Clinical trial NCT03828747
Conditions: Alzheimer's Disease
Sponsor: Genentech, Inc.
Start date: 2019-01-25; Completion date: 2023-08-30
Enrollment: 272 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study will evaluate the clinical efficacy, safety, pharmacokinetics, and pharmacodynamics of semorinemab in patients with moderate AD. The study consists of a screening period, a double-blind treatment period, an optional open-label extension (OLE) period, and a safety follow-up period. There may be up to two study cohorts.

Detailed description:

Arms: arm 1: Semorinemab will be administered intravenously in the double-blind treatment period, and semorinemab will be administered intravenously in the optional open-label extension period. arm 2: Placebo will be administered intravenously in the double-blind treatment period and semorinemab will be administered intravenously in the optional open-label extension.
Interventions: intervention 1: Semorinemab intervention 2: Placebo intervention 3: [18F]GTP1
Intervention descriptions: intervention 1: Participants will receive semorinemab every 2 weeks (Q2W) for the first three doses of the double-blind treatment period and every 4 weeks (Q4W) thereafter during the double-blind treatment period. Semorinemab will be administered Q4W in the OLE period. intervention 2: Participants will receive placebo every 2 weeks (Q2W) for the first three doses of the double-blind treatment period and every 4 weeks (Q4W) thereafter during the double-blind treatment period. intervention 3: \[18F\]GTP1 will be administered as a solution for intravenous (IV) use, as part of positron emission tomography (PET) imaging.

Protocol documents:
Prot_SAP_000.pdf: 
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The information contained in this document, especially any unpublished data, is the property of 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.
MTAU9937A—Genentech, Inc.
Protocol GN40040, Version 5
PROTOCOL
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, EFFICACY, AND SAFETY 
STUDY OF MTAU9937A IN PATIENTS WITH 
MODERATE ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
GN40040
VERSION NUMBER:
5
EUDRACT NUMBER:
2018-003398-87
IND NUMBERS:
129270, 125702
NCT NUMBER:
NCT03828747
TEST PRODUCTS:
MTAU9937A (RO7105705) and 
[18F]GTP1 (RO6880276)
MEDICAL MONITOR:
, M.D., Ph.D.
SPONSOR:
Genentech, Inc.
APPROVAL DATE:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
14-Dec-2021 20:33:39


MTAU9937A—Genentech, Inc.
2/Protocol GN40040, Version 5
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
4
29 June 2020
3
16 April 2020
2
12 June 2019
Spain
1
12 June 2019
1
3 October 2018
European Union
1
6 December 2018


MTAU9937A—Genentech, Inc.
3/Protocol GN40040, Version 5
PROTOCOL AMENDMENT, VERSION 5:
RATIONALE
Following data read out of the double-blind treatment period of the study, Protocol 
GN40040 has been amended to reduce patient, caregiver, and site burden by removing 
and reducing the frequency of specific study assessments that are considered unlikely to 
contribute additional scientific value during the open-label extension (OLE).  The study 
has also been amended to remove Cohort 3 and language related to a potential 
expansion in the study size.  Changes to the protocol, along with a rationale for each 
change, are summarized below:

Recent updates on clinical studies have been added to the background on
MTAU9937A and fluorine-18 Genentech tau probe 1 ([18F]GTP1) (Sections 1.2.2,
1.3, and 1.3.1).

The study design has been amended to remove Cohort 3.  Under protocol
Version 4, the protocol allowed for extension of the double-blind treatment period to
73 weeks for those patients who missed more than three doses of blinded study
drug because of the COVID-19 pandemic.  However, the proportion of patients
having missed more than three study drug doses in the double-blind period was not
significant; therefore, no patients were enrolled into Cohort 3 (Sections 2.1.1, 2.1.2,
2.1.3, 3.1.1, 3.1.1.1, 3.3.1, 6, 6.2 ,6.4.1, and 6.4.2).  Appendices 5 and 6 have been
removed and subsequent appendices renumbered accordingly.

Language related to a potential expansion in the study size has been removed. The
option to enroll up to 100 additional patients to further mitigate the impact of the
COVID-19 pandemic on the study had been incorporated in protocol Version 4.
This expansion is now considered unnecessary (Sections 3.1.1, 3.2, 4.1, 6.1, and
9.4).

Given that no treatment effect was observed on [18F]GTP1 tau positron emission
tomography (PET) in the double-blind treatment period, [18F]GTP1 PET has been
removed during the OLE at Week 145 for Cohort 1, Week 157 for Cohort 2, and at
the treatment discontinuation visit (for both cohorts).  The provision for optional
[18F]GTP1 tau PET imaging assessments for patients potentially recruited after
implementation of protocol Version 4 has also been removed (Section 4.5.8;
Appendices 14).

OLE clinical Outcome Assessments (COAs), with the exception of the
Columbia-Suicide Severity Rating Scale, have been removed at Week 121 for
Cohort 1 and Week 133 for Cohort 2 to reduce patient, caregiver, and site burden.
The remaining COA timepoints are considered sufficient to monitor longitudinal
progression during the OLE (Appendices 2 and 4).

Based on the low variability of MTAU9937A pharmacokinetics and the rare
occurrence of anti-drug antibodies (ADAs), the collection of serum pharmacokinetic
(PK) and ADA samples has been reduced to only once during the OLE, at Week 97
for Cohort 1 and Week 109 for Cohort 2. All other OLE PK and ADA sample
collection timepoints have been removed (Appendices 2 and 4).


MTAU9937A—Genentech, Inc.
4/Protocol GN40040, Version 5

The Medical Monitor has been changed; applicable study summary pages and 
emergency medical contact information (Section 5.4.1) have been updated 
accordingly. 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol.


MTAU9937A—Genentech, Inc.
5/Protocol GN40040, Version 5
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 26
1.1
Background on Alzheimer’s Disease..................................... 26
1.2
Background on MTAU9937A................................................. 27
1.2.1
Nonclinical Information .......................................................... 27
1.2.2
Clinical Information ................................................................ 28
1.3
Background on [18F]GTP1 ..................................................... 29
1.3.1
Clinical Safety and Tolerability............................................... 31
1.4
Study Rationale and BenefitRisk Assessment..................... 31
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
2.1
Efficacy Objectives ................................................................ 33
2.1.1
Primary Efficacy Objective..................................................... 33
2.1.2
Secondary Efficacy Objectives .............................................. 33
2.1.3
Exploratory Efficacy Objectives ............................................. 33
2.2
Safety Objectives................................................................... 34
2.3
Pharmacokinetic Objectives .................................................. 34
2.4
Immunogenicity Objectives.................................................... 34
2.5
Biomarker Objective .............................................................. 35
3.
STUDY DESIGN......................................................................................... 35
3.1
Description of the Study......................................................... 35
3.1.1
Overview of Study Design and Study Treatment................... 35
3.1.1.1
Study Periods ........................................................................ 38
3.1.2
Internal Monitoring Committee............................................... 40
3.2
End of Study and Length of Study......................................... 41
3.3
Rationale for Study Design.................................................... 41
3.3.1
Rationale for MTAU9937A Dose and Schedule..................... 41
3.3.2
Rationale for Patient Population ............................................ 42
3.3.3
Rationale for Amyloid Enrichment ......................................... 42
3.3.4
Rationale for Use of Investigational Tau 
Radioligand [18F]GTP1 .......................................................... 43


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3.3.5
Rationale for Biomarker Assessments................................... 43
3.3.6
Rationale for Requiring Caregiver Participation..................... 44
3.3.7
Rationale for Control Group................................................... 44
3.3.8
Rationale for Pharmacokinetic Sampling............................... 44
3.3.9
Rationale for Use of Clinician and Observer 
Reported Outcome Assessments.......................................... 44
4.
MATERIALS AND METHODS .................................................................... 45
4.1
Patients.................................................................................. 45
4.1.1
Inclusion Criteria.................................................................... 45
4.1.2
Exclusion Criteria................................................................... 48
4.2
Method of Treatment Assignment and Blinding..................... 53
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 54
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 54
4.3.1.1
MTAU9937A and Placebo ..................................................... 54
4.3.1.2
[18F]GTP1 Tau PET Radioligand ........................................... 54
4.3.1.3
Amyloid PET Radioligands .................................................... 54
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 55
4.3.2.1
MTAU9937A and Placebo ..................................................... 55
4.3.2.2
[18F]GTP1 Tau PET Radioligand ........................................... 56
4.3.2.3
Amyloid PET Radioligand...................................................... 56
4.3.3
Investigational Medicinal Product Accountability ................... 57
4.3.4
Continued Access to MTAU9937A ........................................ 57
4.4
Concomitant Therapy ............................................................ 57
4.4.1
Permitted Therapy................................................................. 58
4.4.2
Cautionary Therapy ............................................................... 58
4.4.2.1
Herbal Therapies................................................................... 58
4.4.3
Prohibited Therapy ................................................................ 58
4.5
Study Assessments ............................................................... 58
4.5.1
Informed Consent Forms and Screening Log........................ 58
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 59


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4.5.3
Physical Examinations........................................................... 59
4.5.4
Neurologic Examinations....................................................... 60
4.5.5
Lumbar Puncture................................................................... 60
4.5.6
Vital Signs.............................................................................. 60
4.5.7
Clinical Outcome Assessments ............................................. 60
4.5.7.1
Mini-Mental State Examination.............................................. 62
4.5.7.2
Clinical Dementia Rating Scale ............................................. 62
4.5.7.3
Alzheimer’s Disease Assessment Scale–
Cognitive Subscale, 11-Item Version..................................... 62
4.5.7.4
Alzheimer’s Disease Cooperative 
StudyActivities of Daily Living Inventory .............................. 62
4.5.7.5
Neuropsychiatric Inventory .................................................... 63
4.5.7.6
Caregiver Global Impression Scales for 
Alzheimer’s Disease .............................................................. 63
4.5.7.7
Columbia-Suicide Severity Rating Scale ............................... 63
4.5.8
Amyloid and Tau Positron Emission Tomography................. 63
4.5.9
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64
4.5.10
Electrocardiograms................................................................ 66
4.5.11
Samples for Whole Genome and SNP 
Sequencing (at Participating Sites Only) ............................... 67
4.5.12
Optional Samples for Research Biosample 
Repository ............................................................................. 68
4.5.12.1
Overview of the Research Biosample Repository.................. 68
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 69
4.5.12.3
Sample Collection.................................................................. 69
4.5.12.4
Confidentiality........................................................................ 70
4.5.12.5
Consent to Participate in the Research 
Biosample Repository............................................................ 70
4.5.12.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 70
4.5.12.7
Monitoring and Oversight....................................................... 71
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 71
4.6.1
Study Treatment Discontinuation........................................... 71


