Clinical trial NCT01723826
Conditions: Alzheimer's Disease
Sponsor: Genentech, Inc.
Start date: 2012-12-07; Completion date: 2017-02-08
Enrollment: 360 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase II, open-label extension (OLE), multicenter study will evaluate the long-term safety and tolerability of crenezumab in participants with mild to moderate Alzheimer's disease who have participated in and completed the treatment period of the Phase II Study ABE4869g (NCT01343966) or ABE4955g (NCT01397578). Participants who received placebo in Study ABE4869g (NCT01343966) or ABE4955g (NCT01397578) will receive crenezumab. Anticipated time on study treatment is 144 weeks.

Detailed description:

Arms: arm 1: Participants will receive intravenous infusion of crenezumab every 4 weeks for 144 weeks.
Interventions: intervention 1: Crenezumab
Intervention descriptions: intervention 1: Participants will receive intravenous infusion of crenezumab every 4 weeks for 144 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
A MULTICENTER, OPEN-LABEL, LONG-TERM SAFETY 
EXTENSION OF PHASE II STUDIES ABE4869g AND ABE4955g 
IN PATIENTS WITH MILD TO MODERATE ALZHEIMER’S 
DISEASE  
NCT Number: 
NCT01723826 
Document Date: 
Protocol Version 6: 22-November-2014 
 
 


 
Title
22-Nov-2014 17:45:31
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
Genentech, Inc. (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 Genentech except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered. 
 
Crenezumab—Genentech, Inc. 
Protocol GN28525, Version 6 
PROTOCOL 
TITLE: 
A MULTICENTER, OPEN-LABEL, LONG-TERM 
SAFETY EXTENSION OF PHASE II STUDIES 
ABE4869g AND ABE4955g IN PATIENTS WITH 
MILD TO MODERATE ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: GN28525 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2012-003242-33 
IND NUMBER: 
IND 100,839 
TEST PRODUCT: 
Crenezumab (RO5490245) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
DATE FINAL: 
Version 1:  13 July 2012 
DATES AMENDED: 
Version 2:  31 August 2012 
Version 3:  23 August 2013 
Version 4:  19 August 2014 
Version 5:  28 August 2014 
Version 6:  See electronic date stamp below 


Crenezumab—Genentech, Inc. 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 16 
PROTOCOL SYNOPSIS .................................................................................... 17 
1. 
BACKGROUND .......................................................................................... 27 
1.1 
Background on Alzheimer’s Disease ..................................... 27 
1.2 
Background on Crenezumab (MABT5102A) ......................... 28 
1.3 
Study Rationale and Benefit-Risk Assessment ...................... 28 
1.3.1 
Clinical Experience with Study ABE4869g 
(Completed) ........................................................................... 29 
1.3.2 
Clinical Experience with Study ABE4955g 
(Completed) ........................................................................... 29 
1.3.3 
Safety Experience in the Phase II Program ........................... 30 
1.3.3.1 
Deaths ................................................................................... 30 
1.3.3.2 
Discontinuations .................................................................... 31 
1.3.3.3 
Serious and Non-Serious Adverse Events ............................. 31 
1.3.3.4 
Adverse Events of Special Interest ........................................ 32 
1.3.3.5 
Additional Safety Information ................................................. 34 
1.3.4 
Clinical Pharmacokinetics ...................................................... 34 
1.3.5 
Immunogenicity ..................................................................... 35 
1.3.6 
Benefit-Risk Summary ........................................................... 36 
2. 
OBJECTIVES .............................................................................................. 37 
2.1 
Efficacy Objectives ................................................................ 37 
2.2 
Safety Objective .................................................................... 37 
2.3 
Exploratory Objectives ........................................................... 37 
3. 
STUDY DESIGN ......................................................................................... 38 
3.1 
Description of Study .............................................................. 38 
3.1.1 
Overview of Study Design ..................................................... 38 
3.1.2 
Internal Safety Monitoring Committee ................................... 40 
3.2 
End of Study .......................................................................... 41 
3.3 
Rationale for Study Design .................................................... 41 
3.4 
Outcome Measures ............................................................... 41 
3.4.1 
Primary Outcome Measures .................................................. 41 


 
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3.4.2 
Exploratory Outcome Measures ............................................ 41 
4. 
MATERIALS AND METHODS .................................................................... 42 
4.1 
Patients .................................................................................. 42 
4.1.1 
Inclusion Criteria .................................................................... 43 
4.1.2 
Exclusion Criteria ................................................................... 43 
4.2 
Method of Treatment Assignment and Blinding ..................... 46 
4.2.1 
Formulation, Packaging, and Handling .................................. 46 
4.2.1.1 
Crenezumab (MABT5102A) .................................................. 46 
4.2.2 
Crenezumab Dosage, Administration, and 
Compliance ............................................................................ 46 
4.2.2.1 
Subcutaneous Dosing ........................................................... 46 
4.2.2.2 
Intravenous Dosing ................................................................ 46 
4.2.3 
Investigational Medicinal Product Accountability ................... 47 
4.2.4 
Post-Trial Access to Crenezumab ......................................... 47 
4.2.5 
Permitted Therapy ................................................................. 48 
4.2.6 
Prohibited Therapy ................................................................ 48 
4.3 
Study Assessments ............................................................... 49 
4.3.1 
Informed Consent Forms and Screening Log ........................ 49 
4.3.2 
Medical History and Demographic Data ................................ 49 
4.3.3 
Physical Examinations ........................................................... 49 
4.3.4 
Vital Signs .............................................................................. 50 
4.3.5 
Neurologic Examination ......................................................... 50 
4.3.6 
Magnetic Resonance Imaging Assessments ......................... 50 
4.3.7 
Columbia-Suicide Severity Rating Scale 
(C-SSRS) ............................................................................... 50 
4.3.8 
Neurocognitive and Functional Assessments ........................ 51 
4.3.9 
Laboratory Assessments ....................................................... 51 
4.3.10 
Electrocardiograms ................................................................ 52 
4.4 
Patient, Treatment, Study, and Site 
Discontinuation ...................................................................... 52 
4.4.1 
Patient Discontinuation .......................................................... 52 
4.4.2 
Study Treatment Discontinuation ........................................... 53 


 
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4.4.3 
Study and Site Discontinuation .............................................. 53 
5. 
ASSESSMENT OF SAFETY ....................................................................... 54 
5.1 
Safety Plan ............................................................................ 54 
5.1.1 
Amyloid-Related Imaging Abnormalities – 
Edema/Effusion (ARIA-E) ...................................................... 54 
5.1.2 
Amyloid-Related Imaging Abnormalities–
Hemorrhage (ARIA-H) ........................................................... 56 
5.1.3 
Pneumonia ............................................................................ 57 
5.1.4 
Deaths ................................................................................... 58 
5.2 
Safety Parameters and Definitions ........................................ 58 
5.2.1 
Adverse Events ..................................................................... 58 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor) ...................................................................... 59 
5.2.3 
Non-Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) .............................. 59 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters ................................................ 60 
5.3.1 
Adverse Event Reporting Period ........................................... 60 
5.3.2 
Eliciting Adverse Event Information ....................................... 61 
5.3.3 
Assessment of Severity of Adverse Events ........................... 61 
5.3.4 
Assessment of Causality of Adverse Events ......................... 62 
5.3.5 
Procedures for Recording Adverse Events ............................ 62 
5.3.5.1 
Diagnosis versus Signs and Symptoms................................. 63 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events .................................................................................... 63 
5.3.5.3 
Persistent or Recurrent Adverse Events ................................ 64 
5.3.5.4 
Abnormal Laboratory Values ................................................. 64 
5.3.5.5 
Abnormal Vital Sign Values ................................................... 65 
5.3.5.6 
Abnormal Liver Function Tests .............................................. 65 
5.3.5.7 
Deaths ................................................................................... 66 
5.3.5.8 
Pre-Existing Medical Conditions ............................................ 66 
5.3.5.9 
Worsening of Alzheimer’s Disease ........................................ 66 


 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization .......................... 67 
5.3.5.11 
Adverse Events Associated with an Overdose ...................... 67 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .......................................................... 67 
5.4.1 
Emergency Medical Contacts ................................................ 68 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of 
Special Interest ...................................................................... 68 
5.4.3 
Reporting Requirements for Pregnancies .............................. 69 
5.4.3.1 
Pregnancies in Female Patients ............................................ 69 
5.4.3.2 
Pregnancies in Female Partners of Male Patients ................. 69 
5.4.3.3 
Abortions ............................................................................... 70 
5.4.3.4 
Congenital Anomalies/Birth Defects ...................................... 70 
5.5 
Follow-Up of Patients after Adverse Events .......................... 70 
5.5.1 
Investigator Follow-Up ........................................................... 70 
5.5.2 
Sponsor Follow-Up ................................................................ 70 
5.6 
Post-Study Adverse Events ................................................... 71 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ................................................................. 71 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ....................... 72 
6.1 
Determination of Sample Size ............................................... 72 
6.2 
Summaries of Conduct of Study ............................................ 72 
6.3 
Summaries of Treatment Group Comparability ..................... 72 
6.4 
Safety Analyses ..................................................................... 72 
6.4.1 
Adverse Events ..................................................................... 73 
6.4.2 
Clinical Laboratory Evaluations ............................................. 73 
6.4.3 
MRI Evaluations .................................................................... 73 
6.4.4 
Anti-Therapeutic Antibodies ................................................... 73 
6.5 
Pharmacodynamic Analyses ................................................. 73 
6.6 
Pharmacokinetic Analyses ..................................................... 73 
6.7 
Exploratory Analyses ............................................................. 73 


 
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6.8 
Interim Analyses .................................................................... 73 
7. 
DATA COLLECTION AND MANAGEMENT ............................................... 74 
7.1 
Data Quality Assurance ......................................................... 74 
7.2 
Electronic Case Report Forms ............................................... 74 
7.3 
Source Data Documentation .................................................. 74 
7.4 
Use of Computerized Systems .............................................. 75 
7.5 
Retention of Records ............................................................. 75 
8. 
ETHICAL CONSIDERATIONS .................................................................... 76 
8.1 
Compliance with Laws and Regulations ................................ 76 
8.2 
Informed Consent .................................................................. 76 
8.3 
Institutional Review Board or Ethics Committee .................... 77 
8.4 
Confidentiality ........................................................................ 77 
8.5 
Financial Disclosure .............................................................. 78 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 78 
9.1 
Study Documentation ............................................................ 78 
9.2 
Site Inspections ..................................................................... 78 
9.3 
Administrative Structure ......................................................... 78 
9.4 
Protocol Amendments ........................................................... 78 
10. REFERENCES ........................................................................................... 80 
 
 
LIST OF TABLES 
Table 1 
Adverse Event Severity Grading Scale ....................................... 61 
Table 2 
Causal Attribution Guidance ....................................................... 62 
 
 
LIST OF FIGURES 
Figure 1 
Study Timeline ............................................................................ 40 


 
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LIST OF APPENDICES 
APPENDIX 1  Study Flowchart:  Screening to Week 33 ..................................... 82 
APPENDIX 2 Study Flowchart:  Week 37 to Week 77 ........................................ 86 
APPENDIX 3 Study Flowchart:  Week 81 to Week 121 ...................................... 89 
APPENDIX 4 Study Flowchart:  Week 125 to Week 145 and Follow-Up 
Visits ........................................................................................... 92 
APPENDIX 5  Study Flowchart:  Safety Follow-Up Assessments after Early 
Termination ................................................................................. 95 
APPENDIX 6 Neurocognitive and Functional Assessments ............................... 96 


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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A MULTICENTER, OPEN-LABEL, LONG-TERM 
SAFETY EXTENSION OF PHASE II STUDIES 
ABE4869g AND ABE4955g IN PATIENTS WITH 
MILD TO MODERATE ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: GN28525 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2012-003242-33 
IND NUMBER: 
IND 100,839 
TEST PRODUCT: 
Crenezumab (RO5490245) 
MEDICAL MONITOR: 
, M.D., Ph.D. 
SPONSOR: 
Genentech, Inc. 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return a copy of this form to the contract research organization’s representative.  
Please retain the original for your study files. 
 
 


 
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17/Protocol GN28525, Version 6 
PROTOCOL SYNOPSIS 
TITLE: 
A MULTICENTER, OPEN-LABEL, LONG-TERM SAFETY 
EXTENSION OF PHASE II STUDIES ABE4869g AND ABE4955g IN 
PATIENTS WITH MILD TO MODERATE ALZHEIMER’S DISEASE 
PROTOCOL NUMBER: 
GN28525 
VERSION NUMBER: 
6 
EUDRACT NUMBER: 
2012-003242-33 
IND NUMBER: 
IND 100,839 
TEST PRODUCT: 
Crenezumab (RO5490245) 
PHASE: 
II 
INDICATION: 
Alzheimer’s Disease 
SPONSOR: 
Genentech, Inc. 
 
Objectives 
Primary Objective 
The primary objective for this study is as follows: 
• 
To assess the long-term safety and tolerability of crenezumab administered subcutaneously 
every 2 weeks (q2w) or intravenously every 4 weeks (q4w), in eligible patients with 
Alzheimer’s disease who participated in Study ABE4869g or ABE4955g and completed the 
Week 73 study visit, including brain magnetic resonance imaging (MRI) 
Efficacy Objectives 
There are no efficacy objectives for this study, although select efficacy outcome measures will 
continue to be collected. 
Safety Objectives 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of crenezumab in patients with Alzheimer’s disease 
focusing on treatment-emergent adverse events, vital signs, routine laboratory analysis, 
immunogenicity, and cerebral imaging abnormalities (assessed by MRI) 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To evaluate the long-term effect of crenezumab on disease progression using the 
Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog [12-item]) 
• 
To evaluate the long-term effect of crenezumab on disease progression using 
Clinical Dementia Rating, Sum of Boxes (CDR-SOB) 
• 
To evaluate the long-term effect of crenezumab on patient functioning using the 
Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) 
• 
To evaluate the long-term effect of crenezumab on disease progression using supplemental 
neurocognitive measures (i.e., Exploratory Neurocognitive Test Panel [ENTP]) selected to 
assess episodic memory performance, executive functions, verbal fluency, working memory, 
and psychomotor speed 
• 
To evaluate the long-term effect of crenezumab on behavior using the 
Neuropsychiatric Inventory (NPI) 


