 
APOEε4 status (Goos et al. 2010).  Taken together, accumulating evidence suggests 
that cerebral mHs are common in cross-sectional observational studies of healthy elderly 
subjects, and the increase in prevalence over time may be part of the natural history of 
aging, which indicates a specific underlying vascular pathologic state, in particular 
hypertensive vasculopathy or cerebral amyloid angiopathy. 
When anti-amyloid β antibodies bind to amyloid deposited around blood vessels, an 
FcγR−mediated immune response may be elicited.  This compromises vascular integrity 
and results in amyloid−related imaging abnormalities-edema/effusion or amyloid−related 
imaging abnormalities-hemosiderin deposition.  The hypothesis that FcγR−mediated 
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abnormalities-edema/effusion and/or amyloid−related imaging 
abnormalities-hemosiderin deposition is supported by results from clinical studies that 
have shown that patients with Alzheimer’s disease who were treated with anti-amyloid β 
antibodies with full effector function developed amyloid−related imaging 
abnormalities-edema/effusion (symptomatic and asymptomatic).  In these patients 
ARIA events tend to occur early after treatment initiation and are dose and APOEε4 
dependent. 
Crenezumab, a human IgG4, has reduced FcR binding compared with IgG1/IgG2 and, 
thus, has reduced effector function that theoretically might lower the risk of amyloid-
related imaging abnormalities-edema/effusion.  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.  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 amyloid-related imaging 
abnormalities-effusion/edema has been observed as of 27 May 2017 (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 amyloid-
related imaging abnormalities-edema/effusion during the open-label extension. 
Since development of asymptomatic cerebral microhemorrhages may occur within the 
natural history of Alzheimer’s disease at a rate of approximately 10% per year, the 
appearance of new cerebral microhemorrhages should not automatically disqualify a 
patient from further treatment.  However, as the occurrence of new cerebral 
microhemorrhages may also result from amyloid clearance associated with 
amyloid-lowering therapy and high numbers of new cerebral microhemorrhages might 
impose a risk for future ischemic and hemorrhagic strokes, study drug must be 
discontinued in specific circumstances (refer to Section 5.1.2 for details of withdrawal 
rules). 
In this Phase III study, a safety monitoring plan has been designed to monitor the 
potential risk of amyloid−related imaging abnormalities-edema/effusion and 
amyloid−related imaging abnormalities-hemosiderin deposition.  This plan consists of the 
following key elements: 
• 
Exclusion criteria:  
– 
According to the magnetic resonance imaging central reader, magnetic 
resonance imaging evidence of a) > 2 lacunar infarcts, b) any territorial 
infarct > 1 cm3, or c) any white matter lesion that corresponds to an overall 
Fazekas score of 3 that requires at least one confluent hyperintense lesion on 
the fluid−attenuated inversion recovery sequence, which is ≥ 20 mm in any 
dimension  
– 
Evidence of > 4 microbleeds and/or areas of leptomeningeal hemosiderosis 
(amyloid−related imaging abnormalities-hemosiderin deposition) as assessed 


 
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by central review of T2* gradient-recalled echo magnetic resonance imaging 
(see Magnetic Resonance Imaging Charter for further details)  
• 
Prior to all magnetic-resonance imaging evaluations, the patient and caregiver will 
be contacted to determine if the patient has any CNS-related symptoms.  If present, 
a symptom-led assessment will be performed at the visit 
• 
Brain magnetic resonance imaging (including fluid−attenuated inversion recovery 
sequence and T2*-weighted gradient-recalled echo sequences) will be performed 
every 3 months in the first year and at least every 6 months in subsequent years to 
detect amyloid−related imaging abnormalities-edema/effusion and amyloid−related 
imaging abnormalities-hemosiderin deposition (see Appendix 1)  
• 
All magnetic resonance imaging scans will be read in a timely fashion and will 
evaluate amyloid−related imaging abnormalities-edema/effusion and 
amyloid−related imaging abnormalities-hemosiderin deposition as well as other 
abnormalities.  Assessments will be made by independent blinded radiologists at a 
central contract imaging vendor. 
• 
Patients who exhibit new amyloid−related imaging abnormalities-edema/effusion or 
amyloid−related imaging abnormalities-hemosiderin deposition (but do not qualify 
for treatment discontinuation as defined below) will be rescanned within 
approximately 4 weeks after the last magnetic resonance imaging scan to evaluate 
the evolution of the findings.  
 
Amyloid−related imaging abnormalities-edema/effusion or amyloid−related imaging 
abnormalities-hemosiderin deposition findings may require dose modification or 
treatment discontinuation.  The rules to be applied in specific cases are detailed in 
Section 5.1.2. 
5.1.2 
Management of Amyloid-Related Imaging Abnormalities 
including Required Dose Adjustments 
To date, there has been limited clinical experience of ARIAs with crenezumab; however, 
data from studies on other mAb treatments reveal that ARIA events tend to occur early 
after treatment initiation, are dose and APOEε4 dependent, are manageable with MRI 
monitoring, and do not lead to significant adverse outcomes (see Section 5.1.1). 
All clinical trials with crenezumab include APOEε4 genotyping, MRI safety 
monitoring, and an ARIA-based dose intervention algorithm. 
The following dose adjustments and discontinuation rules for magnetic resonance 
imaging−related findings will apply: 
5.1.2.1 
Amyloid−Related Imaging Abnormalities-Edema/Effusion 
(ARIA-E) 
Asymptomatic amyloid−related imaging abnormalities-edema/effusion with Barkhof 
Grand Total Score <4 (Barkhof et al. 2013): 
• 
Continue study drug at the same dose (i.e., 60 mg/kg crenezumab) 


 
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• 
Repeat magnetic resonance imaging 4 weeks later 
– 
If amyloid−related imaging abnormalities-edema/effusion is stable or decreased, 
continue study drug and monthly magnetic resonance imaging monitoring until event 
resolves.  Once amyloid−related imaging abnormalities-edema/effusion completely 
resolves, conduct magnetic resonance imaging monitoring as per Appendix 1. 
– 
If amyloid−related imaging abnormalities-edema/effusion increases (Barkhof Grand 
Total Score ≥ 4) or symptoms develop, refer to the rule below. 
 
Symptomatic amyloid−related imaging abnormalities-edema/effusion (any size) or 
asymptomatic amyloid−related imaging abnormalities-edema/effusion with Barkhof 
Grand Total Score ≥4: 
• 
Temporarily interrupt study drug and implement monthly magnetic resonance 
imaging monitoring 
• 
Once symptoms and amyloid−related imaging abnormalities-edema/effusion resolve, 
reintroduce study drug at the same dose and perform an magnetic resonance 
imaging after 4 weeks of dosing.  If no new magnetic resonance imaging is detected, 
resume magnetic resonance imaging monitoring as per Appendix 1. 
 