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8/Protocol GN40040, Version 5
4.6.2
Patient Discontinuation from Study........................................ 72
4.6.3
Study Discontinuation............................................................ 72
4.6.4
Site Discontinuation............................................................... 72
5.
ASSESSMENT OF SAFETY....................................................................... 73
5.1
Safety Plan ............................................................................ 73
5.1.1
Potential Risks Associated with MTAU9937A........................ 73
5.1.1.1
Infusion-Related Reactions or Hypersensitivity ..................... 73
5.1.1.2
Neuroimaging Abnormalities.................................................. 73
5.1.1.3
Immunogenicity ..................................................................... 75
5.1.2
Potential Risks Associated with [18F]GTP1 and 
Amyloid PET Radiopharmaceuticals ..................................... 75
5.1.2.1
Infusion-Related Reactions.................................................... 75
5.1.2.2
Radiation Risk ....................................................................... 75
5.1.3
Management of Patients Who Experience 
Specific Adverse Events........................................................ 75
5.1.3.1
Treatment Interruption ........................................................... 75
5.1.3.2
Management Guidelines for Infusion-Related 
Reactions............................................................................... 76
5.1.3.3
Management of Increases in QT Interval............................... 76
5.2
Safety Parameters and Definitions ........................................ 77
5.2.1
Adverse Events ..................................................................... 77
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 78
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 79
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 79
5.3.1
Adverse Event Reporting Period ........................................... 79
5.3.2
Eliciting Adverse Event Information....................................... 80
5.3.3
Assessment of Severity of Adverse Events ........................... 80
5.3.4
Assessment of Causality of Adverse Events ......................... 81
5.3.5
Procedures for Recording Adverse Events............................ 82
5.3.5.1
Infusion-Related Reactions.................................................... 82
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 82


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5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 82
5.3.5.4
Persistent or Recurrent Adverse Events................................ 83
5.3.5.5
Abnormal Laboratory Values ................................................. 83
5.3.5.6
Abnormal Vital Sign Values ................................................... 84
5.3.5.7
Abnormal Liver Function Tests.............................................. 85
5.3.5.8
Deaths ................................................................................... 85
5.3.5.9
Preexisting Medical Conditions.............................................. 86
5.3.5.10
Lack of Efficacy or Worsening of Alzheimer’s 
Disease.................................................................................. 86
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 86
5.3.5.12
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 87
5.3.5.13
Clinical Outcome Assessment Data ...................................... 88
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 88
5.4.1
Emergency Medical Contacts................................................ 89
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 89
5.4.2.1
Events That Occur prior to Initiation of Study 
Drug or [18F]GTP1 Radioligand or an Amyloid 
Radioligand............................................................................ 89
5.4.2.2
Events That Occur after Initiation of Study Drug 
or [18F]GTP1 Radioligand or an Amyloid 
Radioligand............................................................................ 89
5.4.3
Reporting Requirements for Pregnancies.............................. 90
5.4.3.1
Pregnancies in Female Patients............................................ 90
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 90
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 91
5.5
Follow-Up of Patients after Adverse Events .......................... 91
5.5.1
Investigator Follow-Up........................................................... 91
5.5.2
Sponsor Follow-Up ................................................................ 92
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 92


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5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 92
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 93
6.1
Determination of Sample Size ............................................... 93
6.2
Summaries of Conduct of Study............................................ 93
6.3
Summaries of Treatment Group Comparability ..................... 93
6.4
Efficacy Analyses .................................................................. 94
6.4.1
Primary Efficacy Endpoints.................................................... 94
6.4.2
Secondary Efficacy Endpoints............................................... 94
6.5
Safety Analyses..................................................................... 94
6.6
Pharmacokinetic Analyses..................................................... 95
6.7
Immunogenicity Analyses...................................................... 95
6.8
Biomarker Analyses............................................................... 95
6.9
Interim Analyses .................................................................... 96
6.9.1
Optional Interim Analysis....................................................... 96
7.
DATA COLLECTION AND MANAGEMENT ............................................... 96
7.1
Data Quality Assurance......................................................... 96
7.2
Electronic Case Report Forms............................................... 96
7.3
Electronic Clinician-Reported Outcome Data ........................ 97
7.4
Source Data Documentation.................................................. 97
7.5
Use of Computerized Systems .............................................. 98
7.6
Retention of Records............................................................. 98
8.
ETHICAL CONSIDERATIONS.................................................................... 98
8.1
Compliance with Laws and Regulations ................................ 98
8.2
Informed Consent.................................................................. 99
8.3
Institutional Review Board or Ethics Committee.................. 100
8.4
Confidentiality...................................................................... 100
8.5
Financial Disclosure ............................................................ 101
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 101
9.1
Study Documentation .......................................................... 101
9.2
Protocol Deviations.............................................................. 101


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11/Protocol GN40040, Version 5
9.3
Site Inspections ................................................................... 102
9.4
Administrative Structure....................................................... 102
9.5
Dissemination of Data and Protection of Trade 
Secrets ................................................................................ 102
9.6
Protocol Amendments ......................................................... 103
10. REFERENCES ......................................................................................... 104
LIST OF TABLES
Table 1
Administration of First and Subsequent Infusions of 
MTAU9937A (or Placebo)........................................................... 56
Table 2
Clinical Outcome Assessments................................................... 61
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 80
Table 4
Causal Attribution Guidance ....................................................... 81
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 40
LIST OF APPENDICES
Appendix 1
Cohort 1 Schedule of Activities ................................................. 109
Appendix 2
Cohort 1 Schedule of Activities (Open-Label Extension) .......... 116
Appendix 3
Cohort 2 Schedule of Activities ................................................. 121
Appendix 4
Cohort 2 Schedule of Activities (Open-Label Extension) .......... 128
Appendix 5
National Institute on AgingAlzheimer’s Association Criteria 
for Alzheimer’s Disease Dementia............................................ 133
Appendix 6
Anaphylaxis Precautions........................................................... 135
Appendix 7
World Health Organization Toxicity Grading Scale for 
Determining Severity of Adverse Events................................... 136


MTAU9937A—Genentech, Inc.
12/Protocol GN40040, Version 5
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, EFFICACY, AND SAFETY 
STUDY OF MTAU9937A IN PATIENTS WITH 
MODERATE ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
GN40040
VERSION NUMBER:
5
EUDRACT NUMBER:
2018-003398-87
IND NUMBERS:
129270, 125702
NCT NUMBER:
NCT03828747
TEST PRODUCTS:
MTAU9937A (RO7105705) and 
[18F]GTP1 (RO6880276)
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 retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your Contract Research Associate.


MTAU9937A—Genentech, Inc.
13/Protocol GN40040, Version 5
PROTOCOL SYNOPSIS
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY, AND 
SAFETY STUDY OF MTAU9937A IN PATIENTS WITH MODERATE 
ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
GN40040
VERSION NUMBER:
5
EUDRACT NUMBER:
2018-003398-87
IND NUMBERS:
129270, 125702
NCT NUMBER:
NCT03828747
TEST PRODUCTS:
MTAU9937A (RO7105705) and 
[18F]GTP1 (RO6880276)
PHASE:
Phase II
INDICATION:
Alzheimer’s Disease
SPONSOR:
Genentech, Inc.
Objectives and Endpoints
This study will evaluate the clinical efficacy, safety, pharmacokinetics, and pharmacodynamics 
of MTAU9937A in patients with moderate Alzheimer’s disease (AD), ages 5085, who are 
amyloid positive by cerebrospinal fluid (CSF) or amyloid positron emission tomography (PET). 
Specific objectives and corresponding endpoints for the study are outlined below.
Primary Efficacy Objective 
The primary efficacy objective for this study is to evaluate the effects of MTAU9937A compared 
with placebo on cognition and function on the basis of the following endpoints:

Change from baseline to the last visit of the double-blind treatment period (Week 49 for 
Cohort 1 and Week 61 for Cohort 2) in cognitive function as measured by the Alzheimer’s 
Disease Assessment Scale, Cognitive Subscale, 11-item version (ADAS-Cog11)

Change from baseline to the last visit of the double-blind treatment period (Week 49 for 
Cohort 1 and Week 61 for Cohort 2) in functional capacities as measured by the 
Alzheimer's Disease Cooperative StudyActivities of Daily Living Inventory (ADCS-ADL)
Secondary Efficacy Objectives
The secondary efficacy objectives for this study along with the corresponding endpoints are as 
follows:

To evaluate the effect of MTAU9937A on global cognition and function compared with 
placebo on the basis of the following endpoint:

Change from baseline to the last visit of the double-blind treatment period (Week 49 for 
Cohort 1 and Week 61 for Cohort 2) on the Clinical Dementia RatingSum of Boxes
(CDR-SB)

To evaluate the effect of MTAU9937A on cognition compared with placebo on the basis of 
the following endpoint:

Change from baseline to the last visit of the double-blind treatment period (Week 49 for 
Cohort 1 and Week 61 for Cohort 2) on the Mini-Mental State Examination (MMSE)


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Exploratory Efficacy Objectives
The exploratory efficacy objectives for this study are as follows:

To evaluate the effect of MTAU9937A on behavioral symptoms compared with placebo on 
the basis of the following endpoint:

Change from baseline to the last visit of the double-blind treatment period (Week 49 for 
Cohort 1 and Week 61 for Cohort 2) on the Neuropsychiatric Inventory (NPI) 

To evaluate the effect of MTAU9937A on caregiver impression of changes in patient 
cognition and functional abilities compared with placebo on the basis of the following 
endpoint:

Ratings on the Caregiver Global Impression Scales for Alzheimer’s disease (CaGI-Alz) 
at the last visit of the double-blind treatment period (Week 49 for Cohort 1 and Week 
61 for Cohort 2)
Safety Objectives
The safety objectives for this study are to evaluate the safety and tolerability of MTAU9937A 
compared with placebo on the basis of the following endpoints:

Nature, frequency, severity, and timing of adverse events and serious adverse events, with 
severity determined according to WHO toxicity grading scale

Changes from baseline in vital signs, physical findings, neurologic findings, ECG, and 
clinical laboratory results during and following MTAU9937A administration

Changes from baseline in suicidal ideation and behavior during and following MTAU9937A 
administration as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS)

Nature, frequency, severity, and timing of neuroimaging abnormalities that could represent 
cerebral vasogenic edema and/or microhemorrhage, during MTAU9937A administration
Pharmacokinetic Objectives
The pharmacokinetic (PK) objective for this study is to characterize the MTAU9937A PK profile 
on the basis of the following endpoint:

Serum concentration of MTAU9937A at specified timepoints
The exploratory PK objectives for this study are as follows:

To characterize the MTAU9937A PK profile in CSF on the basis of the following endpoint:
CSF concentration of MTAU9937A at specified timepoints

To evaluate potential relationships between drug exposure and the efficacy and safety of 
MTAU9937A on the basis of the following endpoints:
Relationship between serum (and CSF if available) concentration or PK parameters for 
MTAU9937A and safety endpoints
Relationship between serum (and CSF if available) concentration or PK parameters for 
MTAU9937A and efficacy endpoints

To evaluate potential relationships between selected covariates and exposure to 
MTAU9937A on the basis of the following endpoint:
Relationship between selected covariates (including but not limited to age and sex) 
and serum concentration or PK parameters for MTAU9937A
Immunogenicity Objectives
The immunogenicity objectives for this study are as follows:

To evaluate the immune response to MTAU9937A on the basis of the following endpoint:
Incidence of anti-drug antibodies (ADAs) during the study relative to the prevalence of 
ADAs at baseline


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
To evaluate the potential effects of ADAs on the basis of the following endpoint:
Relationship between ADA status and efficacy, safety, or PK endpoints
Biomarker Objective
The exploratory biomarker objective for this study is to evaluate the effect of MTAU9937A on 
biomarkers to provide evidence of proof of activity, to aid in defining mechanism of action, to 
evaluate the relationship between changes in biomarkers and efficacy, and to evaluate if 
biomarkers, at baseline, identify a subset of patients with more rapid disease progression and/or 
enhanced clinical benefit to MTAU9937A on the basis of the following endpoints:

Relationship between biomarkers in blood and CSF (if available) and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints

Relationship between change from baseline brain volume and cortical thickness as 
measured by magnetic resonance imaging (MRI) and efficacy, safety, PK, immunogenicity, 
or other biomarker endpoints

Relationship between change from baseline intracerebral tau pathology burden as 
measured by [18F]Genentech tau probe 1 (GTP1) PET and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints
Study Design
Description of Study
This Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
will evaluate the clinical efficacy, safety, pharmacokinetics, and pharmacodynamics of 
MTAU9937A in patients with moderate AD. 
The study consists of a screening period, a double-blind treatment period, an optional 
open-label extension (OLE) period, and a safety follow-up period.  An extended baseline visit 
(up to 15 days) is included in the double-blind treatment period, following randomization and 
prior to the initiation of study drug.  Study drug (MTAU9937A or placebo) will be administered 
intravenously in the double-blind treatment period, and MTAU9937A will be administered 
intravenously in the optional OLE period.  Study drug administration will occur every 2 weeks 
(Q2W) for the first three doses of the double-blind treatment period and every 4 weeks (Q4W) 
thereafter during the double-blind treatment period.  Because of anticipated disruptions in study 
drug administration associated with the global COVID-19 pandemic, there may be up to two
study cohorts, as described below:

Cohort 1:  Patients who had completed or discontinued from the double-blind treatment 
period (i.e., completed Week 49 assessments) prior to implementation of Protocol 
Version 3. For Cohort 1, the Week 49 visit represents the end of the double-blind treatment 
period and patients will continue into the OLE or safety follow-up periods per the original 
schedule. In addition, patients in other cohorts who are active in the double-blind treatment 
period and have completed blinded studydrug treatment through Week 45 without any 
missed doses will be eligible to revert to the Cohort 1 Schedule of Activities at the Week 49 
visit and continue on to the OLE after completing the Week 49 visit assessments.
If a Cohort 1 patient misses any blinded study drug infusion, the patient will be moved into 
Cohort 2. 

Cohort 2:  Patients who were active in the double-blind treatment period after 
implementation of Protocol Version 3 were assigned to Cohort 2. In Cohort 2, the double-
blind treatment period is extended to Week 61 unless the criteria above for reverting to the 
Cohort 1 Schedule of Activities are fulfilled.
For patients in Cohort 2, if two or more consecutive study drug infusions are missed during the 
double-blind treatment period, study drug administration will be re-initiated with Q2W dosing for 
the next three doses, followed by Q4W dosing thereafter.
For eligible patients in all cohorts, MTAU9937A will be administered Q4W for 96 weeks during
the OLE period.  Study treatment is defined as study drug plus the [18F]GTP1 radioligand used 
during PET imaging procedures.


MTAU9937A—Genentech, Inc.
16/Protocol GN40040, Version 5
Patients will be randomly assigned to receive MTAU9937A (4500 mg) or placebo administered 
by IV infusion in a 1:1 ratio.  All patients participating in the OLE will receive MTAU9937A 
4500 mg IV infusion.  Because both APOE genotype and baseline cognitive performance may 
be associated with subsequent rates of clinical progression, randomization will be stratified by 
both APOE status (ApoE4+ vs. ApoE4) and screening MMSE scores (1618 vs. 1921).
Patients will be selected on the basis of clinical diagnosis of probable AD dementia.  Clinical 
diagnosis for each patient must be supported by information provided on a Diagnostic 
Verification Form (DVF), which must be reviewed and approved by the Sponsor or Sponsor 
delegate.  
Eligible patients must be 5085 years old at the beginning of screening, meet diagnostic criteria 
for probable AD dementia, and have evidence of cerebral amyloidosis as indicated by CSF 
analysis (i.e., CSF-enrolled patients) or positive amyloid PET scan by qualitative read 
(i.e., PET-enrolled patients).  The choice between CSF versus PET for determination of cerebral 
amyloidosis should be made on the basis of the capability of an individual site and/or the 
preference of an individual patient.  If a patient is amyloid negative based on one of the two 
modalities (CSF assessment or amyloid PET), then the patient may undergo assessment with 
the other modality during screening; amyloid positivity by either modality is sufficient for 
eligibility.
At the time of screening, patients must have a MMSE score between 16 and 21 (inclusive) and 
a Clinical Dementia RatingGlobal Score (CDR-GS) of 1 or 2.  Patients will be eligible for the 
study regardless of whether they are receiving standard-of-care symptomatic medications for 
AD (e.g., cholinesterase inhibitors, memantine, and/or the medical food supplement 
Souvenaid).  These medications must have been stable for 2 months prior to screening, and 
there should be no a priori planned initiation, discontinuation, or dose changes for these 
medications during the study (double-blind treatment and OLE treatment periods). However, 
following the initiation of study drug, standard-of-care symptomatic medications for AD may be 
initiated, dose adjusted, or discontinued as deemed clinically appropriate.
Patients must have baseline and longitudinal tau-related biomarker evaluation via 
[18F]GTP1 PET imaging. For patients undergoing [18F]GTP1 PET imaging, PET scans will be 
performed at the baseline and Week 49 (for Cohort 1) or Week 61 (for Cohort 2) visits during 
the double-blind treatment period.
Patients will also have the option to have CSF collected via lumbar puncture (LP) at the 
screening and/or baseline visits and the last study visit during the double-blind treatment period
(i.e., at Week 49 for Cohort 1 and Week 61 for Cohort 2).  Patients continuing to the optional 
OLE period are encouraged to have an LP performed at Week 97 (Cohort 1 or Week 109 
(Cohort 2) and at the conclusion of the OLE period.
[18F]GTP1 PET and MRI evaluation will use a standard protocol.  Screening amyloid PET scans 
and MRIs will be read by a central reader to determine eligibility.
Number of Patients
This study will include approximately 260 patients and will be conducted at approximately 
50 sites in North America and Europe.    
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form by the patient (co-signed by the patient’s legally authorized
representative, if deemed appropriate by the investigator and/or required by the local 
regulations, guidelines, and Institutional Review Board or Ethics Committee)
Patients should be judged by the investigator to have capacity for informed consent 
when signing the Informed Consent Form.  In judging capacity, the investigator must 
confirm that the patient is able to understand the information relevant to the decision to 
participate in the study, appreciate the situation in terms of the treatment and research 
options and their likely outcomes, and weigh the potential risks and benefits of 
participation to arrive at a decision and communicate that decision.
If the patient does not fulfill the above criteria, their assent must be obtained and full 
informed consent must be obtained from a legally authorized representative.


MTAU9937A—Genentech, Inc.
17/Protocol GN40040, Version 5

Ability to comply with the study protocol, in the investigator's judgment

Age between 50 and 85 years, inclusive, at time of signing Informed Consent Form

National Institute on Aging/Alzheimer’s Association core clinical criteria for probable AD 
dementia 

Evidence of the AD pathological process, by a positive amyloid assessment either on CSF 
A142 as measured on Elecsys β-Amyloid(142) Test System OR amyloid PET scan by 
visual read by the core/central PET vendor as specified in the Imaging Review Charter
If a patient is amyloid negative based on CSF assessment, they may undergo an 
amyloid PET scan during screening to potentially be enrolled.  The patient may 
undergo an LP for CSF assessment or an amyloid PET scan only one time each 
during screening. 
If a patient is amyloid negative based on an amyloid PET scan, they may undergo an 
LP for CSF assessment during screening for potential eligibility.  The patient may 
undergo an LP for CSF assessment or an amyloid PET scan only one time each 
during screening. 
Under certain circumstances, a previously acquired amyloid PET scan may be used for 
study inclusion.  If the previously acquired amyloid PET scan is considered valid and is 
read negative by the core/central PET vendor, the patient may undergo CSF 
assessment for potential eligibility, but the patient may not undergo an additional 
amyloid PET scan for enrollment. 