 
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18/Protocol GN28525, Version 6 
• 
To evaluate the long-term effects of crenezumab on the amount of assistance patients with 
dementia require in performing daily activities using the Dependence Scale 
• 
To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of 
crenezumab 
• 
To evaluate the PK/PD relationship of crenezumab using exploratory PD biomarkers 
• 
To evaluate changes in MRI biomarkers, such as global and regional brain volumes and 
functional connectivity 
Study Design 
Description of Study 
Study GN28525 is a Phase II, open-label extension (OLE), multicenter study to evaluate the 
long-term safety and tolerability of crenezumab in patients with mild-to-moderate 
Alzheimer’s disease who have participated in and completed the treatment period of the 
Phase II Study ABE4869g or ABE4955g.  Patients from Studies ABE4869g and ABE4955g who 
discontinued from study treatment early but remained on study for safety evaluations, or 
discontinued prior to completion of the Week 73 study visit, are not eligible for this OLE study. 
ABE4869g (ABBY) is a completed Phase II, multicenter, global, randomized, double-blind, 
parallel-group, placebo-controlled study to evaluate the safety and efficacy of crenezumab in 
patients with mild-to-moderate Alzheimer’s disease.  Four hundred forty-six patients were 
randomized and 444 patients were dosed at approximately 100 sites in North America and 
Europe. 
ABE4955g (BLAZE) is a completed Phase II, multicenter, global, randomized, double-blind, 
parallel-group, placebo-controlled study to evaluate the effects of crenezumab on brain amyloid 
burden, as assessed by florbetapir- positron emission tomography (PET), and other biomarkers 
in patients with mild-to-moderate Alzheimer’s disease.  Ninety-one patients were randomized 
and 61 were dosed at approximately 30 sites in North America and Europe. 
This OLE study includes patients who have been diagnosed with Alzheimer’s disease and have 
a Mini-Mental State Examination (MMSE) score of 10 or more at the time of screening, which is 
lower than in Studies ABE4869g and ABE4955g (MMSE 18 – 26) to account for the disease 
progression in the course of these studies.  An MMSE score of less than 10 at the beginning of 
the OLE study would substantially increase the risk that a patient would not be able to complete 
the study assessments and to comply with the protocol’s requirements in the future.  
Patients will undergo a neuroradiological evaluation using a standard MRI protocol and 
T2* gradient echo MRI to exclude any significant MRI abnormality and presence of cerebral 
superficial siderosis or more than eight cerebral microhemorrhages.  Only patients with 4 or less 
cerebral microhemorrhages at screening are allowed to participate in Studies ABE4869g and 
ABE4955g and study drug will be discontinued in patients with an increase of six or more in the 
number of asymptomatic microhemorrhages in these studies since high numbers of cerebral 
microhemorrhages have been associated with future risk of ischemic and hemorrhagic strokes.  
The microhemorrhage threshold for entry in this study is intended to minimize potential safety 
risks associated with microhemorrhages, but would not preclude the majority of the patients 
from Study ABE4869g or ABE4955g from rolling over into this OLE study.  However, this might 
exclude patients from participating in the OLE study due to the number of cerebral 
microhemorrhages that would not have led to treatment discontinuation in the Study ABE4869g 
or ABE4955g.  Patients with medical or psychiatric contraindication or clinically significant 
abnormalities that, in the investigator's judgment, would substantially increase the risk 
associated with the patient's participation in the study or interfere with the evaluation of the 
patient's response will not be included in the study.  
All patients enrolled in the OLE study were to receive active drug at the same dosing frequency, 
dose level, and route of administration they were assigned to after the Week 73 visit of 
Study ABE4869g or ABE4955g.  Patients who received matching placebo in Study ABE4869g 
or ABE4955g were to receive active drug (i.e., crenezumab 300 mg subcutaneously [SC] q2w 
for patients who were randomized in the SC cohort [Part 1] or 15 mg/kg IV q4w for patients who 
were randomized in the intravenous [IV] cohort [Part 2]).  However, evaluation of efficacy in 
ABE4869g and ABE4955g indicates that there was no consistent treatment effect in patients 
who received 300 mg q2w SC that would support continuation of this dose level.  In contrast, 


 
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there appears to be a trend towards reduction in cognitive decline in patients who received 
15 mg/kg q4w IV.  Considering these efficacy results and the available safety information, all 
patients in the OLE study will be dosed at 15 mg/kg q4w IV.  All patients who have been 
receiving active drug in the SC dosing arm will be transferred into the IV dosing arm. 
The study consists of three periods:  a screening period (up to 14 days), the window between 
the last dose in ABBY/BLAZE and the first dose in OLE may last 6 weeks, but may be 
prolonged on a case by case basis for relevant clinical, administrative, or operational reasons 
(these reasons must be discussed with the medical monitor in advance of screening; if 
necessary, some screening procedures may need to be repeated); period of 144 weeks (Week 1 
[Day 1] to Week 145), and an 8-week safety follow-up period (Weeks 145 to 153).  The final 
safety analysis will be performed at 153 weeks.   The original GN28525 protocol included a 
treatment period of 92 weeks (Week 1 [Day 1] to Week 93).  Version 6 of the GN28525 
protocol expands this treatment period by 52 weeks (13 additional IV doses from Week 97 to 
Week 145).  Patients who are still enrolled in Study GN28525 may enter the additional OLE 
treatment period (Week 97 to Week 145) if they have not discontinued treatment for safety 
reasons.  Patients who have already completed or discontinued from Study GN28525 are not 
eligible to receive additional treatment from Week 97 to Week 145. 
The Week 73 assessment (including MRI) of Studies ABE4869g and ABE4955g will be used to 
determine the patient’s eligibility in this OLE trial.  Data from the Week 73 visit assessments in 
Studies ABE4869g and ABE4955g will be extracted and incorporated in the OLE screening 
datasets.  Patients participating in this OLE study must be enrolled (i.e., Day 1 of the OLE 
treatment period) no later than 14 days after completion of the Week 73 assessments (including 
MRI) of Study ABE4869g or ABE4955g, except for individual exceptions, determined on a case 
by case basis, as mentioned above. 
The first dose of crenezumab is administered on Day 1 of the treatment period, and the last 
dose of treatment is at Week 145.  After patients complete the 144-week treatment period, they 
will enter the follow-up period.  Patients who are prematurely discontinued from the OLE study 
treatment will also discontinue from the OLE study and will be followed for safety for 8 weeks 
after their last dose of crenezumab. 
Patients will remain blinded to their assignment in Study ABE4869g or ABE4955g, and 
investigators are not permitted to provide treatment assignment in ABE4869g or ABE4955g until 
permitted by the Sponsor.     
Number of Patients 
This study is open to all patients who completed Study ABE4869g or ABE4955g and who met 
the eligibility criteria.  Four hundred forty-six patients were randomized, and 444 patients were 
dosed in Study ABE4869g at approximately100 sites in North America and Europe. Ninety-one 
patients were randomized, and 61 were dosed in Study ABE4955g at approximately 30 sites in 
North America and Europe. 
Target Population 
Patients who completed the Week 73 visit of Study ABE4869g or ABE4955g are eligible to 
participate in this OLE study; patients discontinued from study treatment or discontinued from 
study prior to completion of the Week 73 visit, will not be eligible for this OLE study. 
Patients must meet the following criteria for study entry: 
• 
Ability to provide written informed consent by the patient or the patient’s authorized 
representative under applicable local law 
• 
Ability and willingness of the patient to comply with the protocol’s requirements  
• 
Previous participation in Study ABE4869g or ABE4955g and completion of the 
Week 73 visit 
– 
Patients who discontinued from study treatment or from the study prior to completion of 
the Week 73 visit are not eligible. 
• 
Adequate visual and auditory acuity, in the investigator's judgment, to allow for 
neuropsychological testing 
• 
Availability of a person ("caregiver") who can provide information on activities of daily living 
and behavior in order to complete the study-specific assessments 


 
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– 
This caregiver must have sufficient cognitive capacity, in the judgment of the 
investigator, to accurately report upon the patient's function and behavior.  In addition, 
the caregiver must spend sufficient time with the patient to be familiar with the overall 
function and behavior of the patient.  As guidance, a caregiver would ordinarily need to 
spend an average of at least 8 hours per week with the patient in order for the 
caregiver to meet the requirements for this study.   
• 
Diagnosis of probable Alzheimer’s disease according to the National Institute on 
Neurological and Communication Disease and Stroke/Alzheimer’s Disease and Related 
Disorders Association (NINCDS-ADRDA) criteria 
• 
MMSE score of 10 or more at screening 
• 
For male patients with partners with reproductive potential, agreement to use a reliable 
means of contraception (e.g., condoms) during the study and for at least 8 weeks following 
the last dose of study drug 
• 
For female patients, a negative urine dipstick pregnancy test at screening (not required if 
patient has undergone documented surgical sterilization or have not experienced 
menstruation for at least 12 consecutive months) 
Patients who meet any of the following criteria will be excluded from study entry or continued 
participation: 
General 
• 
Early treatment and/or study discontinuation prior to completion of the Week 73 visit of 
Genentech Study ABE4869g or ABE4955g 
• 
Early discontinuation from the treatment schedule of a prior version of Study GN28525 
for safety reasons.  If treatment discontinuation occurred for safety reasons, patients may 
not re-start dosing on extended treatment schedules offered in amendments to 
Study GN28525. 
• 
Inability to tolerate MRI procedures or contraindication to MRI, including but not limited to 
pacemakers; implantable cardioverter defibrillators; cochlear implants; cerebral aneurysm 
clips; implanted infusion pumps; implanted nerve stimulators; metallic splinters in the eye; 
other magnetic, electronic, or mechanical implants; or any other clinical history or 
examination finding that, in the judgment of the investigator, would pose a potential hazard 
in combination with MRI 
• 
Female patient with reproductive potential:  Female patients must either have undergone 
documented surgical sterilization or have not experienced menstruation for at least 
12 consecutive months. 
• 
Severe or unstable medical condition that, in the opinion of the investigator or Sponsor, 
would interfere with the patient's ability to complete the study assessments or would require 
the equivalent of institutional or hospital care 
 
Related to Medical History/Conditions 
• 
History or presence of clinically evident vascular disease potentially affecting the brain 
(e.g., stroke, clinically significant carotid or vertebral stenosis or plaque, aortic aneurysm, 
intracranial aneurysm, cerebral hemorrhage, arteriovenous malformation) 
• 
History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) central nervous system trauma (e.g., cerebral contusion)  
• 
History or presence of clinically relevant intracranial tumor (e.g., meningioma, glioma) 
• 
Presence of infections that affect the brain function or history of infections that resulted in 
neurologic sequelae (e.g., syphilis, neuroborreliosis, viral or bacterial 
meningitis/encephalitis, HIV encephalopathy) 
• 
History or presence of systemic autoimmune disorders potentially causing progressive 
neurologic disease (e.g., multiple sclerosis, lupus erythematosus, anti-phospholipid 
antibody syndrome, Behçet disease) 


 
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• 
History or presence of a neurologic disease other than Alzheimer’s disease that may affect 
cognition, including but not limited to Parkinson’s disease, corticobasal degeneration, 
dementia with Lewy bodies, Creutzfeldt–Jakob disease, progressive supranuclear palsy, 
frontotemporal degeneration, Huntington’s disease, normal pressure hydrocephalus, and 
hypoxia 
• 
Patients with severe or unstable medical conditions (including Alzheimer’s Disease) that, in 
the opinion of the investigator or Sponsor, would interfere with the patient’s ability to 
complete the study assessments, pose an unacceptable risk, or would require the 
equivalent of institutional or hospital care 
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, 
human, or humanized antibodies or fusion proteins  
• 
Evidence of malignancies (except squamous cell cancer or basal cell cancer of the skin), 
acute infections, renal failure that requires dialysis, or other unstable medical disease not 
related to Alzheimer’s disease that, in the investigator’s opinion, would preclude patient 
participation 
– 
Cancer that is not being actively treated with anti-cancer therapy or radiotherapy as 
well as cancers that are considered to have low probability of recurrence (with 
supporting documentation from the treating oncologist if possible) are allowed 
• 
History or presence of atrial fibrillation that, in the investigator’s judgment, poses a risk for 
future stroke  
• 
Chronic kidney disease of Stage ≥ 4, according to the National Kidney Foundation Kidney 
Disease Outcomes Quality Initiative (NKF KDOQI) guidelines for chronic kidney disease 
(CKD) 
• 
Impaired hepatic function, as indicated by transaminases > 2 times the upper limit of normal 
(ULN) or abnormalities in synthetic function tests judged by the investigator to be clinically 
significant  
• 
Impaired coagulation (aPTT > 1.2 × ULN)  
• 
Platelet count < 100,000/µL 
 
Related to MRI Imaging 
• 
Presence at screening of superficial siderosis of central nervous system, more than eight 
cerebral microhemorrhages, or evidence of a prior cerebral macrohemorrhage as assessed 
by T2*-weighted gradient echo (GRE) MRI 
• 
Presence at screening of any other significant cerebral abnormalities, including amyloid-
related imaging abnormalities (ARIA-E), as assessed by MRI  
 
Related to Medication 
• 
Treatment with anticoagulation medications (e.g., heparin, warfarin, thrombin inhibitors, 
Factor Xa inhibitors) within 2 weeks prior to enrollment 
– 
Clopidogrel, dipyridamole, and aspirin are permitted. 
• 
Treatment with anticholinergic antidepressants, typical antipsychotics, or barbiturates, 
within 2 weeks prior to enrollment. 
– 
All other antidepressants and atypical antipsychotics are allowed with certain 
restrictions.  
• 
Chronic use of opiates, opioids, or benzodiazepines  
– 
Intermittent short-term use is allowed except within 5 half-lives prior to any 
neurocognitive assessment.  
• 
Any biologic therapy within 75 weeks prior to enrollment 
– 
Crenezumab and routinely recommended vaccinations are allowed.  
• 
Any investigational agent (other than crenezumab) within 75 weeks prior to enrollment 


 
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• 
Treatment with anticholinergic antidepressants, typical antipsychotics, barbiturates, or 
narcotics within 5 half-lives or 3 months prior to screening, whichever is longer 
– 
All other antidepressants and atypical antipsychotics are allowed.  Chronic use of 
benzodiazepines is not allowed; however, the intermittent use of benzodiazepines is 
allowed, except within 2 days prior to any neurocognitive assessment. 
Length of Study 
The study consists of three periods:  a screening period (up to 14 days), the window between 
the last dose in ABBY/BLAZE and the first dose in OLE may last 6 weeks, but may be 
prolonged on a case by case basis for relevant clinical, administrative, or operational reasons 
(these reasons must be discussed with the medical monitor in advance of screening; if 
necessary, some screening procedures may need to be repeated); a treatment period of 144 
weeks (Week 1 [Day 1] to Week 145), and an 8-week safety follow-up period (Weeks 145 to 
153).  The final safety analysis will be performed at 153 weeks. 
End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date on which the last data point required for statistical analysis or safety follow-up is received 
from the last patient, whichever occurs later.  LPLV is expected to occur 153 weeks after the 
last patient is enrolled. 
Efficacy Outcome Measures 
There are no efficacy outcome measures for this study. 
Primary Outcome Measures 
Safety and tolerability will be assessed through regular neurologic and physical examinations 
and MRI assessments.  In addition, the following information will be collected and analyzed: 
• 
Frequency of adverse events during the treatment period 
• 
Nature and severity of adverse events during the treatment period 
• 
Changes in vital signs and physical and neurological findings 
• 
Changes in clinical laboratory test results including routine hematology, chemistry, 
coagulation, and urinalysis 
• 
Incidence of human anti-therapeutic antibody (ATA) formation 
• 
Incidence of ARIA-E and amyloid-related imaging abnormalities-hemorrhage (ARIA-H) 
Exploratory Outcome Measures  
The exploratory outcome measures for this study are as follows: 
• 
Change in ADAS-Cog (12-item) score from baseline to Week 153 
• 
Change in CDR-SOB score from baseline to Week 153 
• 
Change in Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory 
(ADCS-ADL) score from baseline to Week 153 
• 
Change in the following ENTP scores from baseline to Week 153: 
– 
Free and Cued Selective Reminding Test (FCSRT) 
– 
Trail-Making Test (TMT) 
– 
Digit Span Test (DST) 
– 
Digit Symbol Substitution Test (DSST) 
– 
Letter Fluency Test (LFT) 
– 
Category Fluency Test (CFT) 
• 
Change in NPI score from baseline to Week 153 
• 
Change in NPI Caregiver Distress Scale score from baseline to Week 153 
• 
Change in Dependence Scale total score from baseline to Week 153 