Any new onset of amyloid−related imaging abnormalities-edema/effusion:  Treat the 
same as the first event, based on symptoms and Barkhof Grand Total Score.  However, 
in the case where a patient is diagnosed with three recurrent, symptomatic 
amyloid−related imaging abnormalities-edema/effusion events or exacerbations of 
previous events, permanently discontinue the study drug.  Implement monthly magnetic 
resonance imaging monitoring until resolution of both symptoms and amyloid−related 
imaging abnormalities-edema/effusion.  As per the protocol (please refer to 
Section 4.6.2), maintain the patient in the study until study end and perform 
assessments as per the schedule of assessments.   
5.1.2.2 
Amyloid−Related Imaging Abnormalities-Hemosiderin 
Deposition (ARIA-H) 
Dose reduction:  Patients who develop > 8 amyloid−related imaging 
abnormalities-hemosiderin deposition cumulatively* will receive a lower dose of the 
study drug (i.e., 30 mg/kg) at any dosing visits for the rest of the study. 
Study drug discontinuation:  Patients who develop > 10 amyloid−related imaging 
abnormalities-hemosiderin deposition cumulatively* will be permanently discontinued 
from the study drug. 
*Sum of amyloid−related imaging abnormalities-hemosiderin deposition at baseline and 
newly detected amyloid−related imaging abnormalities-hemosiderin deposition during 
the study. 


 
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5.1.3 
Prevention and Management of Hypersensitivity and Infusion 
Reactions  
Crenezumab will be administered to patients under close medical supervision in a 
setting with access to 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. 
5.1.4 
Additional Safety Monitoring 
Laboratory tests, including hematology and chemistry, will be performed throughout the 
study.  ECGs will be recorded regularly (see Appendix 1).  Symptom-led examinations will 
be performed as required during the study to assess physical and neurologic events that 
are not consistent with normal disease progression.  The Columbia-Suicide Severity 
Rating Scale will be used for prospective suicidality assessment.  Pregnancy testing will 
be performed at each visit in women of child-bearing potential.  Samples to assess 
immunogenicity will be collected prior to and throughout the treatment and follow-up 
periods. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 


 
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• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10  
• 
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) 
• 
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 [NCI CTCAE]; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2  
for reporting instructions). 


 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
include the following: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. 
• 
Pneumonia:  In the Phase II program, a numerical imbalance in pneumonia cases 
was observed, with more events reported in crenezumab-treated patients versus 
placebo-treated patients.  It is of paramount importance to carefully document any 
pneumonia cases and other serious respiratory infections that occur in this study, by 
means of providing all relevant information required by the eCRF.  A chest X-ray is 
required under the following circumstances: 
– 
Serious and non-serious pneumonia 
– 
Serious and non-serious lower respiratory tract infections 
– 
Serious upper respiratory infections. 
• 
In addition, whenever possible, additional relevant investigations should be 
conducted (e.g., WBC counts, pathogen identification by means of hemocultures, 
bronchoalveolar lavage).  
• 
When a pneumonia case is diagnosed, a blood sample for fluorescence-activated 
cell sorting analysis must be collected as soon as feasible for the site and the 
patient.  
– 
In addition, in order to investigate any potential effects of study drug on the immune 
system, blood samples for B and T cells’ phenotyping (i.e., fluorescence-activated 
cell sorting analysis) will be collected in all enrolled patients at Baseline and 
Week 25. 
 
5.2.4 
Selected Adverse Events 
To further elucidate potential clinical implications of amyloid−related imaging 
abnormalities findings, patients will be asked if they experience CNS adverse events up 
to 1 week before each magnetic resonance imaging 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 


 
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summarized separately in the clinical study report.  Additional data on associated 
symptoms (as defined on the eCRF) and safety magnetic resonance imaging scans will 
be collected for the following selected adverse events: 
• 
Amyloid−related imaging abnormalities-edema/effusion:  Amyloid-related imaging 
abnormalities suggestive of vasogenic edema and sulcal effusions 
• 
Amyloid−related imaging abnormalities-hemosiderin deposition:  Amyloid-related 
imaging abnormalities suggestive of microhemorrhage and hemosiderin deposits. 
 
New amyloid-related imaging abnormalities-edema/effusion or amyloid-related imaging 
abnormalities-hemosiderin deposition noted on study-related MRI scans should be 
reported as adverse events in these circumstances: 
• 
They are symptomatic (i.e., accompanied by CNS symptoms)  
AND/OR 
• 
They result in a change in study treatment (dose modification, interruption, or 
discontinuation; see Section 5.1.2) 
 
Any accompanying symptoms should also be captured as separate adverse events. 
ARIA-E should be reported separately from ARIA-H.  
It is possible that more than one new area of ARIA-H is identified on the same MRI.  If 
meeting the criteria above, these should be reported collectively as one new adverse 
event, and the number of areas should be specified.  The same should be done separately 
for ARIA-E.  
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1  
for definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.4 −5.6  
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 


 
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procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
In addition, after initiation of a PET ligand but prior to initiation of study drug, all 
serious adverse events occurring within 48 hours of PET ligand administration should 
be reported regardless of relatedness to the PET ligand (see Section 5.4.2 ). After this 
48-hour timepoint, only serious adverse events s considered related to the PET ligand 
should be reported.  Non-serious adverse events (occurring at any timepoint) 
considered to be related to the PET ligand should also be reported.  
After initiation of study drug, all adverse events will be reported until 2 elimination 
half-lives after the last dose of study drug (8 weeks) after 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 2 provides guidance for assessing adverse event severity. 
Table 2 
Adverse Event Severity Grading Scale 
Severity 
Description 
Mild 
Discomfort noticed, but no disruption of normal daily activity 
Moderate 
Discomfort sufficient to reduce or affect normal daily activity 
Severe 
Incapacitating with inability to work or to perform normal daily activity 
Note:  Regardless of severity, some events may also meet seriousness criteria.  
Refer to definition of a serious adverse event (see Section 5.2.2). 
 
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) 


 
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• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated 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. 


 
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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. 
• 
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.  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) 


 
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• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 × ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
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). 


 
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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 
 
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.  The term "sudden death" should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or, in 
the case of an unwitnessed death, within 24 hours after the patient was last seen alive 
and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death. 
If the death is attributed to progression of Alzheimer’s disease, "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. 


 
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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches"). 
5.3.5.10 
Lack of Efficacy or Worsening of Alzheimer’s Disease 
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on guidelines (e.g., NIAAA New Diagnostic Criteria and 
Guidelines for AD; see Appendix 2 and Appendix 3).  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.   
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 
The patient has not experienced an adverse event. 
  