AD dementia of moderate severity, as defined by a screening MMSE score of 1621 points, 
inclusive, and a CDR-GS of 1 or 2
MMSE obtained during the screening period for Study GN39763 may be used provided 
this is obtained within 8 weeks of the randomization date for Study GN40040 and 
provided the screen failure was not due to evidence of amyloid negativity.

Currently not receiving non-investigational AD medications except for as defined below:
If the patient is receiving non-investigational AD medications, the dosing regimen must 
have been stable for 2 months prior to the start of screening.  There should be no 
a priori intent to initiate, discontinue, or alter the dose of any AD therapy for the 
duration of the study.  However, following the initiation of study drug, standard-of-care 
symptomatic medications for AD may be initiated, dose adjusted, or discontinued as 
deemed clinically appropriate.

Inclusion subject to Sponsor review of clinical criteria at screening (via the DVF)

Availability of a person (referred to as the “caregiver” throughout this protocol) who in the 
investigator's judgment:
Has frequent and sufficient contact with the patient (i.e., 10 hours/week) to be able to 
provide accurate information regarding the patient’s cognitive, behavioral, and 
functional abilities; agrees to provide information at clinic visits (for items which require 
caregiver input for scale completion); signs the necessary consent form; and has 
sufficient cognitive capacity to accurately report upon the patient’s behavior and 
cognitive and functional abilities
Is in sufficiently good general health to have a high likelihood of maintaining the same 
level of interaction with the patient and participation in study procedures throughout the 
study duration
Every effort should be made to have the same caregiver participate throughout the duration 
of the study for completing the designated caregiver clinical outcome assessments (COAs).

Fluency in the language of the tests administered at the study site

Completion of at least 6 years of formal education after the age of 5 years

Willingness and ability to complete all required aspects of the study (including MRI, clinical 
genotyping, and, if applicable, PET imaging)
The patient should be capable of completing study procedures either alone or with the 
help of caregiver(s). 


MTAU9937A—Genentech, Inc.
18/Protocol GN40040, Version 5

Adequate visual and auditory acuity, in the investigator’s judgment, to perform the 
neuropsychological testing (eye glasses and hearing aids are permitted)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain from 
donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate of 
1% per year during the treatment period and for 9 weeks after the final dose of 
study drug or 4 days after the final dose of [18F]GTP1 radioligand or an amyloid 
radioligand, whichever is longer.  Women must refrain from donating eggs during this 
same period. 
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).  The definition of childbearing potential may be 
adapted for alignment with local guidelines or requirements. 
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male partner sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use a 
condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 9 weeks after 
the final dose of study drug or 4 days after the final dose of [18F]GTP1 radioligand or 
an amyloid radioligand, whichever is longer, to avoid exposing the embryo.  Men must 
refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of preventing drug exposure. 
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 
9 weeks after the final dose of study drug or 4 days after the final dose of [18F]GTP1 
radioligand or an amyloid radioligand, whichever is longer
Women of childbearing potential must have a negative serum pregnancy test result 
during screening and a negative urine pregnancy test result each day of dosing or of 
PET imaging prior to administration of study drug or radioligand. 

Inability to tolerate MRI procedures or contraindication to MRI, including, but not limited to, 
presence of pacemakers not compatible with MRI, aneurysm clips, artificial heart valves, 
ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an 
MRI scan; or any other clinical history or examination finding that, in the judgment of the 
investigator, would pose a potential hazard in combination with MRI

Contraindication to PET imaging:  planned, or recent (within 12 months prior to screening) 
exposure to ionizing radiation (including other PET imaging) that in combination with the 
planned administrations of [18F]GTP1 radioligand (if applicable) or an amyloid radioligand (if 
applicable) would result in a cumulative exposure that exceeds recommended local
guidelines


MTAU9937A—Genentech, Inc.
19/Protocol GN40040, Version 5

For patients undergoing LP for confirmation of amyloid positivity: contraindication to 
lumbar dural puncture, including coagulopathy, concomitant anticoagulation (except for a 
platelet inhibitor such as aspirin or clopidogrel), thrombocytopenia (platelet count50,000), 
prior lumbar spinal surgery, significant deformity of the lumbosacral region, or other factor 
that precludes safe LP in the opinion of the investigator

Body mass index 40 

Hospitalization during the 4 weeks prior to screening
In jurisdictions where hospitalization status can be classified as observational or an 
inpatient admission, this exclusion criterion specifically refers to an inpatient admission.

Planned procedure or surgery during the study that in the investigator’s opinion would affect 
cognitive assessments or otherwise interfere with compliance with the protocol

Residence in a skilled nursing facility such as a convalescent home or long-term care 
facility
Residence in an assisted living facility is not exclusionary.
Patients who subsequently require residence in such facilities during the study may 
continue in the study and be followed for efficacy and safety, provided that they have a 
caregiver who meets the minimum requirement.

Blood transfusion within 8 weeks prior to screening or planned transfusion during the study

Poor peripheral venous access

Any serious medical condition or abnormality in clinical laboratory tests that remains 
abnormal on retest and, in the investigator’s judgment, precludes the patient’s safe 
participation in and completion of the study, or bias the assessment of the clinical or mental 
status of the participant to a significant degree.  Including, but not limited to:
Severe chronic kidney disease (Stage 4 or 5, according to National Kidney Foundation 
guidelines) 
Hypertension not stably controlled by current medication (e.g., sustained systolic blood 
pressure > 160 mmHg or diastolic blood pressure > 95 mmHg) 
Diabetes not stably controlled by current medication (e.g., hemoglobin A1c 8%, or any 
history of clinically significant hypoglycemia, hyperosmolar syndrome, ketoacidosis, or 
other significant complication of diabetes within 2 years before screening) 
Heart failure (e.g., New York Heart Association Class II or higher) 
Clinically significant, abnormal ECG at screening (e.g., evidence of significant 
conduction blockade, or evidence of prior myocardial infarction, unless associated with 
a known myocardial infarction more than 2 years before screening) 

History of cancer, except as follows:
If considered to be cured
An appropriately treated carcinoma in situ of the cervix or Stage I uterine cancer
If there has been no significant clinical progression during the past 5 years, with no 
active anti-cancer therapy or radiotherapy and, in the opinion of the investigator, is not 
likely to progress or require treatment in the ensuing 5 years
Prostate cancer or basal cell carcinoma, where there has been no significant 
progression over the previous 2 years

QT interval corrected through use of Fridericia’s formula (QTcF) 470 ms in females 
and > 450 ms in males, demonstrated by at least two ECGs 30 minutes apart


MTAU9937A—Genentech, Inc.
20/Protocol GN40040, Version 5

Abnormal screening thyroid function tests or tests that remain abnormal on retest or require 
a new treatment or an adjustment of current treatment
Abnormal screening thyroid function tests should be defined as a thyroid-stimulating 
hormone level that is outside the normal range AND either a free thyroxine (T4) or a 
total T4 level that is outside the normal range. 
A patient may be rescreened if there is no improvement in cognition in the 
investigator's judgment after 2 months of adequate treatment for thyroid function. 

Screening folic acid or vitamin B12 levels that are sufficiently low or remain low on retest 
such that deficiency requires initiation or alteration of treatment and/or may be contributing 
to cognitive impairment
A patient may be rescreened if there is no improvement in cognition after 2 months of 
adequate treatment for folic acid or vitamin B12 deficiency. 
Cerebrovascular/Neurologic/Psychiatric Exclusion
Patients who meet any of the following cerebrovascular/neurologic/psychiatric criteria will be 
excluded from study entry:

History of seizures, with the exception of childhood febrile seizures or other remote, 
non-recurrent seizure

History of prior traumatic brain injury graded as moderate or severe, defined as a head 
injury resulting in loss of consciousness lasting 30 minutes or longer, an initial Glasgow 
Coma Scale of 12 or worse at presentation, posttraumatic amnesia or confusion lasting 
24 hours or longer, or any associated abnormal brain imaging finding at presentation

Any evidence of a condition other than AD that may affect cognition, including, but not 
limited to, dementia with Lewy bodies, vascular dementia, Parkinson’s disease, corticobasal 
degeneration, Creutzfeldt-Jakob disease, progressive supranuclear palsy, frontotemporal 
degeneration, Huntington disease, normal pressure hydrocephalus, hypoxia, severe sleep 
apnea or other chronic sleep disturbance, or baseline intellectual disability

History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder 
A history of major depression is acceptable if patient has had no episode within the 
past year, is considered in remission, or depression is controlled by treatment. 

At risk of suicide in the opinion of the investigator

Substance abuse, meeting criteria for alcohol, cannabis, phencyclidine, other hallucinogen, 
inhalant, opioid, sedative, hypnotic, anxiolytic, or stimulant use disorder of any severity (per 
the Diagnostic and Statistical Manual of Mental Disorders, Version 5) within the past 
2 years
Investigators may elect to obtain a urine drug screen if clinically indicated. 

History or presence of clinically evident vascular disease potentially affecting the brain 
(e.g., clinically significant carotid, vertebral stenosis, or plaque; aortic aneurysm; intracranial 
aneurysm; cerebral or other intracranial hemorrhage; arteriovenous malformation) that, in 
the opinion of the investigator, has the potential to affect cognitive function

History or presence of any stroke with clinical symptoms within the past 2 years, or 
documented history within the last 6 months of an acute event consistent, in the opinion of 
the investigator, with a transient ischemic attack 

History of cerebral amyloid angiopathy or MRI evidence of > 6 microhemorrhages, any 
macrohemorrhage, or superficial siderosis comprising more than one region or a single 
region > 1 cm

History or presence of intracranial tumor that is clinically relevant (e.g., glioma, cerebral 
metastasis) in the opinion of the investigator

Presence of infections that affect brain function or history of infections that resulted in 
neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, viral or bacterial 
meningitis/encephalitis)


MTAU9937A—Genentech, Inc.
21/Protocol GN40040, Version 5

History or presence of CNS or systemic autoimmune disorders potentially causing 
progressive neurologic disease with associated cognitive deficits (e.g., multiple sclerosis, 
lupus erythematosus, antiphospholipid antibody syndrome, Behçet disease)

MRI evidence of more than two lacunar infarcts, any territorial infarct 1 cm3, or significant 
fluid-attenuated inversion recovery hyperintense lesions in the cerebral deep white matter 
corresponding to a Fazekas deep white matter score of 3 or that otherwise may, in the 
investigator’s opinion, contribute to cognitive dysfunction
Infection and Immune Disorder Exclusion
Patients who meet any of the following infection and immune disorder criteria will be excluded 
from study entry:

Systemically, clinically significantly immunocompromised patients, owing to continuing 
effects of immunosuppressive medication

Positive for hepatitis C virus (HCV) antibody at screening
Patients who have undergone curative treatment for HCV and have serologic evidence 
of sustained undetectable HCV RNA levels may be considered for inclusion after 
discussion with the Medical Monitor.