 
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• 
Changes in MRI biomarkers, such as global and regional brain volumes, from baseline to 
Week 153 
• 
Serum crenezumab concentration at protocol-specified time points; PK parameters 
including trough serum concentrations at steady state (Ctrough, ss) will be explored, as 
applicable 
• 
Plasma Abeta1-40 and Abeta1-42 concentrations 
Investigational Medicinal Products 
Test Product 
All patients enrolled in the OLE study will receive active drug at 15 mg/kg IV q4w.  Patients who 
received placebo in Study ABE4869g or ABE4955g will also receive active drug 
(i.e., crenezumab 15 mg/kg IV q4w). 
Comparator  
Not applicable. 
Statistical Methods 
Primary Analysis 
The safety analyses will include all enrolled patients who received at least one dose of study 
drug in this OLE study following their completion of Study ABE4869g or ABE4955g. 
These patients will be grouped based on treatment assignment in the OLE study and 
Study ABE4869g or ABE4955g.  Primary safety analysis will be performed after enrolled 
patients have completed Week 153 visit of the OLE study. 
Safety will be assessed by monitoring adverse events, clinical laboratory evaluations, 
MRI evaluations, and immunogenicity as measured by ATAs.  Patients will be analyzed 
according to actual treatment received. 
Determination of Sample Size   
This study is open to all patients who completed Study ABE4869g or ABE4955g and who met 
the eligibility criteria.  Accordingly, the sample size for this study is not based on a formal 
sample size calculation. 
Interim Analyses 
No interim analysis is planned for this study. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
Abeta 
accumulation of extracellular β-amyloid 
AChE 
acetylcholinesterase 
ADAD 
autosomal dominant Alzheimer’s disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale Cognitive Subscale 
ADCS-ADL  
Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory 
AESI 
adverse event of special interest 
ARIA-E 
amyloid-related imaging abnormalities (vasogenic edema and sulcal effusions) 
ATA 
anti-therapeutic antibody 
APP 
amyloid precursor protein 
aPTT 
activated partial thromboplastin time 
ARIA-E 
amyloid-related imaging abnormalities-edema/effusions 
ARIA-H 
amyloid-related imaging abnormalities-hemorrhage 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
β-hCG 
Beta human chorionic gonadotropin 
BUN 
blood urea nitrogen 
CAA 
cerebral amyloid angiopathy 
CCQ 
Caregiver Characterization Questionnaire 
CDR 
Clinical Dementia Rating 
CDR-SOB 
Clinical Dementia Rating, Sum of Boxes 
CFT 
Category Fluency Test 
CKD 
chronic kidney disease 
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 
Ctrough, ss 
trough serum concentration at steady state 
DSST 
Digit Symbol Substitution Test 
DST 
Digit Span Test 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ENTP 
Exploratory Neurocognitive Test Panel 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (CONT’D) 
Abbreviation 
Definition 
ePRO 
electronic patient-reported outcome 
FCSRT 
Free and Cued Selective Reminding Test 
FDA 
Food and Drug Administration 
FLAIR 
fluid-attenuated inversion recovery 
GRE 
gradient echo 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
IxRS 
interactive voice or web-based response system 
LFT 
Letter Fluency Test 
LPLV 
last patient, last visit 
LRTI 
lower respiratory tract infection 
MB 
microbleeds 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NINCDS- 
ADRADA 
National Institute of Neurological and Communicative Diseases and 
Stroke/Alzheimer’s Disease and Related Disorders Association 
NKF KDOQI 
National Kidney Foundation Kidney Disease Outcomes Quality Initiative 
NPI 
Neuropsychiatric Inventory 
OLE 
open-label extension 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PK 
pharmacokinetic 
PT 
preferred term 
q2w 
every 2 weeks 
q4w 
every 4 weeks 
RPCP 
randomized placebo-controlled portion 
RBC 
red blood cell 
SC 
subcutaneous(ly) 
SRI 
safety run-in 
TE 
echo time 
TLRTI 
total lower respiratory tract infections 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS (CONT’D) 
Abbreviation 
Definition 
TMT 
Trail-Making Test 
ULN 
upper limit of normal 
U.S. 
United States 
WBC 
white blood cell 
 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON ALZHEIMER’S DISEASE 
Alzheimer’s disease is the most common cause of dementia, affecting an estimated 
4.5 million individuals in the United States and 26.6 million worldwide (Hebert et al. 2003; 
Brookmeyer et al. 2007).  The disease is characterized pathologically by the 
accumulation of extracellular β-amyloid (Abeta) plaques and intracellular neurofibrillary 
tangles in the brain.  Diagnosis is made through the clinical assessment of the 
neurologic and neuropsychiatric signs and symptoms of Alzheimer’s disease and the 
exclusion of other causes of dementia.  Alzheimer’s disease is commonly classified into 
mild, moderate, and severe stages by a brief cognitive screening examination, the 
Mini-Mental State Examination (MMSE; Folstein et al. 1975).  Approved medical 
therapies that inhibit acetylcholinesterase (AChE) activity or antagonize 
N-methyl-d-aspartate receptors in the brain may temporarily improve the symptoms of 
Alzheimer’s disease in some patients but do not modify the progression of the disease 
(Cummings 2004).   
Genetic factors in early- and late-onset familial Alzheimer’s disease are now well 
documented.  The APOE4 allele is strongly associated with late-onset familial and 
sporadic Alzheimer’s disease, with a reported allele frequency of 50%−65% in patients 
with Alzheimer’s disease, which is approximately three times that in the general 
population and for other neurologic disorders (Saunders et al. 1993; Prekumar 
et al. 1996).  In addition to Alzheimer’s disease, the APOE4 allele has been implicated in 
other amyloid-forming disorders, including cerebral amyloid angiopathy (CAA) 
(Prekumar et al.1996).  Thus, patients who carry the APOE4 allele may represent an 
etiologically distinct population of patients with Alzheimer’s disease.   
The deposition of extracellular amyloid plaques in the brain is a hallmark pathologic 
finding in Alzheimer’s disease, first reported by Alois Alzheimer in 1906.  These amyloid 
plaques are primarily composed of Abeta peptides (Haass and Selkoe 2007) generated 
by the sequential cleavage of amyloid precursor protein (APP) via β- and γ-secretase 
activity.  Abeta, particularly in its oligomerized forms, is toxic to neurons and is believed 
to be causative in Alzheimer’s disease.  Therapies that reduce Abeta levels in the brain 
may alleviate cognitive dysfunction and block further synaptic loss, axon degeneration, 
and neuronal cell death.   
Abeta can be transported actively across the blood−brain barrier (Deane et al. 2004).  
In murine models of Alzheimer’s disease, systemic delivery of antibodies to Abeta 
increases Abeta levels in plasma while reducing levels in the central nervous system 
through several proposed mechanisms, including dissolution of brain Abeta plaque, 
phagocytic removal of opsonized Abeta, and finally via efflux of Abeta from the brain as 
a result of an equilibrium shift of Abeta resulting from circulating antibodies 
(Morgan 2005).  Current anti-Abeta clinical therapeutic development approaches are 
largely based on these proposed mechanisms. 


 
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1.2 
BACKGROUND ON CRENEZUMAB (MABT5102A) 
Crenezumab (MABT5102A) is a fully humanized immunoglobulin (Ig) G4 (IgG4) 
monoclonal antibody to Abeta selected for its ability to bind both monomeric and 
oligomeric forms of Abeta in vitro.  Crenezumab binds both Abeta1-40 and Abeta1-42, 
inhibits Abeta aggregation, and promotes Abeta disaggregation.  Since crenezumab is a 
human IgG4 backbone antibody, it has reduced Fcγ receptor (FcγR) binding affinity 
compared with human IgG1 or IgG2, which is predictive of reduced immune effector 
response.  These properties, combined with the ability to systemically deliver 
crenezumab to decrease Abeta levels in the central nervous system in a murine model 
of Alzheimer’s disease, suggest that this anti-Abeta therapeutic approach may offer 
clinical efficacy while reducing the risk of toxicity, with the ultimate goal of modifying 
disease progression in patients with Alzheimer’s disease with lower risk of cerebral 
vasogenic edema or hemorrhages. 
See the crenezumab (MABT5102A) Investigator's Brochure for additional details on 
nonclinical and clinical studies. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
This open-label extension (OLE) study will investigate the long-term safety and 
tolerability of crenezumab in patients with Alzheimer’s disease.  Currently, there are no 
approved treatments to prevent the progression of Alzheimer’s disease; crenezumab is 
being studied as a potential treatment for this indication.  Alzheimer’s disease is a 
chronic disease that is anticipated to require continued treatment over many years, data 
from this study will help to define the long-term safety profile of crenezumab. 
Nonclinical data collected to date have not revealed any body system- or organ-specific 
toxicities associated with crenezumab. 
Two Phase II studies with crenezumab have recently completed dosing.  
Study ABE4869g was a Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study designed to evaluate the safety and efficacy of crenezumab in 
patients 50−80 years of age who have been diagnosed with mild-to-moderate 
Alzheimer’s disease.  The study enrolled 446 patients.  Treatment duration was 68 
weeks (the last dose was administered on the first day of Week 69), and final 
assessments for efficacy occurred at Week 73.  Dosing was completed in October 2013, 
the study was unblinded in January 2014, and the study was completed in May 2014.  
Study ABE4955g was a Phase II, randomized, double-blind, parallel-group, 
placebo-controlled study designed to evaluate the effects of crenezumab on brain 
amyloid burden as assessed by florbetapir-positron emission tomography (PET), and 
other biomarkers in patients 50−80 years of age who have been diagnosed with 
mild-to-moderate Alzheimer’s disease.  The study enrolled 91 patients.  Treatment 
duration was 68 weeks (the last dose was administered on the first day of Week 69), and 


 
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final assessments for efficacy occurred at Week 73. Dosing was completed in 
January 2014, and the study was unblinded in February 2014.  
An additional Phase II study is ongoing in an autosomal dominant Alzheimer’s disease 
(ADAD) population.  Study GN28352 is a Phase II, randomized, double-blind, 
parallel-group, placebo-controlled study designed to evaluate the safety and efficacy of 
crenezumab in participants 30−60 years of age who are carriers of the PSEN1 E280A 
mutation and who do not meet criteria for mild cognitive impairment because of 
Alzheimer’s disease or dementia because of Alzheimer’s disease.  The first patient was 
enrolled in December 2013, and the study is currently ongoing.  Safety data are limited. 
1.3.1 
Clinical Experience with Study ABE4869g (Completed) 
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 have been diagnosed with 
mild-to-moderate Alzheimer’s disease.  Four hundred forty-six patients were enrolled 
and 444 were dosed in the study:  184 in a subcutaneous (SC) cohort, 247 in an 
intravenous (IV) cohort, and 13 in a safety run-in cohort (see below).  The first patient in 
ABE4869g was dosed in April 2011.  Dosing was completed on 29 October 2013, and 
the study was unblinded on 28 January 2014.  Initial unblinded safety information is 
detailed below (Section 1.3.3); full evaluation of safety, efficacy, and pharmacokinetics is 
ongoing.   
In Study ABE4869g, the 72-week change from baseline in the Alzheimer Disease 
Assessment Scale Cognitive Subscale (ADAS-cog12) and Clinical Dementia Rating 
Scale Sum of Boxes Scores (CDR-SOB) served as co-primary endpoints.  A trend 
towards reducing cognitive decline at 72 weeks post-baseline was observed in patients 
with an MMSE of 18 − 26 in the 15-mg/kg IV cohort (1.8 ADAS-cog12 points difference 
versus placebo; 80% Confidence Interval [CI]: 0.0, 3.5 points; 16.8% reduction in decline; 
p = 0.19).  This ADAS-cog12 treatment effect was augmented with increasingly milder 
patients in the IV cohort, increasing to 2.2 points difference versus placebo (80% CI: 0.4, 
4.1 points; 23.8%; p = 0.13) in patients with an MMSE of 20 − 26, and to 3.4 points (80% 
CI: 1.4, 5.5 points; 35.4%; p = 0.04) in patients with an MMSE of 22 − 26.  No consistent 
treatment effect was seen in the CDR-SOB in the 15-mg/kg IV cohort at 72 weeks post-
baseline, for patients with an MMSE of 18 − 26, 20 − 26, or 22 − 26.  
A consistent treatment effect was not seen in the ADAS-cog12 or CDR-SOB in the 
SC cohort at 72 weeks post-baseline for patients in the 18 − 26, 20 − 26 or 22 − 26 range.  
1.3.2 
Clinical Experience with Study ABE4955g (Completed) 
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 have been diagnosed with mild-to-moderate Alzheimer’s disease.  This 


 
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is a companion study to Study ABE4869g.  Randomization was completed on 
14 September 2012.  Thirty-nine patients were enrolled and dosed in Part 1 (SC cohort) 
of the study, and 52 patients were enrolled and dosed in Part 2 (IV cohort).  Patients 
were randomized to receive crenezumab or placebo in a 2:1 ratio.  SC dosing was 
completed on 16 October 2013, and IV dosing was completed on 16 January 2014.  The 
study was unblinded on 10 February 2014.  Initial unblinded safety information is 
detailed below (Section 1.3.3); full evaluation of safety, efficacy, and pharmacokinetics is 
ongoing.   
In the 15-mg/kg IV cohort of Study ABE4955g, a 0.7 point difference versus placebo 
(80% CI: − 3.8, 5.2 points; 10.3%; p=0.84) was seen in the mild− to-moderate population 
(MMSE:  18−26) in the ADAS-cog12 at Week 73.  This point difference versus placebo 
in the ADAS-cog12 increased to 3.0 points (80% CI: − 0.7, 6.8 points; 52.0%; p = 0.29) in 
patients with an MMSE of 20−26, although the sample size was small for this subset 
(n = 12 for active, n = 7 or placebo).  In the IV cohort of Study ABE4955g, a 0.23 point 
difference versus placebo (80% CI: − 1.2, 1.7 points; 7.4%; p = 0.84) was seen in the 
mild− to-moderate population in the CDR-SOB at Week 73.  This difference versus 
placebo in the CDR-SOB increased to 0.80 points (80% CI: − 0.5, 2.1; 41.5%; p = 0.44) in 
patients with an MMSE of 20−26.   
In the SC cohort of Study ABE4955g, a consistent treatment effect was not observed in 
the mild-to-moderate population in the ADAS-Cog or the CDR-SOB at Week 73. 
1.3.3 
Safety Experience in the Phase II Program 
Safety information from the Phase II program (ABE4869g, ABE4955g, GN28525) is 
summarized in this section.  Unblinded safety data from the randomized 
placebo-controlled portion (RPCP) of ABE4869 and ABE4955g (as of 27 May 2014) are 
summarized, as are all known fatalities as of 27 May 2014 in all three studies 
(ABE4869g, ABE4955g, GN28525).  There have been no fatalities in study GN28352. 
During the RPCP of the Phase II program, 346 patients were treated with SC or IV 
crenezumab for up to 68 weeks, and 176 patients received placebo for up to 68 weeks 
(this includes the 2:1 randomized IV and SC cohorts of ABE4869g and ABE4955g, but 
not the safety run-in [SRI] cohort of ABE4869g). 
1.3.3.1 
Deaths   
During the RPCP of the Phase II program, there were 5 deaths.  All 5 deaths occurred in 
patients treated with crenezumab, and none were assessed as related to study drug by 
the investigator.  This represents 1.4% of patients receiving crenezumab compared with 
0% of patients receiving placebo.  The rate of death in the crenezumab arm is within the 
expected rates of death in the Alzheimer’s disease clinical trial population treated with 
placebo (0%− 1.9%) or with Abeta-directed passive immunotherapy (2.1%−2.4%) 
(Doody et al. 2014; Salloway et al. 2009; Salloway et al. 2014).   