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 


 
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5.3.5.13 
Patient-Reported Outcome Data  
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data.  Investigators and site staff are not 
expected to review PRO data for adverse events. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
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 (see Section 5.4.2 for further details) 
• 
Adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for All Sites  
Medical Monitor: 
 M.D. (Primary) 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Medical Monitor: 
 
 
 
 
 
M.D. (Secondary) 
Telephone No.: 
  
 
 
 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 


 
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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, Adverse 
Events of Special Interest, and PET Ligand Adverse Events 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, serious 
adverse events caused by a protocol-mandated intervention as well as all serious 
adverse events that occur within 48 hours of PET ligand administration regardless of 
causality should be reported.  The Serious Adverse Event/Adverse Event of Special 
Interest Reporting paper Form provided to investigators should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the event), either by faxing or by scanning and emailing the form using the 
fax number or email address provided to investigators. 
For PET ligand-related adverse events, the clinical site will complete a PET 
ligand-specific non-serious adverse event reporting paper form and submit it to the 
Sponsor or its designee by scanning and emailing the form using the email address 
provided on the form.   
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 8 weeks after the last dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Once the EDC system is 
available, all information will need to be entered and submitted via the EDC system.   
Instructions for reporting serious adverse events that occur  > 8 weeks after the last dose 
of study treatment are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 8 weeks after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 


 
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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 last dose of study drug.  A Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), either by faxing or by scanning and 
emailing the form using the fax number or email address provided to investigators.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  The pregnant partner 
will need to sign an Authorization for Use and Disclosure of Pregnancy Health 
Information to allow for follow-up on her pregnancy.  After the authorization has been 
signed, the investigator will submit a Clinical Trial Pregnancy Reporting Form when 
updated information on the course and outcome of the pregnancy becomes available.  
An investigator who is contacted by the male patient or his pregnant partner may provide 
information on the risks of the pregnancy and the possible effects on the fetus, to 
support an informed decision in cooperation with the treating physician and/or 
obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (as the Sponsor considers 
abortions to be medically significant), recorded on the Adverse Event eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
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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, electronic mail, and/or a 
monitoring visit to obtain additional case details and outcome information (e.g., from 
hospital discharge summaries, consultant reports, autopsy reports) in order to perform 
an independent medical assessment of the reported case. 
5.6 
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 
8 weeks  after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the Serious Adverse Event/Adverse Event of Special Interest Reporting Form 
using the fax number or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
Crenezumab Investigator's Brochure  
 


 
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To determine reporting requirements for PET ligands used, in those countries that have 
health authority approval of the PET ligands the approved local product information 
will be used.  In countries where the PET ligand does not have health authority 
approval, the Investigator’s Brochure will be used. 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The purpose of this study is to investigate the treatment effect of crenezumab relative to 
placebo.  The primary efficacy analysis will be based on an intent-to-treat (ITT) 
population, which will include all randomized patients who receive at least one dose of 
study drug, with patients grouped according to their randomly assigned treatment. 
Approximately 750 patients will be randomized in the Global Enrollment Phase of this 
study.  
 
 
 
.  The China subpopulation will include 
patients enrolled at sites in mainland China, Hong Kong, and/or Taiwan (according to 
applicable Chinese regulations) during both the Global Enrollment Phase and the China 
Extension Phase. 
The primary analyses of this study will include patients enrolled during the Global 
Enrollment Phase; data from patients enrolled after the close of Global Enrollment will be 
included in analyses separate from the primary analyses. 
6.1 
DETERMINATION OF SAMPLE SIZE 
Determination of sample size is based on patients enrolled in the Global Enrollment 
Phase.  In this study, 750 patients will be enrolled with 375 patients per treatment arm 
(crenezumab or placebo) during the Global Enrollment Phase.  
 
 
 
 
The estimate of sample size required to demonstrate efficacy with regard to CDR-SB is 
based on the following assumptions: 
• 
The mean change in CDR-SB from baseline to Week 105 is 2.6 points in the 
placebo arm 


 
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• 
A common SD across treatment arms for change from baseline to Week 105 in 
CDR-SB of approximately 3.07 (this corresponds to a coefficient of variation of 
118% for change in CDR-SB from baseline to Week 105 in a prodromal to mild AD 
population in the placebo arm) 
• 
The dose level has a true effect of a 30% relative reduction in deterioration of 
CDR-SB 
• 
35% of randomized patients will dropout by Week 105 
 
This sample size will have 80% power to detect a true treatment effect of 30% relative 
reduction in deterioration of CDR-SB at 2-sided α of 0.05.  
In the event that the rescue strategy or change in dose is required, the number of 
patients enrolled in the new dose group and its concurrently enrolled placebo arm will be 
750 patients (375 patients per treatment arm) during the Global Enrollment Phase.  All 
patients already enrolled on 60 mg/kg of study treatment and corresponding 
concurrently enrolled placebo patients will be replaced with new patients.  
A blinded assessment of the pooled standard deviation of CDR-SB change from baseline 
will be performed by the Sponsor at a specified timepoint prior to unblinding.  As a 
result, the sample size may be increased from 750 up to 1126 patients (563 patients per 
arm). Further details will be described in the Statistical Analysis Plan (SAP).  The 
sample size will not be reduced on the basis of this assessment.  Other factors external 
to the study may also trigger a decision to increase sample size. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Enrollment, patient disposition, and incidence of protocol deviations will be summarized 
for all randomized patients and grouped according to randomized treatment assignment. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics (such as age, sex, race, disease severity, 
APOEε4 status, use and non-use of background therapy for AD) will be summarized 
descriptively for the ITT population, grouped according to the assigned treatment arm. 
Descriptive summaries of continuous data will present the mean, 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 secondary efficacy analyses will include all randomized patients, with 
patients grouped according to the treatment assigned at randomization. 
6.4 
EFFICACY ANALYSES 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy outcome measure is the change in CDR-SB from baseline (Week 1) 
to Week 105.  For this primary outcome measure, the difference in mean change from 