Positive for hepatitis B surface antigen at screening

Positive for HIV antibody at screening

Serious infection requiring oral or IV antibiotics within 30 days prior to screening

Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins
The following medications are prohibited for a prespecified duration prior to study start, as 
indicated, and during the entire period of study participation (patients who start these 
medications during the study may be withdrawn from study treatment, except under specific 
circumstances as indicated):

Use of any experimental therapy within 90 days or 5 half-lives prior to screening, whichever 
is greater

Use of any passive immunotherapy (immunoglobulin) against tau
An exception will be made for use of MTAU9937A in Genentech Study GN39058, as 
long as the final dose was at least 90 days prior to screening. 

Use of any passive immunotherapy (immunoglobulin) against A, unless the final dose was 
at least 1 year prior to screening

Use of any active immunotherapy (vaccine) that is under evaluation to prevent or postpone 
cognitive decline

Investigational biologic therapy (e.g., therapeutic proteins, monoclonal antibodies, or other 
active or passive immunotherapy) within 1 year of screening, or any expectation to require 
additional investigational biologic therapy for the duration of the trial 

Any previous treatment with medications specifically intended to treat Parkinsonian 
symptoms or any other non-AD neurodegenerative disorder within 1 year of screening 
Certain medications are acceptable if the medicine is for a non-neurodegenerative 
disorder, such as restless leg disorder (e.g., pramipexole). 

Systemic immunosuppressive therapy within 12 months of screening through the entire 
study period
Short courses (2 weeks) of high-dose corticosteroid therapy are permitted.  Chronic 
corticosteroid therapy (>2 weeks) is permitted if the dose is 7.5 mg/day prednisolone 
equivalent and the condition being treated is not expected to deteriorate significantly 
during the study period.

Typical antipsychotic or neuroleptic medication within 6 months of screening, except as 
brief treatment for a non-psychiatric indication (e.g., emesis)


MTAU9937A—Genentech, Inc.
22/Protocol GN40040, Version 5

Daily treatment with any of the following classes of medication, except for intermittent 
short-term use, which is permitted except within 2 days or 5 half-lives (whichever is longer) 
prior to any COA.  The investigator should contact the Medical Monitor if there are 
questions regarding permitted medications.
Opiates or opioids (including long-acting opioid medication) 
Benzodiazepines, barbiturates, or hypnotics
Any medication with clinically significant centrally-acting antihistamine or 
anticholinergic activity (i.e., those medications with significant levels of blood-brain 
barrier penetration that are likely to affect cognition and/or behavior)

Stimulant medications (amphetamine, methylphenidate preparations, or modafinil), unless 
the dose has been stable within the 6 months prior to screening and is expected to be 
stable throughout the study
End of Study
The end of this study is defined as the date when the last patient, last visit occurs or the date at 
which safety follow-up is received from the last patient, whichever occurs later.  The end of the 
study is expected to occur up to 45 months after the last patient is enrolled.
Length of Study
The entire study, from screening of the first patient to the end of the study, is expected to last up 
to 60 months.  
Investigational Medicinal Products
Test Product (Investigational Drug)
MTAU9937A is the investigational medicinal product (IMP) in this study.  Depending on local
classification, the [18F]GTP1 tau PET radioligand and/or the amyloid PET radioligand(s) may be 
considered non-investigational medicinal products or IMPs.
Study drug (MTAU9937A or placebo) will be administered intravenously in the double-blind 
treatment period, and MTAU9937A will be administered intravenously in the optional OLE 
period.  Study drug administration will occur Q2W for the first three doses of the double-blind 
treatment period and Q4W thereafter during the double-blind treatment period.  MTAU9937A 
will be administered Q4W in the OLE period.
Non-Investigational Medicinal Products
Depending on local classification, the [18F]GTP1 tau PET radioligand and/or the amyloid PET 
radioligand(s) may be considered non-investigational medicinal products or IMPs.
Statistical Methods
Primary Analysis
The co-primary efficacy endpoints are change in ADAS-Cog11 and ADCS-ADL scores from 
baseline to the last visit of the double-blind treatment period (Week 49 for Cohort 1 or Week 61 
for Cohort 2).  The difference in mean change from baseline to the last visit of the double-blind 
treatment period between MTAU9937A- and placebo-treated patients will be estimated using an 
analysis of covariance model adjusting for ApoE4 status (ApoE4+ vs. ApoE4), screening 
MMSE (1618 vs. 1921), baseline [18F]GTP1 PET standard uptake value ratio, age, and 
baseline ADAS-Cog11 or ADCS-ADL scores, and if appropriate, the number of missed study 
drug infusions during the double-blind treatment period due to the COVID-19 pandemic.  
Confidence intervals, as well as least squares estimates, will be used to aid in interpretation of 
study results.
Determination of Sample Size
This study will enroll approximately 260 patients randomized to either an IV active dose arm or 
to an IV placebo dose arm in a 1:1 ratio.  This sample size provides approximately 80% power 
to detect a 35% relative reduction in mean ADAS-Cog11 change from baseline when 
MTAU9937A is compared with placebo assuming an average decline of 6 points for 
placebo-treated patients, a standard deviation across patients of 7.5, a 10% dropout rate, and a 
two-sided 0.2 significance level.


MTAU9937A—Genentech, Inc.
23/Protocol GN40040, Version 5
Interim Analyses
Optional Interim Analysis
Given the hypothesis generating nature of this study, the Sponsor may conduct up to two 
interim analyses of efficacy.  The decision to conduct such an interim analysis and its timing will 
be documented in the Sponsor’s study master file prior to the conduct of the interim analysis.  
The Clinical Study Report will also document that such an interim analysis occurred.  The 
interim analysis, should it occur, will be performed and interpreted by members of the Sponsor 
study team and management who would then be unblinded to treatment group (MTAU9937A or 
placebo).


MTAU9937A—Genentech, Inc.
24/Protocol GN40040, Version 5
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
[18F]GTP1
fluorine-18 Genentech tau probe 1
A
-amyloid 
AD
Alzheimer’s disease
ADA
antidrug antibody, also known as anti-therapeutic antibody (ATA)
ADAS-Cog11
Alzheimer’s Disease Assessment ScaleCognitive Subscale, 11-item 
version
ADCS-ADL
Alzheimer’s Disease Cooperative StudyActivities of Daily Living 
Inventory
ADL
activities of daily living
CaGI-Alz
Caregiver Global Impression Scales for Alzheimer’s disease
CDR
Clinical Dementia Rating
CDR-GS
Clinical Dementia RatingGlobal Score
CDR-SB
Clinical Dementia RatingSum of Boxes
Cmax
maximum concentration
COA
clinical outcome assessment
CRO
contract research organization
CSF
cerebrospinal fluid
C-SSRS
Columbia-Suicide Severity Rating Scale
DVF
Diagnostic Verification Form
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
Fc
fragment crystallizable
FcRn
neonatal Fc receptor
FDA
Food and Drug Administration
GLP
Good Laboratory Practice
GTP1
Genentech tau probe 1
HbA1c
hemoglobin A1c
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HV
healthy volunteer
ICH
International Council for Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product


MTAU9937A—Genentech, Inc.
25/Protocol GN40040, Version 5
Abbreviation
Definition
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LP
lumbar puncture
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NIA-AA
National Institute on AgingAlzheimer’s Association
NPI
Neuropsychiatric Inventory
OLE
open-label extension
PD
pharmacodynamic
PET
positron emission tomography
PK
pharmacokinetic
Q2W
every 2 weeks
Q4W
every 4 weeks
QTcF
QT interval corrected through use of Fridericia’s formula
QW
once a week
RBR
Research Biosample Repository
SNP
single nucleotide polymorphism
T4
thyroxine
TK
toxicokinetic
ULN
upper limit of normal
WES
whole exome sequencing
WGS
whole genome sequencing
YTE
combination of M249Y, S251T, and T253E mutations in the heavy chain 
component of an antibody Fc region


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1.
BACKGROUND
1.1
BACKGROUND ON ALZHEIMER’S DISEASE 
Alzheimer’s disease (AD) is the most common cause of dementia, affecting an estimated 
5.7 million individuals in the United States (Alzheimer’s Association 2018).  Worldwide, it 
is estimated that 46.8 million people have AD or other dementias (Prince et al. 2015).  
The disease is characterized pathologically by the accumulation in the brain neocortex of 
extracellular -amyloid (A) peptide-containing plaques and intracellular neurofibrillary 
tangles containing aggregates of the microtubule associated protein tau.  Diagnosis is 
made through the clinical assessment of the neurologic and neuropsychiatric signs and 
symptoms of AD and the exclusion of other causes of cognitive dysfunction.  AD is 
commonly classified into preclinical, prodromal, mild, moderate, and severe stages by 
the presence and severity of clinically relevant functional and/or cognitive decline, and 
categorization is often facilitated by global measures, such as the Clinical Dementia 
Rating (CDR) scale (Morris 1993) or the Mini-Mental State Examination (MMSE; Folstein 
et al. 1975).  Approved medical therapies that inhibit acetylcholinesterase activity or 
antagonize N-methyl-D-aspartate receptors in the brain may temporarily improve the 
symptoms of AD in some patients but do not modify the progression of the disease 
(Cummings 2004).
The deposition of extracellular amyloid plaques and intracellular tau aggregates in the 
brain are the hallmark pathologic findings in AD, first reported by Alois Alzheimer in 
1906.  Intracellular neurofibrillary tangles are composed of aggregated and abnormally 
phosphorylated tau protein.  Tau, encoded by the MAPT gene, is expressed in the 
human brain as six splice isoforms, with lengths of 352441 amino acids.  The six 
isoforms comprise combinations of three variant near-amino-terminal repeat domains 
(0N, 1N, and 2N) and two variant carboxy-terminal repeat domains (3R and 4R) 
(Wang and Mandelkow 2016).  While the intracellular aggregates are found as 
neurofibrillary tangles in the neuronal soma and as neuropil threads in the dendritic 
compartment, it is believed that the spread of tau pathology through the brain is 
mediated by soluble tau in the extracellular brain environment (Braak and Tredici 2015; 
Wang and Mandelkow 2016). 
The spatial distribution of tau pathology in patients with AD correlates with decline in the 
cognitive domains subserved by the affected cortical networks (Ossenkoppele et al. 
2016).  Knockout of the tau gene in an AD transgenic mouse model is protective against 
cognitive deficits (Roberson et al. 2007).  Therapies that reduce the spread of tau in the 
brain may alleviate cognitive dysfunction and block further synaptic loss, axon 
degeneration, and neuronal cell death. 
Targeting the spread of tau in the moderate stages of AD may prove to be more 
efficacious than prior interventions that have targeted Ain this stage of the disease and 
failed to ameliorate further clinical decline (Doody et al. 2013, 2014; Salloway et al. 
2014; Egan et al. 2018).  Whereas most of the accumulation of Aβ pathology may have 