 
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The causes of death were as follows:  1) Alzheimer’s disease progression characterized 
by an inability to perform most tasks, including walking and talking (ABE4869g, SC); 2) 
central respiratory paralysis in the context of a rapidly progressive form of Alzheimer’s 
disease (ABE4869g, SC); 3) community-acquired pneumonia, on a background of 
chronic obstructive pulmonary disease (COPD; ABE4869g, IV); 4) “sudden death” 
(ABE4955g, IV); 5) respiratory failure due to a right-sided pleural effusion of unknown 
etiology (differential diagnosis being pneumonia versus malignancy) (ABE4955g, IV).   
Deaths were not related to serum crenezumab steady-state (AUC or Cmax) in the RPCP 
of the Phase II Studies ABE4869g and ABE4955g.   
In addition, as of 27 May 2014, four patients treated with crenezumab died outside of the 
RPCP of the Phase II program.  All 4 deaths were assessed as not related to study drug 
by the investigator.  Three of the 4 patients received crenezumab, and 1 patient received 
placebo during their participation in the RPCP of ABE4869g or ABE4955g. The causes 
of deaths were as follows: 1) pneumonia (occurred in a patient who withdrew from the 
study and occurred outside the reporting period, 6 months after the last dose of study 
drug) (ABE4869g, IV); 2) colon adenocarcinoma (ABE4869g roll-over to GN28525, SC); 
3) acute delirium (ABE4869g roll-over to GN28525, SC); 4) Alzheimer’s disease 
progression without further details, as the caregiver refused to be contacted (ABE4869g, 
placebo IV roll-over to GN28525 crenezumab IV).  No patients died in the SRI cohort of 
ABE4869g.  
1.3.3.2 
Discontinuations 
During the RPCP of the Phase II program, patients discontinued treatment due to an 
adverse event in 12 (3.5%) patients receiving crenezumab and in 10 (5.7%) patients 
receiving placebo.  In the ABE4869g SC cohort, 2 (1.6%) patients receiving crenezumab 
and 3 (4.8%) patients receiving placebo discontinued treatment due to an adverse event.  
In the ABE4869g IV cohort, 8 (4.9%) patients receiving crenezumab and 3 (3.6%) 
patients receiving placebo discontinued treatment due to an adverse event.  In the 
ABE4955g SC cohort, 1 patient (3.8%) receiving crenezumab and 0 (0%) patients 
receiving placebo discontinued treatment due to an adverse event.  In the ABE4955g IV 
cohort, 1 patient (2.9%) receiving crenezumab and 4 (23.5%) patients receiving placebo 
discontinued treatment due to an adverse event.   
1.3.3.3 
Serious and Non-Serious Adverse Events 
During the RPCP of the Phase II program, serious adverse events were reported in 
57 (16.5%) patients receiving SC or IV crenezumab, and in 21 (11.9%) patients 
receiving SC or IV placebo.  An imbalance in serious adverse events of total lower 
respiratory tract infections (TLRTI; including preferred terms [PT] of pneumonia, lower 
respiratory tract infection [LRTI] and bronchitis) driven by pneumonia was observed in 
the RPCP of the Phase II program, with 6 cases versus 2 cases (1.7% vs. 1.1%) of 
TLRTI and 6 cases versus 1 case (1.7% vs. 0.6%) of pneumonia observed in the 
crenezumab and placebo arms, respectively.  An imbalance in non-serious adverse 


 
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events of TLRTI also driven by pneumonia was observed in the RPCP of the Phase II 
program, with 18 cases versus 6 cases (5.2% vs. 3.4%) of non-serious TLRTI, and 
5 cases versus 0 cases (1.4% vs. 0%) of non-serious pneumonia observed in the 
crenezumab and placebo arms, respectively.   
Adverse events (serious and non-serious) reported in > 5% of crenezumab or placebo 
patients in the RPCP of the Phase II program included urinary tract infection (11.6% vs. 
11.4%, crenezumab vs. placebo, respectively), nasopharyngitis (11.3% vs. 11.9%), 
cerebral microhemorrhage (10.1% vs. 11.4%), fall (10.1% vs. 6.8%), upper respiratory 
tract infection (9.8% vs. 9.1%), headache (9.8% vs. 7.4%), anxiety (9.2% vs. 7.4%), 
diarrhea (8.1% vs. 9.1%), dizziness (7.5% vs. 10.2%), agitation (7.5% vs. 2.8%), 
arthralgia (7.2% vs. 5.1%), back pain (6.9% vs. 9.7%), nausea (6.9% vs. 6.8%), fatigue 
(6.4% vs. 6.3%), contusion (6.1% vs. 1.7%), depression (5.5% vs. 8.5%), cough (5.5% 
vs. 2.8%), and vomiting (5.2% vs. 5.1%). 
Adverse events were not related to dose in the RPCP of the Phase II Studies ABE4869g 
and ABE4955g. 
1.3.3.4 
Adverse Events of Special Interest 
1.3.3.4.1 
Amyloid-Related Imaging Abnormalities (ARIA) and 
Macrohemorrhages 
During the RPCP of the Phase II program, a single case of asymptomatic 
amyloid-related imaging abnormalities (ARIA-E; sulcal effusion in the 
 occipital, 
parietal and temporal region and in the 
 occipital region) was reported in a 
− year-
old 
 patient on IV crenezumab in ABE4869g in the Week 23 
magnetic resonance imaging (MRI) assessment (after the sixth IV infusion).  No events 
of ARIA-E were reported as assessed by brain MRI in ABE4955g.   
This single case represents 0.2% of all patients enrolled in the RPCP of the Phase II 
program, 0.3% of all patients who received crenezumab in the RPCP of the Phase II 
program, and 0.5% of all patients who received IV crenezumab in the RPCP of the 
Phase II program.  Safety data collected in the crenezumab Phase II program indicate 
that the risk of ARIA-E in crenezumab-treated patients is similar to the background rate 
of ARIA-E in the mild− to-moderate Alzheimer’s disease population (0.2% − 0.4%).  The 
background incidence rate of ARIA-E in patients with mild− to-moderate Alzheimer’s 
disease is based on results from placebo groups over 18 months in four large Phase III 
clinical studies (bapineuzumab and solanezumab)(Carlson et al. 2011; Eli Lilly August 
2012 PRNewswire press release).   
In the ABE4869g SC cohort, incident superficial siderosis was reported in 1 patient 
receiving placebo and in no patients receiving crenezumab.  One patient in the 
ABE4869g SC cohort had superficial siderosis detected at screening, was incorrectly 
randomized, and received 6 biweekly doses of crenezumab before being discontinued.  
In the ABE4869g IV cohort, superficial siderosis was reported in 1 patient receiving 


 
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placebo and in no patients receiving crenezumab.  One case of incident superficial 
siderosis was reported in a patient receiving placebo in the ABE4955g IV cohort; no 
other cases of superficial siderosis were reported in ABE4955g.   
In the ABE4869g IV cohort, 1 macrohemorrhage was reported in 1 patient receiving 
crenezumab; this was a macrohemorrhage approximately 
 cm in length along the 
 hippocampus, most likely subependymal.  It is not known if this macrohemorrhage 
was symptomatic or asymptomatic.  No macrohemorrhages were reported in patients 
receiving placebo in the ABE4869g IV cohort, in patients in the ABE4869g SC cohort, or 
in patients in ABE4955g.  
During the RPCP of the Phase II program, incident microhemorrhages were reported in 
40 (11.6%) patients receiving crenezumab and in 22 (12.5%) patients receiving placebo.  
One microhemorrhage was reported to be symptomatic in an SC placebo patient.   In the 
SC cohort of Study ABE4869g, the proportion of patients who experienced incident 
microhemorrhages was higher in patients receiving placebo (10 patients, 16.1%) than in 
patients receiving crenezumab (16 patients, 13.1%).  In the IV cohort of Study 
ABE4869g, the proportion of patients who experienced incident microhemorrhages was 
higher in patients receiving placebo (11 patients, 13.1%) than in patients receiving 
crenezumab (15 patients, 9.2%).  In the SC cohort of Study ABE4955g, the proportion of 
patients who experienced incident microhemorrhages was higher in patients receiving 
crenezumab (4 patients, 15.4%) than in patients receiving placebo (0 patients).  In the IV 
cohort of Study ABE4955g, the proportion of patients who experienced incident 
microhemorrhages was higher in patients receiving crenezumab (5 patients, 14.3%) than 
placebo (1 patient, 5.9%).  The imbalance in incident microhemorrhages between 
patients who received crenezumab and placebo in Study ABE4955g may be due to the 
small number of events.  
Adverse events of special interest were not related to serum crenezumab steady-state 
AUC or Cmax in the RPCP of Phase II. 
1.3.3.4.2 
Pneumonia and Other Lower Respiratory Tract Infections 
In the RPCP of Phase II clinical trials in mild-to-moderate Alzheimer’s disease 
(ABE4869g and ABE4955g), there was an imbalance in the overall rates of pneumonia 
(including serious and non-serious), with 3.2% (11/346) of crenezumab-treated patients 
and 0.6% (1/176) of patients receiving placebo experiencing pneumonia.  Of these 
12 pneumonia cases, 7 were assessed as serious (in 4 patients receiving crenezumab 
IV, 2 patients receiving crenezumab SC, and 1 patient receiving placebo).  
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 et al. 2008), but 
rates (both total and serious) are slightly higher in crenezumab-treated patients (3.2%) 
and slightly lower in placebo-treated patients (0.6%) than rates reported in the active and 
placebo arms of clinical trials in Alzheimer’s disease (Doody et al. 2014; Henley et al. 


 
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2014; Salloway et al. 2014).  There is no clinical evidence of immunosuppression (e.g., 
effects on white blood cells or neutrophils; or pattern of infection type, e.g., opportunistic 
infections).  In addition, no evidence of immunosuppression or of a lung toxicity effect 
has been observed in preclinical studies.  Based on the currently available data, a 
causal relationship between the drug and events of pneumonia cannot be established or 
ruled out.  Pneumonia is considered a potential risk to be monitored closely, and is 
added to this protocol as an adverse event of special interest.  
1.3.3.5 
Additional Safety Information 
In the ongoing OLE study (GN28525) as of 27 May 2014, three deaths occurred 
(additional details above).  As of 27 May 2014, serious adverse events were reported in 
15 SC patients (10.1%) and 18 IV patients (8.5%).  Eight SC patients (5.4%) and 2 IV 
patients (0.9%) discontinued treatment due to an adverse event.  Asymptomatic ARIA-E 
was reported in 1 IV patient (0.5%; the same patient with ARIA-E in ABE4869g) and no 
SC patients.  Superficial siderosis was reported in one SC patient (0.7%) and no IV 
patients.  No macrohemorrhages were reported in SC or IV patients.  Incident 
asymptomatic microhemorrhages were reported in 6 SC patients (4.1%) and 3 IV 
patients (1.4%).  
Additional safety information for the ABE4869g, ABE4955g, GN28525, and GN28352 
studies are provided in the Investigator’s Brochure. 
Based on a review of Phase II safety data to date, while imbalances in deaths and 
pneumonia were observed in the RPCP, a drug-related causal relationship has not been 
established.  New fatalities in the ongoing OLE study (GN28525) will be closely 
monitored, and exposure-adjusted fatality rates using the total-person time on 
crenezumab treatment will be compared to expected rates from published data.   
1.3.4 
Clinical Pharmacokinetics 
The pharmacokinetics of crenezumab have been evaluated in two Phase I studies 
(ABE4427g and ABE4662g) and in the two Phase II studies (ABE4869g and ABE4955g) 
and will be further assessed upon completion of the ongoing, OLE study (GN28525) and 
the Phase II study (GN28352) in PSEN1 E280A mutation carriers.  Overall, the observed 
clearance and volume of distribution in the Phase I studies are consistent with those for 
other humanized IgG monoclonal antibodies that exhibit kinetics in the linear 
concentration range (Mould and Sweeney 2007; Dirks and Meibohm 2010; Deng et al. 
2011).   
In Study ABE4427g, crenezumab was given either as a single (0.3−10 mg/kg) or weekly 
(0.5 −5 mg/kg) IV bolus to patients with mild-to-moderate Alzheimer’s disease.  
Following single-dose administration, crenezumab pharmacokinetics were characterized 
by linear exposure across the dose range tested, slow clearance (2.5−3.3 mL/day/kg) 
and a long half-life (17−26 days).  With weekly administration, there did not appear to be 


 
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any time-dependent change in crenezumab kinetics, as evidenced by similar terminal 
elimination half-life estimates (18−23 days) relative to the single-dose arm.  
 
 
 
In the Phase II studies (Study ABE4869g and Study ABE4955g), serum crenezumab 
concentrations were measured in samples collected after bi-weekly SC (300 mg every 
2 weeks [q2w]) or monthly IV (15 mg/kg every 4 weeks [q4w]) administration in patients 
with mild−to-moderate Alzheimer’s disease.  In general, serum pharmacokinetic (PK) 
concentrations were similar between the two Phase II studies.  In Study ABE4869g, after 
68 weeks of dosing with SC (q2w) or IV (q4w) crenezumab, mean (standard deviation; 
SD) steady state trough serum crenezumab levels were 69 (30) µg/mL and 118 (72) 
µg/mL, respectively.  For patients in the IV and SC treatment groups, steady-state trough 
serum crenezumab levels appeared to have been attained between Week 13 and 
Week 25 (after 3− 6 doses of IV or 6− 12 doses of SC) in both studies.  The trough 
crenezumab levels in cerebrospinal fluid (CSF) were measured in a subset of patients in 
ABE4869g and in all patients in ABE4955g at Week 69.  In preliminary analysis of CSF 
crenezumab concentrations, penetration into CSF was similar between the two studies 
as well as between the SC and IV doses.  In study ABE4869g, the mean (SD) 
CSF/serum ratio was 0.26% (0.16%) and 0.28% (0.17%) for IV and SC dosing, 
respectively.  
 
 
 
Additional PK information for Studies ABE4427g, ABE4662g, and ABE4869g are 
provided in the Investigator’s Brochure. 
1.3.5 
Immunogenicity 
In the Phase I studies anti-therapeutic antibodies (ATAs [directed against crenezumab]) 
were detected in 1 of 36 (Study ABE4427g) and 0 of 22 (Study ABE4662g) 
crenezumab-treated patients.  The presence of a positive ATA response in the single 
patient (1.5-mg/kg dose level; multiple-dose phase) was associated with reduced serum 
crenezumab exposure (50% and 20% lower Day 22 predose and peak concentrations 
compared to the group median).  In a preliminary analysis of ATAs in the Phase II 
studies, treatment-emergent ATAs were detected in 2 of 164 (1.2%) crenezumab-treated 
patients in the IV cohort (Study ABE4869g) and in 7 of 122 (5.7%) crenezumab-treated 
patients in the SC cohort (Study ABE4869g).  No apparent impact of ATAs on 
pharmacokinetics or safety was observed in either the IV or SC cohorts in ABE4869g.  
Treatment-emergent ATAs were not detected in 61 crenezumab-treated patients in the 
IV and SC cohorts of Study ABE4955g. 