 
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baseline to Week 105 between crenezumab- and placebo-treated patients will be 
estimated.  Mixed model repeated measures (MMRMs) adjusting for disease severity, 
APOEε4 status, geographic region, and the use or non-use of anti-dementia medications 
at baseline will be used to estimate the mean change from baseline for the primary 
endpoint.  The analysis will include all randomized patients, with patients grouped 
according to the treatment assigned at randomization. 
The MMRM model will be used to estimate the mean change from baseline for the 
primary endpoint.  The model will include the change from baseline in CDR-SB as the 
dependent variable.  The effects in the model will include baseline score, treatment 
group, visit, treatment-by-visit interaction and baseline score-by-visit interaction.  Visit 
week will be treated as the repeated variable within a patient.  Patient, treatment, and 
visit week will be treated as class variables.  An unstructured variance−covariance 
structure will be applied to model the within-patient errors; in case of non-convergence, 
compound symmetry will be used.  
The difference in the changes from baseline of each dose group from placebo will be 
estimated at each time point.  The 95% CI and p-value for treatment difference will be 
presented. 
All efforts will be made to minimize missing data.  The Sponsor plans to request patients 
who discontinued early from study treatment to return for collection of safety and limited 
efficacy data until Week 105.  To explore the robustness of MMRM results for the 
primary efficacy conclusions, sensitivity analyses (for example, using multiple imputation 
and pattern mixture models) will be performed.  Descriptive summaries of the number of 
patients with missing data and the timing and reasons for discontinuation from study by 
treatment group will also be provided. 
Additional details will be documented in the SAP. 
6.4.2 
Secondary Efficacy Endpoints 
The absolute change from baseline in the continuous secondary efficacy endpoints listed 
in Section 2 (including cognition endpoints, global endpoints, disease pathology 
biomarkers, and endpoints that measure other AD symptoms and effects) will be 
analyzed using an MMRM analysis model similar to that described above for the primary 
efficacy endpoint. 
In order to protect the overall type I error rate for the study when incorporating the 
hypothesis testing of the primary endpoints and the key secondary endpoints into the 
analysis, the fixed sequence testing procedure (Westfall and Krishen 2001) will be used 
to adjust for multiple comparisons.  These endpoints will be tested in the following order: 
1) Change from baseline to Week 105 in CDR-SB 
2) Change from baseline to Week 105 in ADAS-Cog-13 and ADAS-Cog-11 


 
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3) Change from baseline to Week 105 in iADL  
4) Change from baseline to Week 105 in ADCS-ADL total score 
 
The treatment difference in the primary endpoint (change from baseline to Week 105 in 
CDR-SB) will be tested at a 2-sided 5% overall significance level using the 
O’Brien−Fleming boundary.  If this test result is statistically significant at either the 
interim or the final analysis, the treatment difference in change from baseline to 
Week 105 in ADAS-Cog-13 will be tested at a two-sided 5% significance level.  If the 
treatment effect on ADAS-Cog-13 is statistically significant, the treatment effect on 
ADCS-iADL total score will be tested at a two-sided 5% significance level and likewise 
for ADL if iADL is significant.  If any test result is not statistically significant, testing of 
the subsequent endpoints will not occur. 
6.4.3 
Exploratory Efficacy Analyses 
For time-to-event endpoints, the Kaplan−Meier method will be used to estimate the 
median time-to-event for each treatment arm.  Cox proportional hazard model stratified 
by the randomization stratification factors will be used to estimate the hazard ratio and 
its 95% CI.  The two-sided log-rank test, stratified by the randomization stratification 
factors, will be used to perform hypothesis testing for assessing treatment difference 
between the two treatment arms at a 5% significance level.  
Subgroup analyses of efficacy results may also be performed based on clinically 
relevant baseline factors.  Subgroups will be defined by factors which may include one 
or more of the following:  age, sex, race, dementia status (pAD vs. mAD), APOEε4 
status, geographic region, use and non-use of background therapies for AD, or other 
clinically relevant factors at baseline. 
6.5 
SAFETY ANALYSES 
The safety analysis population will include all randomized patients who received at least 
one dose of study drug, with patients grouped according to the treatment actually 
received. 
• 
Incidence and nature of MRI safety findings:  ARIA-E and ARIA-H 
• 
Incidence, nature, and severity of serious adverse events 
• 
Incidence, nature, and severity of adverse events 
• 
Incidence of adverse events of special interest  
• 
Incidence of treatment discontinuations due to adverse events 
• 
Mean changes in clinical laboratory tests from baseline over time; incidence of 
treatment-emergent abnormal laboratory values and abnormal laboratory values 
reported as adverse events 
• 
Mean change in ECG assessments from baseline over time and incidence of 
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• 
Incidence of immunogenicity as evidenced by antibodies to crenezumab or other 
components of drug product 
• 
Physical and neurologic examination abnormalities 
• 
Mean change in vital signs (blood pressure, heart rate) from baseline over time and 
incidence of abnormal vital sign measurements 
• 
Changes in CSSR-S scores from baseline over time.   
 
6.6 
PHARMACOKINETIC ANALYSES  
Serum concentration data for crenezumab will be tabulated and summarized. 
Descriptive summary statistics will include the arithmetic mean, median, range, SD, and 
coefficient of variation, as appropriate.  Since a sparse PK sampling design is being 
used, population (non-linear mixed-effects) modeling will be used to analyze the dose 
concentration-time data of crenezumab.  Information from other clinical studies may be 
incorporated to establish the PK model.  The 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 concentrations data for crenezumab and the ratio between CSF and serum 
crenezumab will be tabulated and summarized as appropriate from the substudy 
(BN29553-CSF longitudinal). 
6.7 
BIOMARKER ANALYSES  
Plasma Abeta concentrations and MRI-derived measurements over time, such as 
volumetric changes in whole brain, ventricles, hippocampus, or other structures, will be 
analyzed using the same methods used for the primary analysis.  Brain amyloid load, 
brain tau load, and CSF markers of disease will be analyzed in their respective 
substudies (BN29552/BN29553-Amyloid PET longitudinal, BN29552/BN29553-tau 
PET longitudinal, and BN29553-CSF longitudinal).  Further details can be found in 
the pertinent substudy protocol. 
 
 
  
Exploratory analyses of the relationship between crenezumab exposure and biomarker 
(imaging, plasma PD, CSF PD, or genetic), efficacy, or safety measures will be 
performed as appropriate. The results of these analyses may be reported separately 
from the clinical study report. 