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already occurred by the time patients with AD reach the moderate stages of disease, tau 
pathology appears to continue to increase (Jack et al. 2013).  Studies that examine tau 
indices via neuropathology (Nelson et al. 2012), cerebrospinal fluid (CSF) tau levels 
(Kanai et al. 1998) and tau positron emission tomography (PET) imaging (Ishiki et al. 
2015) have each suggested continued progression of tau pathology in patients with AD 
of at least moderate severity.
1.2
BACKGROUND ON MTAU9937A 
1.2.1
Nonclinical Information
MTAU9937A is a pan-tau IgG4 monoclonal antibody that has potential to treat 
tauopathies (including AD and primary tauopathies).  MTAU9937A is designed to bind 
and intercept all extracellular tau isoforms, in order to stop or slow cell-to-cell spread and 
propagation of tau toxicity and pathology throughout cortical and sub-cortical networks.  
The IgG4 backbone was chosen for MTAU9937A because it has reduced Fcreceptor 
binding affinity compared with the human IgG1 subclass, and thus a reduced immune 
effector response.  MTAU9937A has demonstrated protection of neurons in the 
presence of microglia, in response to exposure to toxic species of tau in cell-based 
experiments (see the MTAU9937A Investigator’s Brochure for details).  MTAU9937A has 
also been engineered to contain three mutations (M249Y, S251T, and T253E [YTE]) in 
the heavy chain component of the fragment crystallizable (Fc) region of the antibody that 
enhance binding to the neonatal Fc receptor (FcRn) and have been shown to slow 
peripheral antibody clearance in humans, potentially augmenting exposure levels 
(Robbie et al. 2013). 
A murine surrogate of MTAU9937A showed dose-dependent reduction in accumulation 
of tau pathology in a transgenic model (hTau P301L.Tg) overexpressing human tau.  
In addition, MTAU9937A prevented toxic tau species from entering cultured neurons and 
protected these neurons from tau-mediated toxicity and death.
There were no MTAU9937A-related adverse findings in the Good Laboratory Practice
(GLP) 5-week, repeat-dose toxicity study in which cynomolgus monkeys were 
administered MTAU9937A at doses up to 300 mg/kg/week IV.  MTAU9937A-related 
clinical pathology findings were limited to increases in neutrophils, fibrinogen, globulin 
(possibly because of the presence of high levels of test article), and/or decreases in 
albumin, suggestive of a mild inflammatory response, as well as mild transient 
decreases in glucose and mild decreases in platelets.  The findings were not considered 
adverse as they were mild, transient, or both, and no anatomic findings explained or 
correlated with the findings.  On the basis of this 5-week toxicity study in monkeys, the 
no-observed-adverse-event level was determined to be the highest dose tested, 
300 mg/kg/week (mean area under the concentrationtime curve from toxicokinetic [TK] 
Day 0 to TK Day 30 of 184,000 g day/mL and a maximum concentration [Cmax;
post-first dose] of 7,280 g/mL).


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In addition, MTAU9937A was also locally well tolerated following single SC injection in 
rabbits.
In support of chronic administration of MTAU9937A in patients, a GLP 26-week, 
repeat-dose, toxicity study has been conducted in cynomolgus monkeys and is currently 
in the reporting phase.  Preliminary in-life data show that MTAU9937A was well tolerated 
by cynomolgus monkeys following 27 weekly, IV doses up to 300 mg/kg with no 
MTAU9937A-related adverse effects noted (refer to the MTAU9937A Investigator’s 
Brochure for additional details regarding results of this study).
Refer to the MTAU9937A Investigator's Brochure for further details regarding the 
nonclinical studies.
1.2.2
Clinical Information
The experience with MTAU9937A in humans consists of data from one completed 
Phase I study (GN39058), one completed Phase II study (GN39763), and this ongoing 
Phase II study (GN40040).
Study GN39058 (clinicaltrials.gov identifier NCT02820896) was a randomized, 
placebo-controlled, double-blind, ongoing Phase I study that assessed the safety, 
tolerability, and pharmacokinetics of IV and SC MTAU9937A in 65 healthy volunteers 
(HVs) and 10 patients with mild to moderate AD.  It consisted of a single-ascending dose 
part (six IV cohorts, with doses from 225 mg to 16,800 mg, and one SC cohort at 
1200 mg) and a multiple-dose part (two IV cohorts each receiving 8400 mg IV once a 
week [QW] 4 weeks).  All single-dose cohorts consisted of only HVs; one multiple-dose 
cohort consisted of HVs and the other multiple-dose cohort consisted of patients with 
AD.  The initial single-dose IV cohort consisted of 3 HVs, randomized to a 2:1 ratio 
(MTAU9937A:placebo).  The remainder of the single-dose IV cohorts consisted of 
8 HVs, randomized to a 6:2 ratio (MTAU9937A:placebo).  The single-dose SC cohort 
consisted of 12 HVs, all treated with MTAU9937A.  Each of the two multiple-dose IV 
cohorts consisted of 10 subjects, randomized to an 8:2 ratio (MTAU9937A:placebo).  A 
total of 44 HVs received single doses of MTAU9937A with a range of 22516,800 mg IV 
or SC (32 HVs received IV doses, 12 HVs received SC doses), and 16 participants 
(8 HVs and 8 patients with mild to moderate AD) each received doses of 8400 mg IV 
QW 4 (except for 1 HV, who was mistakenly administered a first dose of 4200 mg, 
followed by three doses of 8400 mg).
Study GN39763 was a global randomized, double-blind, placebo-controlled, 
parallel-group Phase II study investigating the safety and efficacy of MTAU9937A (at 
doses of 1500 mg, 4500 mg, or 8100 mg) in patients with prodromal to mild AD. Of the 
457 patients who were randomized into treatment arms, 441 received at least one dose 
of MTAU9937A or placebo in the blinded portion of the study, 369 completed the 
blinded portion of the study, and 360 received at least one dose of MTAU9937A in the 
OLE portion of the study.  The study was discontinued on 23 September 2020, after 


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top-line analyses of data from the 73-week double-blind, placebo-controlled portion of 
the study indicated similar rates of progression on the primary efficacy endpoint 
(Clinical Dementia Rating Sum of Boxes) in the placebo arm and all three 
MTAU9937A arms.  Similar rates of progression on the secondary efficacy cognitive 
endpoints (Repeatable Battery for the Assessment of Neuropsychological Status Total 
Index and the 13-item version of the Alzheimer's Disease Assessment Scale–Cognitive 
Subscale) and secondary efficacy functional endpoints (Alzheimer's Disease 
Cooperative StudyActivities of Daily Living and Amsterdam Instrumental Activities 
of Daily Living Questionnaire) were seen in the placebo arm and all three 
MTAU9937A arms over the 73-week treatment period.  Furthermore, on the 
exploratory endpoint of brain tau burden as measured by fluorine-18 Genentech tau 
probe 1 ([18F]GTP1) tau PET imaging, similar rates of overall cortical tau 
accumulation were seen in the placebo arm and all three MTAU9937A arms over the 
73-week treatment period.  
MTAU9937A has been generally well tolerated in HVs and patients with AD (please refer 
to the MTAU9937A Investigator's Brochure for further details).  No adverse drug 
reactions have been identified with MTAU9937A.  Potential risks associated with 
MTAU9937A are discussed in Section 5.1.1.
The pharmacokinetics of MTAU9937A were evaluated in Study GN39058 following 
single (22516,800 mg), weekly (8400 mg 4 doses) IV, or single (1200 mg) SC 
administration to HVs and to patients with mild to moderate AD.  Upon IV administration, 
MTAU9937A exhibited biphasic disposition, and the plasma half-life had a range of 
22.845.7 days.  The mean SC bioavailability estimated from the SC cohort (1200 mg) 
was approximately 69%.  Upon weekly IV administration, the pharmacokinetics of 
MTAU9937A were comparable between HVs and patients with AD.  Dose proportionality 
assessment demonstrated that serum pharmacokinetics increased proportionally with 
dose following single-dose IV administration.  MTAU9937A was detected in the CSF, 
suggesting penetration into the CNS.  Pharmacokinetic results from the Phase II study 
(GN39763) in patients with prodromal to mild AD are consistent with PK data from 
HVs and patients with AD in the Phase I study (GN39058).
Refer to the MTAU9937A Investigator's Brochure for further details on clinical studies.
1.3
BACKGROUND ON [18F]GTP1
Tau protein has been identified as one of the key pathological features of AD 
(Grundke-Igbal et al. 1986; Kosik et al. 1986; Wood et al. 1986).  Tau is the primary 
protein composing neurofibrillary tangles, and postmortem studies have shown that 
neurofibrillary tangle density correlates with neurodegeneration and cognitive impairment 
(Duyckaerts et al. 1987; Delaére et al. 1989; Duyckaerts et al. 1990; Arriagada et al. 
1992; McLean et al. 1999).  Thus, a PET imaging agent that binds to aggregated tau has 
the potential to serve as a biomarker for disease severity or neurodegeneration and may 
be useful for monitoring disease progression in therapeutic trials. 