 
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See the Investigator’s Brochure for additional details on nonclinical and clinical studies.  
1.3.6 
Benefit-Risk Summary 
The safety and tolerability of crenezumab in humans has been assessed in 540 patients 
exposed to crenezumab in six studies (two Phase I and four Phase II) that showed an 
acceptable safety profile.  Details are provided above and in the crenezumab 
Investigator’s Brochure.  
Clinical experience to date has not identified any events considered to be adverse drug 
reactions (i.e., a drug causality link has not been established with any of the reported 
adverse events).  Potential safety considerations associated with treatment include 
those inherent to recombinant protein therapeutics as well as those specific to the 
crenezumab molecule or pharmacology. These include pneumonia, the spectrum of 
potential immune-mediated responses (e.g., hypersensitivity reactions, anaphylaxis), 
immunogenicity (anti-drug antibody formation), cerebral vasogenic edema/sulcal effusion, 
cerebral micro-/macro-hemorrhages, and superficial siderosis.  Given the imbalances 
observed in pneumonia reports between crenezumab and placebo during the RPCP of 
the Phase II program, pneumonia is now considered a new potential risk for crenezumab 
treatment. 
Given the early stage of development, the long-term safety profile of crenezumab in 
humans has not yet been fully characterized.  Therefore, not all of the potential adverse 
effects, and the likelihood of their occurrence, are known at this time.  Patients will 
continue to be carefully monitored throughout the clinical development of crenezumab to 
collect additional safety information. 
This OLE study will permit the evaluation of long-term safety and tolerability of 
crenezumab in patients who completed the Week 73 assessment in Study ABE4869g or 
ABE4955g.  In addition, this OLE study will provide the opportunity for eligible patients 
treated with placebo in Studies ABE4869g and ABE4955g to continue into the OLE and 
receive crenezumab. 
Clinical efficacy data from ABE4869g and ABE4955g suggest that there is a potential 
treatment effect with high-dose crenezumab (15 mg/kg IV q4w), but there is a lack of 
consistent benefit with low-dose crenezumab (300 mg SC q2w).  The safety profile of 
crenezumab to date is acceptable.  Furthermore, adverse events were not related to 
dose, and fatalities, serious adverse events, and adverse events of special interest were 
not related to steady-state serum crenezumab exposure (AUC and Cmax).  Therefore, the 
potential treatment benefit, in light of the safety characteristics of crenezumab, supports 
continuing dosing at 15 mg/kg IV q4w in Study GN28525.   
Based on the safety profile and the potential clinical efficacy of crenezumab at 15 mg/kg 
IV q4w, all patients who entered GN28525 in the SC dosing arm will transition to the 
15 mg/kg IV arm. 


 
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The safety of patients participating in this trial will be ensured through the use of 
stringent inclusion and exclusion criteria for study entry, and through close patient 
monitoring.  Investigators will assess the occurrence of adverse events and serious 
adverse events at all patient evaluation time points 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.  Patients will be carefully followed for adverse events 
during the study, including a safety follow-up period. 
2. 
OBJECTIVES 
The primary objective of this study is to assess the long-term safety and tolerability of 
crenezumab administered subcutaneously q2w or intravenously q4w, in eligible patients 
with Alzheimer’s disease who participated in Study ABE4869g or ABE4955g and 
completed the Week 73 study visit, including brain MRI.  
2.1 
EFFICACY OBJECTIVES 
There are no efficacy objectives for this study, although select efficacy outcome 
measures will continue to be collected. 
2.2 
SAFETY OBJECTIVE 
The safety objective of this study is to evaluate the safety and tolerability of crenezumab 
in patients with Alzheimer’s disease focusing on treatment-emergent adverse events, 
vital signs, routine laboratory analysis, immunogenicity, and cerebral imaging 
abnormalities (assessed by MRI). 
2.3 
EXPLORATORY OBJECTIVES 
The exploratory objectives of this study are as follows: 
• 
To evaluate the long-term effect of crenezumab on disease progression using the 
ADAS-Cog (12-item) 
• 
To evaluate the long-term effect of crenezumab on disease progression using 
CDR-SOB 
• 
To evaluate the long-term effect of crenezumab on patient functioning using the 
Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory 
(ADCS-ADL) 
• 
To evaluate the long-term effect of crenezumab on disease progression using 
supplemental neurocognitive measures (i.e., Exploratory Neurocognitive Test Panel 
[ENTP]) selected to assess episodic memory performance, executive functions, 
verbal fluency, working memory, and psychomotor speed 
• 
To evaluate the long-term effect of crenezumab on behavior using the 
Neuropsychiatric Inventory (NPI) 


 
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• 
To evaluate the long-term effects of crenezumab on the amount of assistance 
patients with dementia require in performing daily activities using the 
Dependence Scale 
• 
To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of 
crenezumab 
• 
To evaluate the PK/PD relationship of crenezumab using exploratory PD biomarkers 
• 
To evaluate changes in MRI biomarkers, such as global and regional brain volumes 
and functional connectivity  
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
3.1.1 
Overview of Study Design 
Study GN28525 is a Phase II, OLE, multicenter study to evaluate the long-term safety 
and tolerability of crenezumab in patients with Alzheimer’s disease who have 
participated in and completed the treatment period of the Phase II Study ABE4869g or 
ABE4955g.  Patients from Studies ABE4869g and ABE4955g who discontinued from 
study treatment early but remained on study for safety evaluations, or discontinued prior 
to completion of the Week 73 study visit, are not eligible for this OLE study. 
ABE4869g (ABBY) is a completed Phase II, multicenter, global, randomized, 
double-blind, parallel-group, placebo-controlled study to evaluate the safety and efficacy 
of crenezumab in patients with mild-to-moderate Alzheimer’s disease. Four hundred 
forty-six patients were randomized and 444 patients were dosed at approximately 
100 sites in North America and Europe. 
ABE4955g (BLAZE) is a completed Phase II, multicenter, global, randomized, 
double-blind, parallel-group, placebo-controlled study to evaluate the effects of 
crenezumab on brain amyloid burden, as assessed by florbetapir-PET, and other 
biomarkers in patients with mild-to-moderate Alzheimer’s disease.  Ninety-one patients 
were randomized and 61 were dosed at approximately 30 sites in North America and 
Europe. 
This OLE study includes patients who have been diagnosed with Alzheimer’s disease 
and have an MMSE score of 10 or more at the time of screening, which is lower than in 
Studies ABE4869g and ABE4955g (MMSE 18 – 26) to account for the disease 
progression in the course of these studies.  An MMSE score of less than 10 at the 
beginning of the OLE study would substantially increase the risk that a patient would not 
be able to complete the study assessments and to comply with the protocol’s 
requirements in the future.   
Patients will undergo a neuroradiological evaluation using a standard MRI protocol and 
T2* gradient echo MRI to exclude any significant MRI abnormality and presence of 
cerebral superficial siderosis or more than eight cerebral microhemorrhages.  Only 


 
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patients with 4 or less cerebral microhemorrhages at screening are allowed to participate 
in Studies ABE4869g and ABE4955g and study drug will be discontinued in patients with 
an increase of six or more in the number of asymptomatic microhemorrhages in these 
studies since high numbers of cerebral microhemorrhages have been associated with 
future risk of ischemic and hemorrhagic strokes (Greenberg et al. 2009).  The 
microhemorrhage threshold for entry in this study, which is based on the natural 
incidence of cerebral microhemorrhages in this patient population, is intended to 
minimize potential safety risks associated with cerebral microhemorrhages, but would 
not preclude the majority of the patients from Study ABE4869g or ABE4955g from rolling 
over into this OLE study.  However, this might exclude patients from participating in the 
OLE study due to the number of cerebral microhemorrhages that would not have led to 
treatment discontinuation in the Study ABE4869g or ABE4955g.  Patients with medical 
or psychiatric contraindication or clinically significant abnormalities that, in the 
investigator's judgment, would substantially increase the risk associated with the 
patient's participation in the study or interfere with the evaluation of the patient's 
response will not be included in the study.  
All patients enrolled in the OLE study were to receive active drug at the same dosing 
frequency, dose level, and route of administration they were assigned to after the 
Week 73 visit of Study ABE4869g or ABE4955g.  Patients who received matching 
placebo in Study ABE4869g or ABE4955g were to receive active drug (i.e., crenezumab 
300 mg SC q2w for patients who were randomized in the SC cohort [Part 1] or 
15 mg/kg IV q4w for patients who were randomized in the IV cohort [Part 2]).  However, 
evaluation of efficacy in ABE4869g and ABE4955g indicates that there was no 
consistent treatment effect in patients who received 300 mg q2w SC that would support 
continuation of this dose level.  In contrast, there appears to be a trend towards 
reduction in cognitive decline in patients who received 15 mg/kg q4w IV.  Considering 
these efficacy results and the available safety information, all patients in the OLE study 
will be dosed at 15 mg/kg q4w IV.  All patients who have been receiving active drug in 
the SC dosing arm will be transferred into the IV dosing arm.  
The study consists of three periods:  a screening period (up to 14 days), the window 
between the last dose in ABBY/BLAZE and the first dose in OLE may last 6 weeks, but 
may be prolonged on a case by case basis for relevant clinical, administrative, or 
operational reasons (these reasons must be discussed with the medical monitor in 
advance of screening; if necessary, some screening procedures may need to be 
repeated); a treatment period of 144 weeks (Week 1 [Day 1] to Week 145), and an 
8-week safety follow-up period (Weeks 145 to 153).  The final safety analysis will be 
performed at 153 weeks.   The original GN28525 protocol included a treatment period 
of 92 weeks (Week 1 [Day 1] to Week 93).  Version 6 of the GN28525 protocol expands 
this treatment period by 52 weeks (13 additional IV doses from Week 97 to Week 145).  
Patients who are still enrolled in Study GN28525 may enter the additional OLE 
treatment period (Week 97 to Week 145) if they have not discontinued treatment for 


 
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safety reasons.   Patients who have already completed or discontinued from Study 
GN28525 are not eligible to receive additional treatment from Week 97 to Week 145. 
The Week 73 assessment (including MRI) of Studies ABE4869g and ABE4955g will be 
used to determine the patient’s eligibility in this OLE trial.  Data from the Week 73 visit 
assessments in Studies ABE4869g and ABE4955g will be extracted and incorporated in 
the OLE screening datasets.  Patients participating in this OLE study must be enrolled 
(i.e., Day 1 of the OLE treatment period) no later than 14 days after completion of the 
Week 73 assessments (including MRI) of Study ABE4869g or ABE4955g, except for 
individual exceptions, determined on a case by case basis, as mentioned above. 
The first dose of crenezumab is administered on Day 1 of the treatment period, and the 
last dose of treatment is at Week 145.  After patients complete the 144-week treatment 
period, they will enter the follow-up period.  Patients who are prematurely discontinued 
from the OLE study treatment will also discontinue from the OLE study and will be 
followed for safety for 8 weeks after their last dose of crenezumab. 
Patients will remain blinded to their assignment in Study ABE4869g or ABE4955g, and 
investigators are not permitted to provide treatment assignment in ABE4869g or 
ABE4955g until permitted by the Sponsor. 
The study timeline is presented in Figure 1.  A schedule of assessments is provided in 
Appendix 1. 
Figure 1 Study Timeline 
-2
5
9
13
17
21
97
1
93
109
Week
Original OLE Treatment period
73
69
Day 73 
assessments
Last 
treatment
ABE4869g
ABE4955g
GN28525
IV q4w or SC q2w
SC q2w only
145
153
Safety
follow-up
Final
analysis
Expanded OLE Treatment period
IV q4w only
105
113
101
 
IV = intravenous; OLE = open-label extension; q4w = every 4 weeks; SC = subcutaneous. 
  
3.1.2 
Internal Safety Monitoring Committee 
The incidence and nature of adverse events, serious adverse events, and laboratory 
abnormalities will be assessed on a regular basis by an internal Safety Monitoring 
Committee, composed of a biostatistician, drug safety scientist, statistical programming 
analyst, and a clinical scientist, who may be members of the project team.  The 
committee will continually monitor all serious adverse events.  External experts may be 


 
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consulted.  The incidence and distribution of non-serious adverse events will be 
reviewed frequently (e.g., every 12 weeks).  The committee will recommend changes to 
the study conduct or study termination as required.  The responsibilities and operation of 
the committee will be documented in the Safety Monitoring Committee charter.  The 
feeder studies ABE4869g and ABE4955g are completed and unblinded; therefore, the 
Internal Safety Monitoring Committee will be disbanded at an appropriate time, and 
periodic review of safety data will be conducted by the Sponsor project team. 
3.2 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date on which the last data point required for statistical analysis or safety follow-up 
is received from the last patient, whichever occurs later.  LPLV is expected to occur 
153 weeks after the last patient is enrolled. 
3.3 
RATIONALE FOR STUDY DESIGN 
As Alzheimer’s disease is a chronic disease that is anticipated to require continuous 
treatment over many years, data from this study will help to define the long-term safety 
profile of crenezumab.  Study GN28525 is designed to assess the long-term safety and 
tolerability of crenezumab in Alzheimer’s disease patients beyond the 69 weeks of 
dosing provided in Studies ABE4869g and ABE4955g.  To capture this long-term safety 
and tolerability data, patients will be followed for an additional 144 weeks of dosing.   
3.4 
OUTCOME MEASURES 
3.4.1 
Primary Outcome Measures 
Safety and tolerability will be assessed through regular neurologic and physical 
examinations and MRI assessments.  In addition, the following information will be 
collected and analyzed: 
• 
Frequency of adverse events during the treatment period 
• 
Nature and severity of adverse events during the treatment period 
• 
Changes in vital signs and physical and neurological findings 
• 
Changes in clinical laboratory test results including routine hematology, chemistry, 
coagulation, and urinalysis 
• 
Incidence of human anti-therapeutic antibody (ATA) formation 
• 
Incidence of ARIA-E and amyloid-related imaging abnormalities-hemorrhage 
(ARIA-H) 
 
3.4.2 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
– 
Change in ADAS-Cog (12-item) score from baseline to Week 153 
– 
Change in CDR-SOB score from baseline to Week 153 
– 
Change in ADCS-ADL score from baseline to Week 153 


 
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– 
Change in the following ENTP scores from baseline to Week 153: 
– 
Free and Cued Selective Reminding Test (FCSRT) 
– 
Trail-Making Test (TMT) 
– 
Digit Span Test (DST) 
– 
Digit Symbol Substitution Test (DSST) 
– 
Letter Fluency Test (LFT) 
– 
Category Fluency Test (CFT) 
• 
Change in NPI score from baseline to Week 153 
• 
Change in NPI Caregiver Distress Scale score from baseline to Week 153 
• 
Change in Dependence Scale total score from baseline to Week 153 
• 
Changes in MRI biomarkers, such as global and regional brain volumes, from 
baseline to Week 153 
• 
Serum crenezumab concentration at protocol-specified time points; PK parameters 
including trough serum concentrations at steady state (Ctrough, ss) will be explored, as 
applicable 
• 
Plasma Abeta1-40 and Abeta1-42 concentrations 
 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Patients who completed the Week 73 visit of Study ABE4869g or ABE4955g are eligible 
to participate in this OLE study; patients discontinued from study treatment or 
discontinued from study prior to completion of the Week 73 visit, will not be eligible for 
this OLE study. 
Patients in this study are required to meet standard research criteria for probable 
Alzheimer’s disease (the National Institute of Neurological and Communicative Disorders 
and Stroke and the Alzheimer's Disease and Related Disorder Association 
[NINCDS−ADRDA] criteria) with an MMSE score of 10 or more points at screening.  
Patients will undergo a neuroradiological evaluation using a standard MRI protocol, 
including a T2-weighted FLAIR and T2* gradient echo sequence, to exclude any 
significant MRI abnormality and presence of ARIA-H or ARIA-E.  Specifically, patients 
with more than eight cerebral microhemorrhages at screening will not be eligible for the 
study.  This might exclude patients from participating in the OLE study due to the 
number of cerebral microhemorrhages that would not have led to treatment 
discontinuation in Study ABE4869g or ABE4955g.  Patients with medical or psychiatric 
contraindications or clinically significant abnormalities that, in the investigator's judgment, 
will substantially increase the risk associated with the patient's participation in the study 
or interfere with the evaluation of the patient's response will not be included in the study. 