 
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6.8 
INTERIM ANALYSIS 
Based on information that may emerge during the course of this study, the Sponsor may 
choose to conduct one or more interim analyses.  Interim analyses would be conducted 
by an independent data coordinating center and reviewed by iDMC.  The Sponsor would 
remain blinded.  Interactions between the iDMC and Sponsor would be carried out as 
specified in the iDMC Charter.  The iDMC Charter would document potential 
recommendations the iDMC can make to the Sponsor as a result of the analyses (e.g., 
stop the study for futility).  Below are further specifications in place to ensure the study 
continues to meet the highest standards of integrity should optional interim analyses be 
executed.  
The Sponsor may choose to perform an optional futility analysis.  No adjustment for 
multiple comparisons would be made to the  level for this analysis, given that the 
decision rules for the futility analysis would not allow for the opportunity to stop the 
study early for overwhelming efficacy.  At the time of a futility analysis, the threshold for 
declaring futility would be based on the probability of erroneously stopping the study 
being lower than a pre-specified level, when crenezumab has a true treatment effect on 
CDR-SB (false negative rate).  If the observed treatment effect at the futility analysis is 
smaller than the derived threshold, the iDMC may recommend that the study be stopped 
for futility.  Additional criteria for recommending that the study be stopped for futility may 
be added to the iDMC Charter.  
In addition, the Sponsor may perform an interim assessment for positive efficacy.  The 
type I error rate will be controlled to ensure statistical validity is maintained.  Specifically, 
the Lan-DeMets -spending function that approximates the O’Brien-Fleming boundary 
will be applied to determine the critical value for stopping for positive efficacy at the 
interim analysis (DeMets and Lan 1994).  If the study continues beyond the interim 
analysis, the critical value at the final analysis would be adjusted accordingly to maintain 
the protocol-specified overall type I error rate, per standard Lan-DeMets methodology.  
Control of overall type I error in multiple comparisons of primary and key secondary 
endpoints are described in Section 6.4.  This interim analysis would also be reviewed by 
the iDMC, and the Sponsor would remain blinded.  Additional criteria for recommending 
that the study be stopped for positive efficacy may be added to the iDMC Charter.   
Further details (e.g., timing, data to be reviewed by the iDMC, thresholds, etc.) will be 
documented in the interim SAP.  The interim SAP will be submitted to relevant health 
authorities at least 2 months prior to the conduct of an interim analysis.  
As information external to the study (e.g., from other compounds) becomes available 
during the conduct of the study, the Sponsor may implement changes to the protocol to 
incorporate such learnings into the study, if possible.  Such learnings may be concerned 
with endpoints, biomarkers, and sample size reassessment due to the variability and 
size of treatment effect observed in other compounds, for example.  The Sponsor could 


 
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implement such learnings through a protocol amendment while being blinded, but 
without consultation with the iDMC. 
6.9 
CHINA SUBPOPULATION ANALYSIS 
Approximately 750 patients will be randomized during the Global Enrollment Phase of 
this study.  
 
 
 
 The China subpopulation will 
include patients enrolled at sites in mainland China, Hong Kong, and/or Taiwan 
(according to applicable Chinese regulations) during both the Global Enrollment Phase 
and the China Extension Phase. 
The objective of the China Extension Phase and the China subpopulation analyses is to 
assess the treatment effects of crenezumab in a population of patients in mainland 
China, Hong Kong, and/or Taiwan and to investigate the consistency in treatment 
effects between the China subpopulation and the global population for the purpose of 
registration in China.   
Methods for analyzing data from the China subpopulation will be provided in the SAP.  
Results from these analyses will be summarized in a separate report. 
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 


 
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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. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-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. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 


 
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monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic 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. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 


 
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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. 
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. 


 
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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, 
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 the analyses, data derived from 
exploratory biomarker specimens 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 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. 


 
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8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, subjects’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
The overall procedures for quality assurance of clinical study data are described in the 
Roche standard operating procedures.  This study will be sponsored by F. Hoffmann-La 
Roche Ltd.  Roche will provide clinical operations oversight, site monitoring and 
management, data management support, and medical monitoring. 
Drug distribution may occur through an IxRS (see Section 4.3).  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).  


 
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9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
 
 
 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 


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


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


 
 
Appendix 1  
Schedule of Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
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Assessment/ Procedure 
Screen 
BL 
 
Treatment Period 
ET 
 
Wk-8 to Wk-1 
Day 
1 
Wk1 
Day 
2 
Wk 1 
Wk
5 
Wk
9 
Wk
13 
Wk
17 
Wk 
21 
Wk
25 
W
k 
29 
W
k 
33 
W
k 
37 
W
k 
41 
Wk
45 
W
k 
49 
Wk 
53 
Dose Number 
 
1 a 
 
2 
3 
4 
5 b 
6 b 
7 a 
8 b 
9 b 
10 
11
b 
12
b 
13
b 
14 a 
a 
MRI q 
x 
 
 
 
 
xr 
 
 
xr 
 
 
xr 
 
 
 
xr 
x 
PET / CSF sample q, s 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x w, x 
x w, x 
CDR 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
ADAS-Cog-13 
x 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
ADCS-ADL; FAQ 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
MMSE 
x t 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
NPI-Q 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
FCSRT-IR 
x t 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
EQ-5D 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
QOL-AD 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
ZCI-AD 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
C-SSRS BL/SLV u 
 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
Concomitant medications 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug administration v 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ACDS-ADL = Alzheimer’s Disease Cooperative Study – Activities of Daily Living; AD = Alzheimer’s disease; ADAS-Cog13 = Alzheimer’s Disease Activity Scale 
Cognition (subscale) 13; BL = baseline; CDR = Clinical Dementia Rating; CSF = cerebrospinal fluid; C-SSRS= Columbia Suicide Severity Rating Scale; 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; PET = positron emission tomography; 
PK = pharmacokinetic; QoL-AD = Quality of Life−Alzheimer’s Disease; 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. Patients should return to initial planned schedule per randomization for 
subsequent visits.  For patients who terminate early, assessments listed in the ET visit (week 105) should be completed. 


 
 
Appendix 1  
Schedule of Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
140/Protocol BN29553, Version 2  
In case of rescreening a patient, all screening assessments must be repeated other than the MRI (if performed within 8 weeks of randomization), lumbar 
puncture and amyloid PET scan  if previous results were within eligible ranges. 
 Does not have to be a site visit – telephone call to patient following first infusion 
a  Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., vitals, blood tests and ECGs) 
should be completed prior to dosing on the day of dosing. 
b Visit suitable for home administration of crenezumab. 
c Medical history includes clinically significant diseases, surgeries, respiratory diseases and risk factors, surgeries, cancer history (including prior cancer therapies 
and procedures), smoking history, use of alcohol and drugs of abuse, and all medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic 
remedies, nutritional supplements) used by the patient within 3 months prior to the screening visit.  Demographic data will include age, sex, and self-reported 
race/ethnicity.  Demographics of caregiver will also be collected. 
d Vital signs include measurements of weight, pulse rate, systolic and diastolic blood pressure, respiratory rate, oxygen saturation, and body temperature.  The 
same arm should be used for all blood pressure measurements.  Heart rate and blood pressure should not be measured unless 15 minutes have passed since 
the last blood draw. Vital sign assessments should be performed just prior to study drug administration, at the end of infusion, and 60−90 minutes after the end of 
infusion.  Weight need only be measured prior to study drug administration.  All vitals should be recorded in the eCRF. Height should be recorded at the 
screening visit only. Vital sign assessments should be performed at the site or by the health care provider who is administering study drug; such assessments 
should not be captured separately at the site if such administration is done at a different location (e.g. by a home nurse). 
e All scheduled PK and plasma biomarker samples should be obtained just prior to study drug administration, if possible.  Accurate recording of the time of study 
drug administration, and PK or PD sample is critical.  Unscheduled PK samples should be taken in the event anaphylaxis, anaphylactoid, or serious  
hypersensitivity reactions. 
f At screening, three mandatory whole blood samples will be obtained for DNA extraction for analysis of APOE status 
 