 
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Ability to provide written informed consent by the patient or the patient’s authorized 
representative under applicable local law 
• 
Ability and willingness of the patient to comply with the protocol’s requirements  
• 
Previous participation in Study ABE4869g or ABE4955g and completion of the 
Week 73 visit 
– 
Patients who discontinued from study treatment or from the study prior to 
completion of the Week 73 visit are not eligible. 
• 
Adequate visual and auditory acuity, in the investigator's judgment, to allow for 
neuropsychological testing 
• 
Availability of a person ("caregiver") who can provide information on activities of 
daily living and behavior in order to complete the study-specific assessments 
– 
This caregiver must have sufficient cognitive capacity, in the judgment of the 
investigator, to accurately report upon the patient's function and behavior.  
In addition, the caregiver must spend sufficient time with the patient to be 
familiar with the overall function and behavior of the patient.  As guidance, a 
caregiver would ordinarily need to spend an average of at least 8 hours per 
week with the patient in order for the caregiver to meet the requirements for 
this study.   
• 
Diagnosis of probable Alzheimer’s disease according to the National Institute on 
Neurological and Communication Disease and Stroke/Alzheimer’s Disease and 
Related Disorders Association (NINCDS-ADRDA) criteria (McKhann et al. 1984) 
• 
MMSE score of 10 or more at screening (Folstein et al. 1975) 
• 
For male patients with partners with reproductive potential, agreement to use a 
reliable means of contraception (e.g., condoms) during the study and for at least 
8 weeks following the last dose of study drug 
• 
For female patients, a negative urine dipstick pregnancy test at screening (not 
required if patient has undergone documented surgical sterilization or have not 
experienced menstruation for at least 12 consecutive months)  
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry or 
continued participation: 
General 
• 
Early treatment and/or study discontinuation prior to completion of the Week 73 visit 
of Genentech Study ABE4869g or ABE4955g 
• 
Early discontinuation from the treatment schedule of a prior version of Study 
GN28525 for safety reasons.  If treatment discontinuation occurred for safety 
reasons, patients may not re-start dosing on extended treatment schedules offered 
in amendments to Study GN28525. 


 
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44/Protocol GN28525, Version 6 
• 
Inability to tolerate MRI procedures or contraindication to MRI, including but 
not limited to pacemakers; implantable cardioverter defibrillators; cochlear implants; 
cerebral aneurysm clips; implanted infusion pumps; implanted nerve stimulators; 
metallic splinters in the eye; other magnetic, electronic, or mechanical implants; or 
any other clinical history or examination finding that, in the judgment of the 
investigator, would pose a potential hazard in combination with MRI 
• 
Female patient with reproductive potential:  Female patients must either have 
undergone documented surgical sterilization or have not experienced menstruation 
for at least 12 consecutive months. 
• 
Severe or unstable medical condition that, in the opinion of the investigator 
or Sponsor, would interfere with the patient's ability to complete the study 
assessments or would require the equivalent of institutional or hospital care 
 
Related to Medical History/Conditions 
• 
History or presence of clinically evident vascular disease potentially affecting the 
brain (e.g., stroke, clinically significant carotid or vertebral stenosis or plaque, aortic 
aneurysm, intracranial aneurysm, cerebral hemorrhage, arteriovenous malformation) 
• 
History of severe, clinically significant (persistent neurologic deficit or structural brain 
damage) central nervous system trauma (e.g., cerebral contusion)  
• 
History or presence of clinically relevant intracranial tumor 
(e.g., meningioma, glioma) 
• 
Presence of infections that affect the brain function or history of infections that 
resulted in neurologic sequelae (e.g., syphilis, neuroborreliosis, viral or bacterial 
meningitis/encephalitis, HIV encephalopathy) 
• 
History or presence of systemic autoimmune disorders potentially causing 
progressive neurologic disease (e.g., multiple sclerosis, lupus erythematosus, 
anti-phospholipid antibody syndrome, Behçet disease) 
• 
History or presence of a neurologic disease other than Alzheimer’s disease that may 
affect cognition, including but not limited to Parkinson’s disease, corticobasal 
degeneration, dementia with Lewy bodies, Creutzfeldt–Jakob disease, progressive 
supranuclear palsy, frontotemporal degeneration, Huntington’s disease, normal 
pressure hydrocephalus, and hypoxia 
• 
Patients with severe or unstable medical conditions (including Alzheimer’s Disease) 
that, in the opinion of the investigator or Sponsor, would interfere with the patient’s 
ability to complete the study assessments, pose an unacceptable risk, or would 
require the equivalent of institutional or hospital care  
• 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins  
• 
Evidence of malignancies (except squamous cell cancer or basal cell cancer of the 
skin), acute infections, renal failure that requires dialysis, or other unstable medical 
disease not related to Alzheimer’s disease that, in the investigator’s opinion, would 
preclude patient participation 


 
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– 
Cancer that is not being actively treated with anti-cancer therapy or 
radiotherapy as well as cancers that are considered to have low probability of 
recurrence (with supporting documentation from the treating oncologist if 
possible) are allowed 
• 
History or presence of atrial fibrillation that, in the investigator’s judgment, poses a 
risk for future stroke  
• 
Chronic kidney disease of Stage ≥ 4, according to the National Kidney Foundation 
Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines for chronic 
kidney disease (CKD) 
• 
Impaired hepatic function, as indicated by transaminases > 2 times the upper limit of 
normal (ULN) or abnormalities in synthetic function tests judged by the investigator 
to be clinically significant  
• 
Impaired coagulation (aPTT > 1.2 × ULN)  
• 
Platelet count < 100,000/µL 
 
Related to MRI Imaging 
• 
Presence at screening of superficial siderosis of central nervous system, more than 
eight cerebral microhemorrhages, or evidence of a prior  cerebral macrohemorrhage 
as assessed by T2*-weighted gradient echo (GRE) MRI 
• 
Presence at screening of any other significant cerebral abnormalities, including 
ARIA-E, as assessed by MRI  
 
Related to Medication 
• 
Treatment with anticoagulation medications (e.g., heparin, warfarin, 
thrombin inhibitors, Factor Xa inhibitors) within 2 weeks prior to enrollment 
– 
Clopidogrel, dipyridamole, and aspirin are permitted. 
• 
Treatment with anticholinergic antidepressants, typical antipsychotics, or 
barbiturates, within 2 weeks prior to enrollment. 
– 
All other antidepressants and atypical antipsychotics are allowed with certain 
restrictions (see Section 4.2.5). 
• 
Chronic use of opiates, opioids, or benzodiazepines  
– 
Intermittent short-term use is allowed except within 5 half-lives prior to any 
neurocognitive assessment. 
• 
Any biologic therapy within 75 weeks prior to enrollment 
– 
Crenezumab and routinely recommended vaccinations are allowed. 
• 
Any investigational agent (other than crenezumab) within 75 weeks prior to 
enrollment 
• 
Treatment with anticholinergic antidepressants, typical antipsychotics, barbiturates, 
or narcotics within 5 half-lives or 3 months prior to screening, whichever is longer 
– 
All other antidepressants and atypical antipsychotics are allowed.  Chronic use 
of benzodiazepines is not allowed; however, the intermittent use of 


 
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benzodiazepines is allowed, except within 2 days prior to any neurocognitive 
assessment.  
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
This is an OLE study.  Patients in the OLE study will receive study drug at 15 mg/kg IV 
q4w.  Patients who received active drug in Study ABE4869g or ABE4955g will continue 
to receive active drug.  Patients who received placebo in Study ABE4869g or ABE4955g 
will also receive active drug (i.e., crenezumab 15 mg/kg IV q4w). 
4.2.1 
Formulation, Packaging, and Handling 
4.2.1.1 
Crenezumab (MABT5102A) 
Crenezumab is produced using Chinese hamster ovary cells, purified, and formulated.  
Crenezumab is subjected to a series of quality-control tests to confirm its identity, purity, 
potency, quality, and sterility.  The drug product is a sterile, preservative-free liquid 
intended for SC or IV administration.  
Details on crenezumab and placebo formulation, dosage, configuration, administration, 
and storage are provided in the crenezumab (MABT5102A) Investigator’s Brochure and 
the GN28525 pharmacy manual. 
4.2.2 
Crenezumab Dosage, Administration, and Compliance 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
4.2.2.1 
Subcutaneous Dosing 
All patients previously enrolled in the SC cohort of Study ABE4869g, ABE4955g, or 
GN28525 will receive 15 mg/kg of crenezumab intravenously every 4 weeks as 
described below in Section 4.2.2.2.  Missed treatments will not be made up. 
4.2.2.2 
Intravenous Dosing 
Crenezumab will be given by IV infusion once every 4 weeks.  Missed treatments will not 
be made up. 
For IV use, the drug will be diluted as described in the GN28525 pharmacy manual.  The 
IV drug will be administered 
 
.  IV infusions will be administered by the site staff in a hospital, clinic, 
or practice environment.  All patients will be followed for a minimum of 1 hour postdose 
and vital signs will be measured post-infusion and 60 minutes after the end of the 
infusion as described in the GN28525 pharmacy manual. 
For IV dose calculation in the OLE study, the screening weight refers to the patient’s 
weight at Week 73.  For patients who entered GN28525 immediately upon completion of 


 
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ABE4869g or ABE4955g, the IV dose will be calculated based on the patient’s screening 
weight (reference weight) unless the patient’s current weight changes (increases or 
decreases) ≥ 10% from the screening weight.  For patients who will be transitioned from 
SC dosing to IV dosing during the conduct of GN28525, the IV dose will be calculated 
based on the patient’s current weight at the time of transition (their reference weight).   
For all patients, whether originally in the IV cohort or transitioning from the SC cohort, if 
the current weight changes ≥ 10%, the current weight will become the new reference 
weight for subsequent dosing.  If the patient’s weight again changes by ≥ 10% from the 
reference weight, the IV dose will again be recalculated.  Please refer to the GN28525 
pharmacy manual for further information. 
If a patient experiences a mild infusion-related reaction, the infusion will be halted.  Once 
the reaction has resolved, the infusion will be resumed at half of the most recently used 
rate 
.  Patients who experience a moderate 
infusion-related reaction (e.g., fever, chills) should have their 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 have their infusion stopped 
immediately and should receive aggressive symptomatic treatment, and they should not 
receive additional study drug. 
4.2.3 
Investigational Medicinal Product Accountability 
All investigational medicinal products (IMPs) required for completion of this study will be 
provided by the Sponsor where required by local health authority regulations.  The 
investigational site will acknowledge receipt of IMPs by returning the appropriate 
documentation form 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. 
4.2.4 
Post-Trial Access to Crenezumab 
The Sponsor does not intend to provide crenezumab or other study interventions to 
patients after conclusion of the study or any earlier patient withdrawal.   


 
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4.2.5 
Permitted Therapy  
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
the day of study enrollment (Day 1) through study completion or early termination.  
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  
Except for excluded medications, patients who use other maintenance therapies may 
continue their use (see Section 4.1.2). 
Patients are permitted to take approved Alzheimer’s disease treatments (e.g., AChE 
inhibitors, and memantine).  An approved Alzheimer’s disease treatment may be initiated, 
stopped, or altered in dose or formulation up to, and including, the Week 13 visit.  If an 
approved Alzheimer’s disease treatment is no longer commercially available or no longer 
available through patients’ insurance formulary, the treatment may be substituted with an 
equivalent dose of a comparable medication at any time during the trial.  Stable doses of 
other maintenance medications will also be permitted.  The intermittent use of opiates, 
opioids, soporifics, or benzodiazepines is allowed, except within 5 half-lives prior to any 
neurocognitive assessment (see Section 4.1.2). 
Chronic treatment with benzodiazepines, opiates, or opioids is prohibited; however, 
intermittent, short-term treatment is allowed except within 5 half-lives prior to any 
neurocognitive assessment. 
Non-excluded prescription and over-the-counter medications (see Section 4.1.2) that 
might affect cognitive function (e.g., non-anticholinergic antidepressants, atypical 
antipsychotics, non-benzodiazepine anxiolytics, soporifics, centrally acting 
anticholinergic antihistamines, centrally acting anticholinergic antispasmodics) are 
allowed a) if initiation or discontinuation of therapy or dose changes do not occur within 
5 half-lives prior to cognitive assessment (however, initiation, discontinuation, or dose 
changes are discouraged), or b) administered intermittently and on a short-term basis, 
they are not used within 5 half-lives prior to neurocognitive assessment.  
During the study, patients may receive any treatment deemed necessary by the 
investigator for the management of their disease.  However, patients requiring 
commencement of prohibited therapies will be discontinued from the study. 
4.2.6 
Prohibited Therapy 
Use of the following therapies is prohibited during the study, unless otherwise specified 
below: 
• 
Anticholinergic antidepressants, typical antipsychotics, or barbiturates 
– 
All other antidepressants and atypical antipsychotics are allowed with certain 
limitations (see Section 4.2.5). 


 
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• 
Anticoagulation medications (e.g., heparin, warfarin, thrombin inhibitors, 
Factor Xa inhibitors) 
– 
Clopidogrel, dipyridamole, and aspirin are permitted. 
• 
Any biologic therapy 
– 
Routinely recommended vaccinations are allowed. 
• 
Any investigational agent 
 
4.3 
STUDY ASSESSMENTS  
Please see Appendix 1 for the schedule of assessments to be performed during this 
study. 
4.3.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in this 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. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  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. 
4.3.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, reproductive status, 
smoking history, use of alcohol and drugs of abuse, and all medications 
(e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, 
nutritional supplements) used by the patient at the time of study enrollment on Day 1. 
A complete medical history should include a negative or positive history for risk factors 
for pneumonia including asthma, COPD, heart disease, and smoking; and any other 
potential risk factor considered significant in the investigator’s judgment. 
Demographic data will include age, sex, and self-reported race/ethnicity. 
4.3.3 
Physical Examinations 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
and gastrointestinal systems.  Any abnormality identified at baseline should be recorded 
on the General Medical History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), 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. 