g At screening, two mandatory RNA samples will be taken 
 (paxgene tubes). 
h Perform after the patient has been in a supine position for 5 minutes.  ECGs for each patient should be obtained from the same machine whenever possible and 
performed prior to any blood draws, brain MRI scans, and lumbar puncture. 
i PK samples will be taken pre- and  60-90 minutes post-infusion. 
j Immunogenicity samples should be obtained prior to study drug administration.  Samples are taken to measure antibody development to crenezumab (ADAs) 
and other drug component products.  Unscheduled samples should be taken in the event anaphylaxis, anaphylactoid, or serious  hypersensitivity reactions. For 
any patient suspected of developing anaphylaxis, or anaphylactoid or serious hypersensitivity reactions warranting discontinuation of dosing, a washout ADA 
sample (16 weeks post-dose) and concurrent PK sample must be collected. 
k Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, CPK, sodium, potassium, calcium, BUN/urea, and serum 
creatinine (and creatinine clearance calculated by the central laboratory).  At the screening, and Week 53, hemoglobin A1C, folic acid, vitamin B12, T4, free T4, 
and thyroid-stimulating hormone levels will also be assessed.  At screening only, serum samples will be tested for HIV and hepatitis B and C virus.  


 
 
Appendix 1  
Schedule of Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
141/Protocol BN29553, Version 2  
l Hematology includes hemoglobin, hematocrit, RBC (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and 
WBC-other total counts.  At baseline and Week 25, immunophenotyping analysis of peripheral blood cells.  In the event of a pneumonia diagnosis, 
immunophenotyping analysis of peripheral blood cells should be repeated. 
m Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and pH.  Microscopic examination performed at the central laboratory if blood 
and/or protein results are positive or strongly positive.  Results do not need to be recorded on the eCRF. 
n At screening only, urine samples will be analyzed for the presence of the following drugs:  amphetamine, benzodiazepines, cannabinoids, opiates, cocaine, 
barbiturates, and methadone.  Results will be used to verify patient eligibility pertaining to drugs of abuse.  Inconclusive results may be repeated during the 
screening period.  Investigators should use their best clinical judgment in cases where results may be erroneous (e.g., permitted use of opiates or ingestion of 
food/food supplements). 
o Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in 
the source documents.  Urine pregnancy testing must also be performed and a negative result obtained prior to receiving injection of a PET radioligand. 
p At visits between Week 5 and Week 101, assessment of neurological or physical adverse events will be symptom-led. 
q CSF sampling, new PET and MRI scans at screening should be performed once all other screening results are available and none exclude the patient from the 
trial. 
r MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  MRI should be performed 
before or at least 3 days following a lumbar puncture.  The patient must be called in advance of the MRI to ask whether he or she is experiencing any CNS 
symptoms. 
s Lumbar puncture must be performed in the morning (between 8:00 a.m. and noon) to minimize potential diurnal variation of CSF parameters.  For post baseline 
visits, lumbar puncture should be performed prior to dosing but on the same day as predose plasma biomarker and serum PK samples are taken.  During 
screening, lumbar puncture should be performed 3 days before MRI – or after MRI has been done for screening.  Post-baseline, if a patient is participating in any 
CSF substudy, the MRI must be completed before the CSF sample is taken.  
t If FCSRT and MMSE are completed following FCSRT/MMSE consent, and patient is not excluded, these assessments would not need to be repeated during 
the screening period.  
u C-SSRS-Baseline form should be used on the baseline visit; subsequent visits should use the “since-last-visit” form. 
v Study drug administration should be performed only after all assessments/rating scales for the patient are completed (unless indicated otherwise).  Study drug 
will be administered to patients as infusion (full details in the pharmacy manual).  Patients should be observed for a minimum of 1 hour after dosing and vitals 
should be assessed immediately after infusion is completed, and then ≥60 minutes post-infusion. 
w CSF sample only in those who have consented to participate in the BN29553-CSF longitudinal substudy. 
x  PET assessment only in those who have consented to participate in the BN29552/BN29553-Amyloid PET longitudinal substudy or BN29552/BN29553-tau 
PET longitudinal substudy.


 
 
Appendix 1  
Schedule of Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
142/Protocol BN29553, Version 2  
Table 2 
Year 2 Assessments 
Assessment/Procedure 
Treatment Period 
 
Follow-up for those not 
entering OLE 
 
Wk 
57 
Wk 
61 
Wk
65 
Wk
69 
Wk 
73 
Wk
77 
Wk
81 
Wk 
85 
Wk 
89 
Wk 
93 
Wk
97 
Wk
101 
Wk 105 
+4 wks 
(or ET) 
Wk 117 
+16 wks 
Wk 153 
+52 wks 
Dose number 
15 a 
16 a 
17 a 
18 a 
19 a 
20 b 
21 a 
22 a 
23 a 
24 a 
25 a 
26 a 
b, c 
 
 
Vital signs d 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Urinalysis e 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Urine pregnancy test f 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Plasma biomarker sample g 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
PK serum sample g 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
Immunogenicity sample h 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
12-lead ECG i 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
 
Physical / neurological 
exam j 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Serum chemistry and 
hematology  k, l 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
MRI n 
 
 
 
 
 
x 
 
 
 
 
 
 
x  
 
 
PET/CSF sample 
 
 
 
 
 
 
 
 
 
 
 
 
x o, p 
 
 
CDR 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
ADAS-Cog-13 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
ADCS-ADL; FAQ 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
MMSE 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
NPI-Q 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 
FCSRT-IR 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
EQ-5D 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
QOL-AD 
 
 
 
 
 
x 
 
 
 
 
 
 
x 
x 
x 
ZCI-AD 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
x 


 
 
Appendix 1  
Schedule of Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
143/Protocol BN29553, Version 2  
Assessment/Procedure 
Treatment Period 
 
Follow-up for those not 
entering OLE 
 
Wk 
57 
Wk 
61 
Wk
65 
Wk
69 
Wk 
73 
Wk
77 
Wk
81 
Wk 
85 
Wk 
89 
Wk 
93 
Wk
97 
Wk
101 
Wk 105 
+4 wks 
(or ET) 
Wk 117 
+16 wks 
Wk 153 
+52 wks 
Dose number 
15 a 
16 a 
17 a 
18 a 
19 a 
20 b 
21 a 
22 a 
23 a 
24 a 
25 a 
26 a 
b, c 
 
 
C-SSRS SLV  
 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Adverse events  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Study drug administration m 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
ACDS-ADL=Alzheimer’s Disease Cooperative Study – Activities of Daily Living; ADAS-Cog13 = Alzheimer’s Disease Activity Scale Cognition (subscale) 13; 
CDR = Clinical Dementia Rating; C-SSRS= Columbia Suicide Severity Rating Scale; 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; QOL-AD = Quality of Life−Alzheimer’s Disease; 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.  Patients should return to initial planned schedule per randomization for 
subsequent visits.  For patients who terminate early, assessments listed in the ET visit should be completed. 
In case of rescreening a patient, all screening assessments must be repeated other than the MRI (if performed within 8 weeks of randomization), lumbar 
puncture and amyloid PET scan if previous results were within eligible ranges. 
a Visit suitable for home administration of crenezumab. 
b  Visit may be split over 2 days.  All cognitive and functional assessments should be completed first.  All safety assessments (e.g., visits, blood tests, and ECGs) 
should be completed on the day of dosing. 
c  Transition to OLE protocol for those eligible to participate. 
d Vital signs include measurements of weight, pulse rate, systolic and diastolic blood pressure, respiratory rate, oxygen saturation, and body temperature.  The 
same arm should be used for all blood pressure measurements.  Heart rate and blood pressure should not be measured unless 15 minutes have passed since 
the last blood draw.  Vital sign assessments should be performed just prior to study drug administration, at the end of infusion, and 60−90 minutes after the end 
of infusion.  All vitals should be recorded in the eCRF.  Vital sign assessments should be performed at the site or by the health care provider who is 
administering study drug; such assessments should not be captured separately at the site if such administration is done at a different location (e.g., by a home 
nurse). 
e Urinalysis will be performed at the site by dipstick for blood, protein, glucose, and pH.  Microscopic examination performed at the central laboratory if blood 
and/or protein results are positive or strongly positive.  Results do not need to be recorded on the eCRF. 


 
 
Appendix 1  
Schedule of Assessments (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
144/Protocol BN29553, Version 2  
f  Females of childbearing potential (including those who have had a tubal ligation) must have a urine pregnancy test performed at the site prior to each dose 
administration. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test at the central laboratory.  Results are to be recorded only in 
the source documents.  Urine pregnancy testing must also be performed and a negative result obtained prior to receiving injection of a PET radioligand, 
g  All scheduled PK samples and plasma PD should be obtained just prior to study drug administration, if possible.  Accurate recording of the time of study drug 
administration and PK or PD sample is critical. Unscheduled PK samples should be taken in the event of anaphylaxis, anaphylactoid, or serious hypersensitivity 
reactions. 
h  Immunogenicity samples should be obtained prior to study drug administration; samples are taken to measure antibody development to crenezumab (ADAs) 
and other drug component products.  Unscheduled samples should be taken in the event of anaphylaxis, anaphylactoid, or serious hypersensitivity reactions.  
For any patient suspected of developing anaphylaxis, or anaphylactoid or serious hypersensitivity reactions warranting discontinuation of dosing, a washout 
ADA sample (16 weeks post-dose) and concurrent PK sample must be collected. 
i Perform after the patient has been in a supine position for 5 minutes.  ECGs for each patient should be obtained from the same machine whenever possible and 
performed prior to any blood draws, brain MRI scans, and lumbar puncture. 
j 
At visits between Week 5 and Week 101, assessment of neurological or physical adverse events will be symptom-led. 
k Serum chemistry includes AST, ALT, alkaline phosphatase, total protein, total bilirubin, serum albumin, CPK, sodium, potassium, calcium, BUN/urea, and serum 
creatinine (and creatinine clearance calculated by the central laboratory).  
l Hematology includes hemoglobin, hematocrit, RBC (with morphology), WBC counts, platelet, basophil, eosinophil, lymphocyte, monocyte, neutrophil, and 
WBC−other total counts. In the event of a pneumonia diagnosis, immunophenotyping analysis of peripheral blood cells should be repeated. 
m Study drug administration should be performed only after all assessments/rating scales for the patient are completed (unless indicated otherwise).  Study drug 
will be administered to patients as infusion (full details in the pharmacy manual).  Patients should be observed for a minimum of 1 hour after dosing and vitals 
should be assessed immediately after infusion is completed, and then ≥60 minutes post infusion. 
n MRI must be performed at least 7 days before dosing and results must be available for review by site staff before dosing can proceed.  The patient will be called 
in advance of the MRI regarding any CNS symptoms experienced.  
o CSF sample only in those who have consented to participate in the BN29553-CSF longitudinal substudy. 
p  PET assessment only in those who have consented to participate in the BN29552/BN29553-Amyloid PET longitudinal substudy or BN29552/BN29553-tau 
PET longitudinal substudy.


 
Crenezumab—F. Hoffmann-La Roche Ltd 
145/Protocol BN29553, Version 2  
Appendix 2  
National Institute on Aging/Alzheimer’s Association Criteria for 
Dementia due to Alzheimer’s Disease 
NIA-AA category 
Description 
Probable Dementia: 
core Clinical Criteria 
Meets criteria for 
dementia described 
earlier in the text, 
and in addition, has 
the following 
characteristics: 
A. Insidious onset. Symptoms have a gradual onset over months to years, 
not sudden over hours or days; 
B. Clear-cut history of worsening of cognition by report or observation; 
and 
C. The initial and most prominent cognitive deficits are evident on history 
and examination in one of the following categories. 
a. Amnestic presentation: It is the most common syndromic 
presentation of AD dementia. The deficits should include impairment 
in learning and recall of recently learned information. There should 
also be evidence of cognitive dysfunction in at least one other 
cognitive domain, as defined earlier in the text. 
b. Non-amnestic presentations: 
Language presentation: The most prominent deficits are in 
word-finding, but deficits in other cognitive domains should be 
present. 
Visuospatial presentation: The most prominent deficits are in 
spatial cognition, including object agnosia, impaired face 
recognition, simultanagnosia, and alexia. Deficits in other 
cognitive domains should be present. 
Executive dysfunction: The most prominent deficits are impaired 
reasoning, judgment, and problem solving. Deficits in other 
cognitive domains should be present. 
D. The diagnosis of probable AD dementia should not be applied when 
there is evidence of (a) substantial concomitant cerebrovascular disease, 
defined by a history of a stroke temporally related to the onset or 
worsening of cognitive impairment; or the presence of multiple or 
extensive infarcts or severe white matter hyperintensity burden; or (b) 
core features of Dementia with Lewy bodies other than dementia itself; or 
(c) prominent features of behavioral variant frontotemporal dementia; or 
(d) prominent features of semantic variant primary progressive aphasia or 
nonfluent/agrammatic variant primary progressive aphasia; or (e) 
evidence for another concurrent, active neurological disease, or a non-
neurological medical comorbidity or use of medication that could have a 
substantial effect on cognition. 
Probable AD 
dementia with 
increased level of 
certainty 
Probable AD dementia with documented decline 
In persons who meet the core clinical criteria for probable AD dementia, 
documented cognitive decline increases the certainty that the condition 
represents an active, evolving pathologic process, but it does not 
specifically increase the certainty that the process is that of AD 
pathophysiology. 
Probable AD dementia with documented decline is defined as follows: 
evidence of progressive cognitive decline on subsequent evaluations 
based on information from informants and cognitive testing in the context 
of either formal neuropsychological evaluation or standardized mental 
status examinations. 