 
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4.3.4 
Vital Signs  
Vital signs will include measurements of heart rate, respiratory rate, temperature, and 
systolic and diastolic blood pressure after the patient has been supine for ≥ 3 minutes. 
4.3.5 
Neurologic Examination 
A complete neurologic examination should include the evaluation of consciousness, 
cranial nerves, motor and sensory system, coordination and gait, and reflexes.  Changes 
from baseline abnormalities should be recorded at each subsequent neurologic 
examination.  New or worsened abnormalities should be recorded as adverse events on 
the Adverse Event eCRF if considered clinically significant in the investigator’s judgment. 
4.3.6 
Magnetic Resonance Imaging Assessments 
Neuroradiologic evaluation will be performed using a standard MRI protocol at screening 
and for routine safety assessments.  The MRI protocol will include the following 
sequences:  T1-weighted 3D GRE, dual-echo fast-spin-echo with T2 and proton density 
weighting (or separate T2-weighted and proton-density-weighted sequences on systems 
that will not accommodate dual-echo acquisition), T2*-weighted GRE, and T2-weighted 
FLAIR.  The minimum requirements for T2*-weighted GRE scans are as follows:  field 
strength of 1.5T or greater, slice thickness of 5 mm or less, and echo time (TE) of 20 ms 
or greater.  Volumetric analysis of the T1-weighted 3D GRE scans is included as an 
exploratory evaluation of the effect of crenezumab on regional brain volume.  All MRIs 
will be evaluated by a central imaging reader. 
4.3.7 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The Columbia-Suicide Severity Rating Scale (C-SSRS) will be used for prospective 
suicidality assessment.  The C-SSRS is a tool used to assess the lifetime suicidality of a 
patient and to track suicidal events through the treatment.  The structured interview 
prompts recollection of suicidal ideation, including the intensity of the ideation, behavior, 
and attempts with actual/potential lethality. 
The scale will be administered by qualified site personnel.  The C-SSRS “baseline” 
will be administered at Day 1, and the C-SSRS “since last visit” will be administered at 
subsequent visits.  Patients who are suicidal based on C-SSRS will be referred for 
appropriate psychiatric evaluation and management as per local clinical practice. 
Note:  Assessing the risk of suicide is a difficult and complex task when applied to an 
individual patient.  Certainly, no single clinical scale can replace a thorough medical 
examination and suicide risk assessment.  Ultimately, the determination of the presence 
of suicidality depends on clinical judgment. 


 
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4.3.8 
Neurocognitive and Functional Assessments 
In this trial, a number of neurocognitive and functional assessments will be administered, 
some to the patient and some to the caregiver.  In addition, a Caregiver Characterization 
Questionnaire (CCQ) will be completed prior to the administration of the caregiver 
assessments at each visit.  All neurocognitive and functional assessments are to be 
performed prior to dosing and any potentially stressful procedures 
(e.g., blood draws, imaging). 
The following assessments will be administered to the patient: 
• 
MMSE 
• 
ADAS-Cog 
• 
CDR (patient portion) 
• 
FCSRT 
• 
TMT 
• 
DST 
• 
DSST 
• 
LFT 
• 
CFT 
 
The following assessments will be administered to the caregiver: 
• 
CCQ 
• 
CDR (caregiver portion) 
• 
ADCS-ADL 
• 
Dependence Scale 
• 
NPI 
 
See Appendix 6 for details regarding the neurocognitive and functional assessments. 
4.3.9 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor for analysis.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
• 
Hematology:  hemoglobin, RBC count, WBC count, and platelets 
• 
Serum chemistry:  sodium, potassium, BUN, estimated glomerular filtration rate, 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl 
transpeptidase, alkaline phosphatase, lactate dehydrogenase, total protein, glucose, 
cholesterol, triglycerides, and creatine phosphokinase. 
• 
Urinalysis, including dipstick (i.e., pH, specific gravity, glucose, protein, ketones, 
blood) and microscopic examination (e.g., sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria) 
• 
Coagulation:  aPTT and INR 


 
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• 
Anti-therapeutic antibodies 
• 
PK assessments:  blood samples will be collected for measurement of serum 
crenezumab concentrations to confirm exposure.  On dosing days, PK blood 
samples will be collected prior to study drug administration unless otherwise 
specified. 
• 
PD assessments: blood samples will be collected from all patients at specified time 
points for the determination of total plasma Abeta levels as an exploratory measure 
of PD response to crenezumab treatment.  Additional plasma, serum, and 
RNA samples will be collected from all patients at specified time points to enable 
exploratory analysis of biomarkers, their response to crenezumab, and their 
association with clinical efficacy. 
 
 
 On dosing days, PD blood samples will be 
collected prior to study drug administration, unless otherwise specified.  
 
4.3.10 
Electrocardiograms 
Single ECG recordings will be obtained at each specified time point (see the schedule of 
assessments in Appendices 1 − 3).  ECGs acquired on different days should be as 
closely time-matched as feasible.  If possible, ECGs should be recorded on the same 
type of machine for each site involved in the study, and the same machine should be 
used for all ECGs for a specific patient. 
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position.  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. 
4.4 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.4.1 
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.  
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 


 
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• 
Patient non-compliance, specifically defined as follows: 
– 
Patient in the SC cohort misses more than two doses within 6 months 
– 
Patient in the IV cohort misses more than one dose within 6 months 
– 
Patients considered non-compliant may need to be withdrawn from the study 
treatment.  Patients should then complete the early treatment discontinuation 
safety follow-up visit (ET FU Week 8). 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  Patients who discontinue from the treatment period prior to Week 145 will be 
asked to return to the clinic within 4 weeks after the last administration of study drug to 
undergo early termination assessments and should return for additional safety 
assessments 8 weeks after the early termination assessments.  See Appendix 5.  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. 
4.4.2 
Study Treatment Discontinuation 
Patients with a serious, life-threatening adverse event, superficial siderosis of central 
nervous system, one new cerebral macrohemorrhage, an increase by one or more in the 
number of symptomatic cerebral microhemorrhages compared with screening, or an 
increase by six or more in the number of asymptomatic cerebral microhemorrhages 
compared with screening, as assessed by T2*-weighted GRE MRI, must not receive 
additional doses of crenezumab, and must be discontinued from the study treatment.  
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced. 
4.4.3 
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. 
• 
Study ABE4689g or ABE4955g is prematurely terminated or fails to demonstrate 
minimal safety, tolerability, or evidence of activity criteria following completion and 
evaluation of Study ABE4689g or ABE4955g. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   


 
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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: 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
Crenezumab has not been approved for use by global health authorities and is currently 
in clinical development.  Thus, the entire safety profile is not known at this time.  Human 
experience is currently limited, and the following information is based on results from 
nonclinical and clinical studies as well as published data on similar molecules.  The 
safety plan for this study is designed to ensure patient safety and will include specific 
eligibility criteria and monitoring assessments as detailed below. 
5.1.1 
Amyloid-Related Imaging Abnormalities – Edema/Effusion 
(ARIA-E) 
The occurrence of imaging abnormalities believed to represent cerebral vasogenic 
edema has been reported in association with the investigational use of compounds that 
are intended to treat Alzheimer’s disease by reducing Abeta in the brain.  
These MRI signal hyperintensities seen in the parenchyma and leptomeninges are now 
more specifically named “amyloid-related imaging abnormalities – edema/effusion” 
(ARIA-E) to cover the MRI alterations seen in the FLAIR sequence thought to represent 
edema in the gray and white matter, and effusion or extravasated fluid in the sulcal 
space (Sperling et al. 2011).  These FLAIR signal abnormalities have, in the majority of 
instances, been asymptomatic, and their presence has been detected by routine brain 
MRI.  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 (Sperling et al. 2012; 
Salloway et al. 2009).  The mechanisms underlying ARIA-E observed in these trials are 
unclear but may at least in part be related to FcγR activity of these anti-Abeta antibodies.  
When anti-Abeta antibodies bind to amyloid deposited around blood vessels, an 
FcγR-mediated immune response may be elicited, compromising vascular integrity and 
resulting in ARIA-E.  The hypothesis that FcγR-mediated immune response may 
contribute to the occurrence of ARIA-E is supported by results from clinical studies that 
have shown that up to 17% of the patients treated with anti-Abeta antibodies with full 
effector function developed ARIA-E that was dependent on the dose level and related to 


 
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ApoE4 status (Sperling et al. 2012).  In that study, the mean number of infusions before 
detection of ARIA-E was 2.4, and most cases of ARIA-E (69%) were identified after the 
first or second infusion (Sperling et al., 2012). 
Crenezumab, a human IgG4, has reduced FcγR binding compared with IgG1/2 and thus 
has reduced effector function that theoretically might lower the risk of ARIA-E. 
The potential for improved safety of crenezumab is supported by safety observed in both 
clinical and nonclinical studies.  In the completed Phase I study (ABE4427g), no signs or 
symptoms of ARIA-E (clinical or radiological) were observed following a single dose of 
up to 10 mg/kg or four weekly doses of up to 5 mg/kg.  In the completed Phase II 
Studies ABE4869g and ABE4955g, a single case of ARIA-E has been observed (see 
above), supporting the reduced risk of developing ARIA-E with crenezumab.  The very 
low rate of ARIA-E in Studies ABE4869g and ABE4955g supports a reduced frequency 
of brain MRIs (every 6 months vs. 3 months) in this study.  For additional details on 
clinical studies, see the Investigator's Brochure. 
In this OLE study, the following safety monitoring plan has been designed to mitigate 
and monitor the potential risk of cerebral ARIA-E: 
• 
Patients included in the study will regularly undergo neurologic examinations to 
evaluate for any neurologic signs or symptoms that are suggestive of the presence 
of ARIA-E (e.g., confusion, dizziness, vomiting, lethargy). 
• 
Brain MRI (including FLAIR) will be performed at least every 6 months to detect 
non-symptomatic ARIA-E. 
• 
All MRIs will be read in real time for the evaluation of ARIA-E by independent 
radiologists at a central contract imaging reader.  Study drug will be held if 
MRI abnormalities consistent with ARIA-E appear. 
• 
Patients who exhibit ARIA-E as assessed by FLAIR MRI will not receive additional 
study drug until the investigator has determined that ARIA-E has resolved 
(as assessed by short-interval MRI and clinical evaluation).  Treatment with 
high-dose dexamethasone should be considered if symptoms of ARIA-E are severe. 
• 
Regardless of severity, all events of ARIA-E that occur at any time after receiving 
study drug are considered to be adverse events of special interest and will be 
reported in an expedited manner (see Section 5.2.3). 
 


 
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5.1.2 
Amyloid-Related Imaging Abnormalities–Hemorrhage (ARIA-H) 
Cerebral microhemorrhages (microbleeds [MBs]) are radiologically defined as small 
dot-like foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue 
properties (i.e., T2*-weighted or SWI) (Greenberg et al. 2009).  This signal loss is 
caused by residual blood breakdown products, hemosiderin, or iron stored in 
macrophages in the brain parenchyma around damaged small vessels.  The most 
common causes for this small vessel damage and subsequent leakage are hypertensive 
vasculopathy and CAA.  CAA is believed to predominantly cause MBs in 
Alzheimer’s disease (Cordonnier et al. 2011). 
MBs in Alzheimer’s disease have a point prevalence of 23% (Cordonnier et al. 2011).  
One longitudinal study found that in Alzheimer’s disease patients the incidence of one or 
more MBs after a mean follow-up of 2 years was 12% (Goos et al. 2010).  Recently, the 
occurrence of MBs has also been identified as an adverse event in anti-amyloid 
vaccination trials, and together with superficial siderosis, they have been termed 
“amyloid-related imaging abnormalities-hemorrhage (ARIA-H) (Sperling et al. 2011).  
Limited data on ARIA-H occurrence is available, but a recent retrospective analysis in 
Alzheimer’s disease patients treated with anti-Abeta antibodies with full effector function 
reported that 24 out of 207 participants (11.6%) developed ARIA-H (Sperling et al. 2012).  
Acute occurrence of MBs is not considered clinically symptomatic 
(Greenberget al., 2009).  In fact, study patients who received active drug and developed 
ARIA-H without ARIA-E were all clinically asymptomatic (Sperling et al. 2012). 
In the completed Phase II studies ABE4869g and ABE4955g, patients underwent an MRI 
assessment at least every 3 months that included a T2*-weighted sequence; new MBs 
were detected in 11.6% of patients receiving crenezumab and 12.5% of patients 
receiving placebo.  For additional details on clinical studies see the 
Investigator's Brochure. 
In this OLE study, the following safety monitoring plan has been designed to mitigate 
and monitor the potential risk of cerebral ARIA-H: 
• 
Patients with superficial siderosis of central nervous system, more than eight 
cerebral microhemorrhages, or evidence of a prior cerebral macrohemorrhage 
(as assessed by a central reader based on T2*-weighted GRE MRI) will be excluded 
from the trial.   
• 
Brain MRIs (T2*-weighted GRE sequences) will be performed at least every 
6 months to detect superficial siderosis of central nervous system, and cerebral 
micro- or macrohemorrhages.   


 
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• 
All MRIs will be read in real time for the evaluation of ARIA-H by independent 
radiologists at a central contract imaging reader.  Study drug will be discontinued if 
patients who exhibit superficial siderosis of central nervous system, one new 
cerebral macrohemorrhage, an increase by one or more in the number of 
symptomatic cerebral microhemorrhages compared with screening, or an increase 
by six or more in the number of asymptomatic cerebral microhemorrhages 
compared with screening.   
• 
Patients who exhibit new asymptomatic cerebral microhemorrhages, but do not 
qualify for treatment discontinuation as defined above, will be re-scanned within 
8 weeks after the last MRI scan to evaluate their stability.   
• 
Regardless of severity, all events of ARIA-E that occur at any time after receiving 
study drug are considered to be adverse events of special interest and will be 
reported in an expedited manner (see Section 5.2.3).   
 