Appendix 2  
National Institute on Aging/Alzheimer’s Association Criteria for 
Dementia due to Alzheimer’s Disease (cont.) 
Crenezumab—F. Hoffmann-La Roche Ltd 
146/Protocol BN29553, Version 2  
Probable AD dementia in a carrier of a causative AD genetic mutation 
In persons who meet the core clinical criteria for probable AD dementia, 
evidence of a causative genetic mutation (in APP, PSEN1, or PSEN2), 
increases the certainty that the condition is caused by AD pathology. The 
workgroup noted that carriage of the ɛ4 allele of the apolipoprotein E 
gene was not sufficiently specific to be considered in this category. 
Probable AD 
dementia with 
evidence of the AD 
pathophysiological 
process 
AD dementia is part of a continuum of clinical and biological phenomena. 
AD dementia is fundamentally a clinical diagnosis. To make a diagnosis 
of AD dementia with biomarker support, the core clinical diagnosis of AD 
dementia must first be satisfied. 
Relevant biomarkers include amyloid-β(CSF or PET); tau (CSF or PET)  
 
Source:  McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due 
to Alzheimer’s disease: Recommendations from the National Institute on 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimer’s & Dement 2011;7:263−9. 
 


 
Crenezumab—F. Hoffmann-La Roche Ltd 
147/Protocol BN29553, Version 2  
Appendix 3  
National Institute on Aging/Alzheimer’s Association Criteria for 
Prodromal Alzheimer’s Disease (Mild Cognitive Impairment due 
to Alzheimer’s Disease) 
NIA-AA category 
Clinical and cognitive criteria 
Clinical Criteria 
: 
Cognitive concern reflecting a change in cognition reported by patient or 
informant or clinician (i.e., historical or observed evidence of decline 
over time) 
 
Objective evidence of Impairment in one or more cognitive domains, 
typically including memory (i.e., formal or bedside testing to establish 
level of cognitive function in multiple domains) 
 
Preservation of independence in functional abilities 
 
Not demented 
 
Etiology of MCI 
consistent with AD 
pathophysiological 
process 
Rule out vascular, traumatic, medical causes of cognitive decline, where 
possible 
 
Provide evidence of longitudinal decline in cognition, when feasible 
 
Report history consistent with AD genetic factors, where relevant 
Prodromal AD 
dementia with 
evidence of the AD 
pathophysiological 
process 
pAD is part of a continuum of clinical and biological phenomena. pAD is 
fundamentally a clinical diagnosis. To make a diagnosis of pAD with 
biomarker support, the core clinical diagnosis of pAD must first be 
satisfied. 
Relevant biomarkers include amyloid-β(CSF or PET); tau (CSF or PET)  
 
 
Source:  Albert MS, DeKosky ST, Dickson B, et al. The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: Recommendations from the National Institute on 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimer’s & Dement 2011;7:270-279


 
Crenezumab—F. Hoffmann-La Roche Ltd 
148/Protocol BN29553, Version 2  
Appendix 4  
Diagnostic Verification Form 
Instructions  
 
The Medical Monitor or assignee will review the form and indicate whether a subject 
may continue with screening. Confirmation of review must be given before any 
invasive procedures are conducted. The clinical team or assignee will confirm eligibility 
based on the diagnostic verification form with the site.  
 
Date 
Please list all dates as DD-MMM-
YYYY 
 
Subject Screening Number 
 
Name of Person submitting 
request 
 
Email of Person submitting 
request 
 
Principal Investigator email 
 
Investigator Direct Contact 
Number 
 
Site Telephone Number 
 
Site Fax Number 
 
I have evaluated this patient and confirm that the information 
documented on this form represents the best information (based on 
clinical evaluation and other information sources) available at this 
time 
Investigator (or Sub-Investigator 
or CDR Rater) Name  
 
 
Investigator (or Sub-Investigator 
or CDR Rater) 
(Electronic signature) 
 
 
 
 
 
 


 
Crenezumab—F. Hoffmann-La Roche Ltd 
149/Protocol BN29553, Version 2  
 
Appendix 5  
Diagnostic Verification Form (cont.) 
 
Verification of diagnosis 
Based upon the review of the screening information made available by the site, I 
confirm the above noted patient has been reviewed and conclude: 
  
 Yes, the patient may continue with screening 
 
 No, the patient cannot continue with screening 
Reviewer 
(electronic signature) 
 
Date of confirmation 
 
 
CLINICAL HISTORY 
 
1 
By patient, caregiver, clinician report, when did the patient first experience or 
exhibit symptoms of cognitive dysfunction (month/year)? 
  
AFFECTED COGNITIVE DOMAINS 
NIA-AA criteria require the involvement of at least one cognitive domain for mild 
cognitive impairment, or at least two domains for dementia. Please indicate which of 
the following cognitive domains are affected AND which test(s) was/were used; if 
known please provide dates of assessment. 
 
 
 Memory (impaired ability to acquire and remember new information) 
 
 Executive function / complex attention (e.g. impaired reasoning, impaired 
problem solving, inability to plan and organize):  
 
 Visuospatial function (inability to recognize faces or common objects, to find 
objects in direct view despite adequate visual acuity, to operate simple tools, or 
to orient clothes on the body):  
 
 Language (impairments in comprehension, naming, word retrieval, verbal 
fluency, grammar; disturbances in understanding emotional content of speech):  
 
 Praxis 
 
 
 


 
Crenezumab—F. Hoffmann-La Roche Ltd 
150/Protocol BN29553, Version 2  
 
Appendix 6  
Diagnostic Verification Form (cont.) 
 
2 
Does the patient currently have Dementia [
] or Mild Cognitive 
Impairment? [
].When was the diagnosis in (2) first made (month/year)? 
 
3 
If the patient has dementia, please detail how functional impairment has 
been established (include patient/caregiver history, and any standardized 
assessment, e.g., CDR) and which areas of the patient’s life have been 
affected: 
 
 
 
 
4 
Has there been cognitive or functional decline in the past 12 months? 
[yes 
 /no 
] 
 
If yes, please give examples of specific deficits that have emerged or 
deteriorated in the past year as reported by the caregiver or clinician: 
 
 
 
If yes, please report any available objective evidence of progression 
(e.g., MMSE or MoCA scores at two time points, with dates): 
 
 
 
 
5 
 
SUPPORTIVE INFORMATION 
 
Please provide details of any other supportive diagnostic information 
(e.g., MRI, amyloid-PET, tau-PET, FDG-PET, CSF biomarkers, etc.)