5.1.3 
Pneumonia 
As described in Section 1.3.3, in the RPCP of Phase II clinical trials in mild-to-moderate 
Alzheimer’s disease (ABBY and BLAZE), there was an imbalance in the rates of 
pneumonia, with 3.2% (11/346) of crenezumab-treated patients and 0.6% (1/176) of 
patients on placebo having pneumonia. Of these 12 pneumonia cases, 7 were assessed 
as serious (4 on crenezumab IV, 2 on crenezumab SC, and 1 on placebo).  
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 et al. 2008), but 
rates (both total and serious) are slightly higher in crenezumab-treated patients (3.2%) 
and slightly lower in placebo-treated patients (0.6%) than rates reported in the active and 
placebo arms of clinical trials in Alzheimer’s disease (Doody et al. 2014; Henley et al. 
2014; Salloway et al. 2014).  There is no clinical evidence of immunosuppression (e.g., 
effects on white blood cells or neutrophils; or pattern of infection type, e.g., opportunistic 
infections).  In addition, no evidence of immunosuppression or of a lung toxicity effect 
has been observed in preclinical studies.  Based on the currently available data, a 
causal relationship between the drug and events of pneumonia cannot be established or 
ruled-out.  Pneumonia is considered a potential risk and will be monitored closely.   
Pneumonia is now considered an adverse event of special interest and should be 
reported in an expedited manner (see Section 5.2.3). 
Patients with signs and/or symptoms suggestive of pneumonia (e.g., cough, fever, 
pleuritic chest pain) should undergo chest radiography for confirmation of diagnosis. 
Additional tests might be considered at the discretion of the treating physician.  Patients 
should be treated as per the standard treatment of care, and any change to study drug 
should be considered within a benefit/risk assessment frame and be in agreement with 
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5.1.4 
Deaths 
As described in Section 1.3.3, in the RPCP of the Phase II clinical trials in mild− to-
moderate Alzheimer’s disease (ABBY and BLAZE), there were 5 deaths. All 5 deaths 
occurred in patients treated with crenezumab, and none were assessed as related to 
study drug by the investigator.  This represents 1.4% (5/346) of patients receiving 
crenezumab compared with 0.0% (0/176) of patients receiving placebo.  The causes of 
death are in line with published literature showing no prevalent cause of death among 
Alzheimer’s disease treatment trials (Henley et al. 2012; Henley et al. 2014; Doody et al. 
2014). 
A causal relationship between crenezumab and the fatal events cannot be established or 
ruled out.  Fatal events will continue to be monitored closely for the identification of any 
potential pattern (e.g., a more frequent cause of death) or a particular population group 
at risk (e.g., gender, age group, particular comorbidity). Exposure-adjusted rates will be 
assessed and compared with published background rates from a similar study 
population (Henley et al. 2012; Henley et al. 2014). 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and non-serious adverse events of special interest, 
measurement of protocol-specified safety laboratory assessments, measurement of 
protocol-specified vital signs, and 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 patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9 
• 
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 
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• 
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: 
• 
Fatal (i.e., the adverse event actually causes or leads to death) 
• 
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 5.3.5.10) 
• 
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) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
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 (rated as mild, moderate, or severe, or according to 
National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) criteria; 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). 
5.2.3 
Non-Serious Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) 
Non-serious 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: 
• 
Cerebral vascular edema (ARIA-E) 


 
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• 
Superficial siderosis of central nervous system (ARIA-H) 
• 
Cerebral microhemorrhages (ARIA-H) or macrohemorrhages 
• 
Occurrence of pneumonia regardless of severity/seriousness or relatedness with 
study drug.  Diagnosis is to be verified by imaging (e.g., chest X-ray) (see 
Sections 3.4.3 and 5.1.3) 
• 
Suspected transmission of an infectious agent by the investigational product, 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. 
• 
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 5.3.5.6) 
 
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. 
Adverse events occurring after informed consent has been obtained but prior to 
initiation of study drug, only serious adverse events caused by a protocol-mandated 
intervention should be reported (e.g., serious adverse events related to invasive 
procedures such as biopsies).  No events during the screening period should be entered 
into the Adverse Event eCRF; they should be captured in the original study AE CRF 
(i.e., Abby or Blaze), if within the reported period for those. 
Only adverse events and serious adverse events that are unresolved when the patient is 
randomized (on Day 1) in Study GN28525 should be carefully recorded over to the 
GN28525 eCRF Database.   


 
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After initiation of study drug, all adverse events and serious adverse events, 
regardless of relationship to study drug, will be reported until at least 8 weeks after the 
last dose of study drug.  After this period, investigators should report any deaths, serious 
adverse events, or other adverse events of special interest (see Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation time points.  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 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 
Table 1 
Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the NCI CTCAE (v4.0), which can be found at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions) per the definition of serious adverse event in Section 5.2.2. 
  


 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating "yes" or 
"no" accordingly.  The following guidance should be taken into consideration 
(see Table 3): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering the effects of discontinuation of study drug, or 
reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event 
 
Table 2 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug and, 
if applicable, reappears upon re-challenge. 
NO 
AEs will be considered related, unless they fulfill the criteria as specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
  
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
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 
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5.3.5.1 
Diagnosis versus Signs and Symptoms 
Adverse events that occur during or within 24 hours after study drug infusion should be 
captured as individual signs and symptoms rather than a diagnosis of allergic reaction or 
infusion reaction. 
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. 
Diagnoses for cerebral vasogenic edema (ARIA-E), superficial siderosis of central 
nervous system, cerebral microhemorrhage, and cerebral macrohemorrhage will be 
made based on MRI.  It is suggested that the descriptions "cerebral vasogenic edema," 
"superficial siderosis of central nervous system," "cerebral microhemorrhage," and 
"cerebral hemorrhage," be used for AE and SAE reporting purposes. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, adverse events occurring 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.  However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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 a mild, non-serious infection, only neutropenia 
should be reported on the eCRF. 
• 
If neutropenia is accompanied by a severe or serious 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. 


 
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5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution between 
patient evaluation time points.  Such events should only be recorded once in the 
Adverse Event eCRF unless their severity increases.  If a persistent AE becomes more 
severe, it should be recorded as a separate event on the Adverse Event eCRF.  The 
initial (less severe) adverse event report should be updated to indicate that the event 
resolved on the date just prior to the day the event became more severe.  If a persistent 
adverse event becomes serious, it should be recorded as a separate event on the 
Adverse Event eCRF and reported to the Sponsor immediately (i.e., no more than 24 
hours after learning that the event became serious; see Section 5.4.2 for reporting 
instructions). The initial (non-serious) adverse event report should be updated to indicate 
that the event resolved on the date just prior to the day the event became serious. 
A recurrent adverse event is one that occurs and resolves between patient evaluation 
time points and subsequently recurs.  All recurrent adverse events should be recorded 
on the Adverse Event eCRF. 
5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment 
For oncology trials, certain abnormal values may not qualify as adverse events. 
 
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 times the upper limit of normal [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 if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 


 
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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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result should 
be reported as an adverse event if it meets any of the following criteria: 
• 
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 
• 
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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
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.  
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 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 


 
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the event) either as a serious adverse event or a non-serious adverse event of special 
interest (see Section 5.4.2). 
5.3.5.7 
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 Alzheimer’s disease. 
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 only be used 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 of 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.   
5.3.5.8 
Pre-Existing Medical Conditions 
A pre-existing medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.5.9 
Worsening of Alzheimer’s Disease 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
Alzheimer’s disease should be recorded as an adverse event if judged by the 
investigator to have unexpectedly worsened in severity or frequency or changed in 
nature at any time during the study.  When recording an unanticipated worsening of 
Alzheimer’s disease on the Adverse Event eCRF, it is important to convey the concept 
that the condition has changed by including applicable descriptors (e.g., “accelerated 
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5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) or 
prolonged hospitalization should be documented and reported as a serious adverse event 
(per the definition of serious adverse event in Section 5.2.2), except as outlined below. 
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol 
• 
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 suffered an adverse event 
• 
Hospitalization due solely to progression of Alzheimer’s disease 
 
The following hospitalization scenarios are not considered to be serious adverse events, 
but should be reported as adverse events instead: 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available 
 
5.3.5.11 
Adverse Events Associated with an Overdose 
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 serious 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 5.4.2). 
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) 
• 
Non-serious adverse events of special interest (see Section 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 


 
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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  
Primary Medical Monitor Contact Information for sites in North America: 
 Medical Monitor:  
, M.D. 
24-Hour Emergency Telephone No.:  
 
Primary Medical Monitor Contact Information for sites in Europe: 
 Medical Monitor:  
, M.D. 
24-Hour Emergency Telephone No.:  
 
Alternate Medical Monitor Contact Information: 
Medical Monitor:  
, M.D., Ph.D. 
Telephone No.: 
Mobile Telephone No.: 
Alternate Telephone No.:  (888) 835-2555 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest 
For reports of serious adverse events and non-serious adverse events of special interest, 
investigators should record all case details that can be gathered immediately 
(i.e., within 24 hours) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to the 
Sponsor’s Safety Risk Management department by the EDC system. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and Fax Coversheet should 
be completed and faxed to Safety Risk Management or its designee immediately 
(i.e., no more than 24 hours after learning of the event), using the fax numbers provided 
below.  Once the EDC system is available, all information will need to be entered and 
submitted via the EDC system.  Instructions for reporting post-study adverse events are 
provided in Section 5.6. 


 
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For Sites in U.S. and Canada: 
Fax No.:  
 
For Sites in France: 
Fax No.:  
 
For Sites in Germany: 
Fax No.: 
 
Alternate Fax No.: 
 (pause) 
 
For Sites in Spain: 
Fax No.: 
 
For Sites in United Kingdom: 
Fax No.: 
 
Relevant follow-up information should be submitted to Genentech’s Drug Safety 
Department or its designee as soon as it becomes available and/or upon request.   
 
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 Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system.  A pregnancy report will automatically be generated and sent to 
Safety Risk Management.  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. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy Fax Coversheet should be completed and faxed to Safety Risk Management 
or its designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
using the fax numbers provided in Section 5.4.2. 
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 Pregnancy Report eCRF should be 
completed by the investigator immediately (i.e., no more than 24 hours after learning of 
the pregnancy) and submitted via the EDC system.  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 


 
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pregnancy.  Once the authorization has been signed, the investigator will update the 
Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy.  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. 
In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as a serious adverse event 
(as the Sponsor considers spontaneous abortions to be medically significant events), 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2).   
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.  If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome.  
If the EDC system is not available at the time of pregnancy outcome, follow reporting 
instructions provided in Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, non-serious 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 


 
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(e.g., from hospital discharge summaries, consultant reports, autopsy reports) in order to 
perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the time of study completion or study discontinuation, the investigator should instruct 
each patient to report to the investigator any subsequent adverse events that the 
patient’s personal physician believes could be related to prior study drug treatment or 
study procedures.   
The investigator should notify the Sponsor of any death, serious adverse event, or other 
adverse event of concern occurring at any time after a patient has discontinued study 
participation if the event is believed to be related to prior study drug treatment.  The 
Sponsor should also be notified if the investigator becomes aware of the development of 
cancer or a congenital anomaly/birth defect in a subsequently conceived offspring of a 
female patient exposed to study drug or the female partner of a male patient exposed to 
study drug. 
The investigator should report these events directly to Safety Risk Management via fax 
machine using the Serious Adverse Event Reporting Form and fax cover sheet as 
follows: 
For Sites in U.S. and Canada:  
Fax No.:  
; Alternative Fax No.:
 
For Sites in Germany: 
Fax No.:  
  
For Sites in France: 
Fax No.:  
  
For Sites in the U.K.:  
Fax No.:  
 
For Sites in Spain:  
Fax No.:  
  
For Sites in Canada: 
Fax No.:  
  
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and non-serious 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. 


 
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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  
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 
6.1 
DETERMINATION OF SAMPLE SIZE 
This study is open to all patients who completed Study ABE4869g or ABE4955g and 
who met the eligibility criteria.  Accordingly, the sample size for this study is not based 
on a formal sample size calculation.   
6.2 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue (early discontinuation of treatment or 
early termination from the study), and complete the study (through Week 153) will be 
tabulated by treatment group.  Reasons for early discontinuation of treatment or early 
termination from the study will be listed and summarized by treatment group.  Any 
eligibility criteria exceptions and other protocol deviations will also be summarized by 
treatment group 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Demographic and baseline characteristics such as age, sex, race, ApoE4 status, and 
baseline MMSE and group assignment in Study ABE4869g and ABE4955g will be 
summarized for all enrolled patients by use of descriptive statistics. 
6.4 
SAFETY ANALYSES 
The safety analyses will include all enrolled patients who received at least one dose of 
study drug in this OLE study following their completion of Study ABE4869g or ABE4955g. 
These patients will be grouped based on treatment assignment in the OLE study and 
Study ABE4869g or ABE4955g.  Primary safety analysis will be performed after enrolled 
patients have completed Week 153 visit of the OLE study. 
Safety will be assessed by monitoring adverse events, clinical laboratory evaluations, 
MRI evaluations, and immunogenicity as measured by ATAs.  Patients will be analyzed 
according to actual treatment received. 


 
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6.4.1 
Adverse Events 
Adverse events will be recorded from the time informed consent is given until a patient 
completes the study or discontinues prematurely.  Adverse events reported during the 
screening period, the 144-week treatment period, and the 8-week follow-up period will be 
summarized separately.  Verbatim descriptions of adverse events will be coded and 
analyzed using appropriate thesaurus terms.  A treatment-emergent adverse event is 
defined as any adverse event reported during or after the first dose of study drug. 
6.4.2 
Clinical Laboratory Evaluations 
Clinical laboratory data (i.e., serum chemistry, hematology evaluations including CBC 
with differential and platelet counts, urinalysis values) will be summarized by descriptive 
statistics by treatment group at the end of the final follow-up visit (Week 153). 
6.4.3 
MRI Evaluations 
Neuroradiologic evaluation with respect to the occurrence of cerebral vasogenic edema, 
superficial siderosis of central nervous system, and cerebral micro- or 
macrohemorrhages will be performed during the 153-week study period and will be 
summarized by treatment group using descriptive statistics. 
6.4.4 
Anti-Therapeutic Antibodies 
The number and percentage of patients with confirmed positive ATA levels will be 
reported for each treatment group at the end of the final follow-up visit (Week 153). 
6.5 
PHARMACODYNAMIC ANALYSES 
Exploratory PD biomarkers will be evaluated in plasma samples collected at specified 
visits indicated in the study flowchart (see Appendices A1 and A2) and will consist of 
Abeta species as well as other plasma markers implicated in Alzheimer’s disease 
progression.  Individual and mean plasma total Abeta1-40 and Abeta1-42 concentrations 
versus time data will be tabulated and plotted by dose level. 
6.6 
PHARMACOKINETIC ANALYSES 
Individual and mean serum crenezumab concentration versus time data will be tabulated 
by dose level, and Ctrough, ss will be reported.  Parameters will be tabulated and 
summarized (e.g., mean, standard deviation, minimum, and maximum).  Additional 
PK analyses may be conducted as appropriate. 
6.7 
EXPLORATORY ANALYSES 
Refer to the Statistical Analysis Plan for analyses related to the exploratory objectives. 
6.8 
INTERIM ANALYSES 
No interim analysis is planned for this study. 


 
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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the data management of 
this study, including quality checking of the data.  Data entered manually will be 
collected via electronic data capture (EDC) using eCRFs.  Sites will be responsible for 
data entry into the EDC system.  In the event of discrepant data, the CRO will request 
data clarification from the sites, which the sites will resolve electronically in the 
EDC system.   
The Sponsor will perform oversight of the data management of this study, and produce 
an EDC Study Specification document that describes the quality checks to be performed 
on the data.  Central laboratory data and central imaging data will be sent directly to 
Genentech, using Genentech’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 record 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 using a Sponsor-designated EDC system.  ‘Sites will receive 
training and a 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, 


 
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patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial-related 
monitoring, Sponsor audits, and IRB/EC review.  The investigational site must also allow 
inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational 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, ePRO 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. 


 
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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 EU/EEA will 
comply with the EU Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the “Consent Forms”) 
before IRB/EC submission.  The final IRB/EC-approved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements. 
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. 


 
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For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.4). 
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 only be 
disclosed to third parties as permitted by the Informed Consent Form 
(or separate authorization for use and disclosure of personal health information) signed 
by the patient, unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other 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, which includes an audit trail containing a complete record of all changes 
to data. 
9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
The study is sponsored by Genentech, Inc., a member of the Roche group; crenezumab 
is being developed by Genentech and AC Immune SA.  This trial will be managed by a 
CRO.  Approximately 390 patients will participate in this study at up to 100 centers in 
North America and Europe. 
Patients will be registered in the study using a central IxRS vendor.   
All laboratory tests of blood specimens will be performed by a central laboratory or the 
Sponsor, as appropriate.   
A central imaging reader will determine the presence of cerebral vasogenic edema by 
FLAIR MRI, and the presence of superficial siderosis of central nervous system and 
cerebral micro- or macrohemorrhages by T2*-weighted GRE MRI scans. 
9.4 
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. 


 
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Approval must be obtained from the IRB/EC and regulatory authorities 
(as locally required) before implementation of any changes, except for changes 
necessary to eliminate an immediate hazard to patients or changes that involve logistical 
or administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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