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[18F]GTP1 has been developed as a positron emitting radioligand for in vivo imaging of 
tau protein aggregates.  [18F]GTP1 has been previously evaluated in a first-in-human 
study (e0040) involving 3 patients with AD, 3 patients with progressive supranuclear 
palsy, and 2 HVs.  The study demonstrated substantial retention of the radioligand in 
brain regions expected to contain tau pathology in patients with AD.  
[18F]GTP1 has also been studied in three additional Phase I studies:  a test re-test study 
(e0048) with 5 patients with AD and 5 elderly HVs, a radiation dosimetry study (e0049) 
with 6 HVs, and a radiation dosimetry study (GN42043) with 6 Japanese HVs.  
In addition, [18F]GTP1 was evaluated in an open-label, longitudinal, natural history study 
(GN30009; clinicaltrials.gov identifier NCT02640092).  Enrollment for Study GN30009 is 
closed; a total of 10 HVs and 62 patients with AD (27 prodromal AD; 19 mild AD; 
16 moderate AD) were enrolled and were administered at least one dose of [18F]GTP1.  
Two of the patients with AD in Study GN30009 also participated in Study e0048.
An open-label study comparing brain imaging with two tau PET radioligands, 
[18F]GTP1 and [18F]PI-2620, in patients with prodromal to mild AD (GN42801) is 
ongoing. Each patient is scanned once with each radioligand.  As of 01 February 2021, 
9 patients had [18F]GTP1 PET scans.
In Study GN39763, which investigated the safety and efficacy of MTAU9937A in 
patients with prodromal to mild AD, 399 patients had at least one [18F]GTP1 baseline 
scan.  As described in Section 1.2.2, the study was terminated due to lack of clinical 
efficacy.
Substudy BN29552/BN29553 (Tau PET Longitudinal Substudy) was a substudy of the 
Phase III Studies BN29552 and BN29553 that intended to evaluate the changes in tau 
burden over time using [18F]GTP1 in patients enrolled in Study BN29552 or BN29553 
with prodromal to mild AD who were treated with crenezumab, an anti-Aantibody, or 
placebo.  The Sponsor terminated the development of crenezumab for the treatment of 
prodromal to mild AD.  At the time of termination of the parent studies, 58 patients (5 
patients from Study BN29552 and 53 patients from Study BN29553) had had at least 
one [18F]GTP1 PET scan.
Substudy WN29922/WN39658 (exploratory tau PET imaging substudy) is a substudy 
of the Phase III Studies WN29922 and WN39658 that intends to assess longitudinal 
changes in tau pathology using [18F]GTP1 in patients with prodromal to mild AD 
receiving gantenerumab or placebo treatment.  As of 21 January 2021, 210 patients 
(119 patients from Study WN29922 and 91 from Study WN39658) have had at least 
one [18F]GTP1 PET scan.
Substudy BN40199 is an optional substudy of the Phase II Study GN28352 intended to 
evaluate the impact of treatment on brain tau load over time using [18F]GTP1 in 


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individuals who carry the PSEN1 E280A autosomaldominant, mutation-causing 
early-onset AD and do not meet criteria for mild cognitive impairment due to AD or 
dementia due to AD and who are treated with crenezumab or placebo; and individuals 
who are not PSEN1 E280A autosomaldominant mutation carriers receiving placebo.  
As of 27 January 2021, 115 patients have had at least one [18F]GTP1 PET scan.
Refer to the [18F]GTP1 Investigator's Brochure for further details on clinical studies.
1.3.1
Clinical Safety and Tolerability
Available safety data from the completed and ongoing clinical studies with [18F]GTP1 
show that exposure to [18F]GTP1 and imaging procedures is generally well tolerated.  
There have been no reported deaths, no adverse events of special interest, and no 
hypersensitivity reactions associated with [18F]GTP1 PET imaging.  Local 
infusion-related reactions, including hematoma, ecchymosis, and injection-site pain, 
were reported; all were non-serious and mild in severity.  Refer to the [18F]GTP1 
Investigator’s Brochure for details on these studies and full nonclinical evaluation of the 
tracer.
1.4
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
MTAU9937A represents a novel potential therapeutic for the treatment of AD.  
As described in Section 1.1, existing therapies for AD provide only modest symptomatic 
benefit and fail to slow progression of the underlying neurodegenerative process.  
Therefore, there is significant unmet medical need, particularly among patients with 
moderate AD, and MTAU9937A may fill that gap by targeting a key pathological protein 
believed to continue to underlie neurodegeneration at the moderate dementia stage of 
this disease.  Study GN40040 is a proof-of-concept study using clinical outcome 
assessments (COAs), a novel tau PET imaging technology, and other biomarkers to test 
the hypothesis that MTAU9937A administration to patients with moderate AD stops or 
slows cell-to-cell spread and propagation of tau pathology in the brain and improves 
clinical outcomes.
There has been no evidence of safety concerns associated with MTAU9937A or its 
murine surrogate in nonclinical models to date, and there has been no obvious 
phenotype reported in tau knockout mice (Harada et al. 1994).  The completed 
toxicology program for MTAU9937A was designed to support IV and SC dosing in 
clinical studies.  In a GLP, 5-week, repeat-dose, toxicity study in cynomolgus monkeys, 
there were no MTAU9937A-related adverse effects following IV doses of up to 
300 mg/kg QW.  In support of chronic administration of MTAU9937A in patients, a GLP, 
26-week, repeat-dose, toxicity study has been conducted in cynomolgus monkeys and is 
currently in the reporting phase.  Preliminary data show that MTAU9937A was well 
tolerated by cynomolgus monkeys following up to 27 IV doses of up to 300 mg/kg QW 
with no MTAU9937A-related adverse effects noted (refer to the MTAU9937A 
Investigator’s Brochure for additional details regarding results of this study).


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On the basis of results from nonclinical studies and the Phase I study in humans 
(GN39058), MTAU9937A is expected to be well tolerated by patients with AD in this 
study (GN40040).  There are no known risks to MTAU9937A.  Potential risks of 
MTAU9937A are described in Section 5.1.1.  Several measures are being taken in this 
study to mitigate possible safety concerns, including strict inclusion and exclusion criteria 
(see Section 4.1), periodic neurologic examinations (Section 4.5.4), magnetic resonance 
imaging (MRI), suicidality monitoring (see Section 4.5.7), and regular safety review by an 
unblinded, Internal Monitoring Committee (IMC; Section 3.1.2).
Because of high unmet need for disease-modifying treatments for moderate AD and the 
benign safety profile of MTAU9937A observed in both nonclinical and clinical studies to 
date, the benefitrisk of MTAU9937A is favorable and supportive of its use in this clinical 
study.
Refer to the MTAU9937A Investigator’s Brochure for additional details regarding 
nonclinical pharmacology, pharmacokinetic (PK), and toxicology data, as well as human 
pharmacology, PK, and safety data.
[18F]GTP1 radioligand will be used in this study to evaluate the baseline tau pathology 
burden and the effect of MTAU9937A on tau pathology progression as measured by tau 
PET in patients with moderate AD.  Measures based on PET imaging with [18F]GTP1 
radioligand are expected to help in understanding the pharmacodynamic (PD) effects of 
MTAU9937A on tau pathology (spread of tau protein aggregates) as well as the 
relationship between change in tau PET and change in other endpoints in this study.  
On the basis of results from nonclinical studies and completed and ongoing studies in 
humans, [18F]GTP1 radioligand is expected to be well tolerated by patients with AD in 
this study.  There are no known risks to [18F]GTP1 radioligand; potential risks of 
[18F]GTP1 radioligand are described in Section 5.1.2.
The benefitrisk of [18F]GTP1 radioligand is favorable and supportive of its use in this 
clinical study.
Refer to the [18F]GTP1 Investigator’s Brochure for additional details.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the clinical efficacy, safety, pharmacokinetics, and 
pharmacodynamics of MTAU9937A in patients with moderate AD, ages 5085, who are 
amyloid positive by CSF or amyloid PET. Specific objectives and corresponding 
endpoints for the study are outlined below.


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2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the effects of MTAU9937A 
compared with placebo on cognition and function on the basis of the following endpoints:

Change from baseline to the last visit of the double-blind treatment period (Week 49
for Cohort 1 and Week 61 for Cohort 2) in cognitive function as measured by the 
Alzheimer’s Disease Assessment Scale, Cognitive Subscale, 11-item version 
(ADAS-Cog11)

Change from baseline to the last visit of the double-blind treatment period (Week 49
for Cohort 1 and Week 61 for Cohort 2) in functional capacities as measured by the 
Alzheimer's Disease Cooperative StudyActivities of Daily Living Inventory 
(ADCS-ADL)
2.1.2
Secondary Efficacy Objectives
The secondary efficacy objectives for this study along with the corresponding endpoints 
are as follows:

To evaluate the effect of MTAU9937A on global cognition and function compared 
with placebo on the basis of the following endpoint:
–
Change from baseline to the last visit of the double-blind treatment period 
(Week 49 for Cohort 1 and Week 61 for Cohort 2) on the Clinical Dementia 
RatingSum of Boxes (CDR-SB)

To evaluate the effect of MTAU9937A on cognition compared with placebo on the 
basis of the following endpoint:
–
Change from baseline to the last visit of the double-blind treatment period 
(Week 49 for Cohort 1 and Week 61 for Cohort 2) on the MMSE
2.1.3
Exploratory Efficacy Objectives
The exploratory efficacy objectives for this study are as follows:

To evaluate the effect of MTAU9937A on behavioral symptoms compared with 
placebo on the basis of the following endpoint:
–
Change from baseline to the last visit of the double-blind treatment period 
(Week 49 for Cohort 1 and Week 61 for Cohort 2) on the Neuropsychiatric 
Inventory (NPI)

To evaluate the effect of MTAU9937A on caregiver impression of changes in patient 
cognition and functional abilities compared with placebo on the basis of the following 
endpoint:
–
Ratings on the Caregiver Global Impression Scales for Alzheimer’s disease 
(CaGI-Alz) at the last visit of the double-blind treatment period (Week 49 for 
Cohort 1 and Week 61 for Cohort 2)


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2.2
SAFETY OBJECTIVES
The safety objectives for this study are to evaluate the safety and tolerability of 
MTAU9937A compared with placebo on the basis of the following endpoints:

Nature, frequency, severity, and timing of adverse events and serious adverse 
events, with severity determined according to WHO toxicity grading scale

Changes from baseline in vital signs, physical findings, neurologic findings, ECG, 
and clinical laboratory results during and following MTAU9937A administration

Changes from baseline in suicidal ideation and behavior during and following 
MTAU9937A administration as assessed by the Columbia-Suicide Severity Rating 
Scale (C-SSRS)

Nature, frequency, severity, and timing of neuroimaging abnormalities that could 
represent cerebral vasogenic edema and/or microhemorrhage, during MTAU9937A 
administration
2.3
PHARMACOKINETIC OBJECTIVES
The PK objective for this study is to characterize the MTAU9937A PK profile on the 
basis of the following endpoint:

Serum concentration of MTAU9937A at specified timepoints
The exploratory PK objectives for this study are as follows:

To characterize the MTAU9937A PK profile in CSF on the basis of the following 
endpoint:
–
CSF concentration of MTAU9937A at specified timepoints

To evaluate potential relationships between drug exposure and the efficacy and 
safety of MTAU9937A on the basis of the following endpoints:
–
Relationship between serum (and CSF if available) concentration or PK 
parameters for MTAU9937A and safety endpoints
–
Relationship between serum (and CSF if available) concentration or PK 
parameters for MTAU9937A and efficacy endpoints

To evaluate potential relationships between selected covariates and exposure to 
MTAU9937A on the basis of the following endpoint:
–
Relationship between selected covariates (including but not limited to age and 
sex) and serum concentration or PK parameters for MTAU9937A
2.4
IMMUNOGENICITY OBJECTIVES
The immunogenicity objectives for this study are as follows:

To evaluate the immune response to MTAU9937A on the basis of the following 
endpoint:
–
Incidence of anti-drug antibodies (ADAs) during the study relative to the 
prevalence of ADAs at baseline


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
To evaluate the potential effects of ADAs on the basis of the following endpoint:
–
Relationship between ADA status and efficacy, safety, or PK endpoints
2.5
BIOMARKER OBJECTIVE
The exploratory biomarker objective for this study is to evaluate the effect of 
MTAU9937A on biomarkers to provide evidence of proof of activity, to aid in defining 
mechanism of action, to evaluate the relationship between changes in biomarkers and 
efficacy, and to evaluate if biomarkers, at baseline, identify a subset of patients with 
more rapid disease progression and/or enhanced clinical benefit to MTAU9937A on the 
basis of the following endpoints:

Relationship between biomarkers in blood and CSF (if available) (listed in 
Section 4.5.9) and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints

Relationship between change from baseline brain volume and cortical thickness as 
measured by MRI and efficacy, safety, PK, immunogenicity, or other biomarker 
endpoints

Relationship between change from baseline intracerebral tau pathology burden as 
measured by [18F]GTP1 PET and efficacy, safety, PK, immunogenicity, or other 
biomarker endpoints
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
3.1.1
Overview of Study Design and Study Treatment
This Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study will evaluate the clinical efficacy, safety, pharmacokinetics, and 
pharmacodynamics of MTAU9937A in patients with moderate AD. 
The study consists of a screening period, a double-blind treatment period, an optional 
open-label extension (OLE) period, and a safety follow-up period (see Figure 1 for the 
study schema and Appendix 1Appendix 4 for the schedules of activities).  An extended 
baseline visit (up to 15 days) is included in the double-blind treatment period, following 
randomization and prior to the initiation of study drug.  Study drug (MTAU9937A or 
placebo) will be administered intravenously in the double-blind treatment period, and 
MTAU9937A will be administered intravenously in the optional OLE period.  Study drug 
administration will occur every 2 weeks (Q2W) for the first three doses of the 
double-blind treatment period and every 4 weeks (Q4W) thereafter during the 
double-blind treatment period.  Because of anticipated disruptions in study drug 
administration associated with the global COVID-19 pandemic, there may be up to two
study cohorts, as described below:


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
Cohort 1:  Patients who had completed or discontinued from the double-blind 
treatment period (i.e., completed Week 49 assessments) prior to implementation of 
Protocol Version 3. For Cohort 1, the Week 49 visit represents the end of the 
double-blind treatment period and patients will continue into the OLE or safety 
follow-up periods per the original schedule (see Appendix 2). In addition, patients in 
other cohorts who are active in the double-blind treatment period and have 
completed blinded study drug treatment through Week 45 without any missed doses 
will be eligible to revert to the Cohort 1 Schedule of Activities (see Appendix 1) at 
the Week 49 visit and continue to the OLE (see Appendix 2) after completing the 
Week 49 visit assessments.
If a Cohort 1 patient misses any blinded study drug infusion, the patient will be
moved into Cohort 2.

Cohort 2:  Patients who were active in the double-blind treatment period after 
implementation of Protocol Version 3 were assigned to Cohort 2. In Cohort 2, the 
double-blind treatment period is extended to Week 61, unless the criteria above for 
reverting to the Cohort 1 Schedule of Activities are fulfilled.
For patients in Cohort 2, if two or more consecutive study drug infusions are missed 
during the double-blind treatment period, study drug administration will be re-initiated 
with Q2W dosing for the next three doses, followed by Q4W dosing thereafter.
For eligible patients in all cohorts, MTAU9937A will be administered Q4W for 96 weeks
during the OLE period.
Study treatment is defined as study drug plus the [18F]GTP1 radioligand used during 
PET imaging procedures.  See Section 4.3 for a description of the study treatments used 
in this study. 
This study will include approximately 260 patients and will be conducted at 
approximately 50 sites in North America and Europe. Patients will be randomly 
assigned to receive MTAU9937A (4500 mg) or placebo administered by IV infusion in a 
1:1 ratio.  All patients participating in the OLE will receive MTAU9937A 4500 mg IV 
infusion.  Because both APOE genotype (de Oliviera et al. 2015) and baseline cognitive 
performance (Kennedy et al. 2015) may be associated with subsequent rates of clinical 
progression, randomization will be stratified by both APOE status (ApoE4+ vs. ApoE4) 
and screening MMSE scores (1618 vs. 1921).
Patients will be selected on the basis of clinical diagnosis of probable AD dementia 
(according to the National Institute on AgingAlzheimer’s Association [NIA-AA] 
Diagnostic Criteria and Guidelines for AD; see Appendix 5; McKhann et al. 2011).  
Clinical diagnosis for each patient must be supported by information provided on a 
Diagnostic Verification Form (DVF), which must be reviewed and approved by the 
Sponsor or Sponsor delegate.  For more details on the DVF approval process, see the 
description of the screening period in Section 3.1.1.1.


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Eligible patients must be 5085 years old at the beginning of screening, meet diagnostic 
criteria for probable AD dementia (McKhann et al. 2011), and have evidence of cerebral 
amyloidosis as indicated by CSF analysis (i.e., CSF-enrolled patients) or positive 
amyloid PET scan by qualitative read (i.e., PET-enrolled patients).  The choice between 
CSF versus PET for determination of cerebral amyloidosis should be made on the basis 
of the capability of an individual site and/or the preference of an individual patient.  If a 
patient is amyloid negative based on one of the two modalities (CSF assessment or 
amyloid PET), then the patient may undergo assessment with the other modality during 
screening; amyloid positivity by either modality is sufficient for eligibility.  Under certain 
circumstances, a previously acquired amyloid PET scan may be used for study inclusion 
(see Section 4.5.8).  If the previously acquired amyloid PET scan is read as amyloid 
negative by the core/central PET vendor, the patient may undergo CSF assessment to 
determine eligibility, but the patient may not undergo an additional amyloid PET scan for 
enrollment.
At the time of screening, patients must have a MMSE score between 16 and 21
(inclusive) and a Clinical Dementia RatingGlobal Score (CDR-GS) of 1 or 2.  Patients 
will be eligible for the study regardless of whether they are receiving standard-of-care 
symptomatic medications for AD (e.g., cholinesterase inhibitors, memantine, and/or the 
medical food supplement Souvenaid).  These medications must have been stable for 
2 months prior to screening, and there should be no a priori planned initiation, 
discontinuation, or dose changes for these medications during the study (double-blind 
treatment and OLE treatment periods). However, following the initiation of study drug, 
standard-of-care symptomatic medications for AD may be initiated, dose adjusted, or 
discontinued as deemed clinically appropriate.
Patients must have baseline and longitudinal tau-related biomarker evaluation via 
[18F]GTP1 PET imaging.  For patients undergoing [18F]GTP1 PET imaging, PET scans 
will be performed at the baseline and Week 49 (for Cohort 1) or Week 61 (for Cohort 2)
visits during the double-blind treatment period.
Patients will also have the option to have CSF collected via lumbar puncture (LP) at the 
screening and/or baseline visits and the last study visit during the double-blind treatment 
period (i.e., at Week 49 for Cohort 1 and Week 61 for Cohort 2).  Patients continuing to 
the optional OLE period are encouraged to have an LP performed at Week 97 (Cohort 1)
or Week 109 (Cohort 2) and at the conclusion of the OLE period.
See Section 4.1 for further details of the inclusion and exclusion criteria.
[18F]GTP1 PET and MRI evaluation will use a standard protocol, provided in the imaging 
technical operations manuals.  Screening amyloid PET scans and MRIs will be read by a 
central reader to determine eligibility (see Section 4.1.2).


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3.1.1.1
Study Periods
The schedules of activities provided in Appendix 1Appendix 4 describe in detail the 
procedures and assessments of the various study periods and cohorts.
Screening
After signing the Informed Consent Form, patients enter a screening period of up to 
8 weeks to determine eligibility.  Extensions to this 8-week period (e.g., to complete an 
assessment of cerebral amyloidosis) may be granted on a case-by-case basis by the 
Medical Monitor.  Initial screening procedures may be staged; for instance, in 
accordance to site and/or patient preference, an initial Early Screening Informed 
Consent Form may be signed that permits MMSE assessment and collection of medical 
history, AD history, personal status, and demographics.  If a patient remains potentially 
eligible for the study on the basis of these results, then the full, main Informed Consent 
Form may be signed to cover the remainder of the screening and study procedures.  
Staging of consent and screening in this manner is not required, and patients may sign 
the full, main Informed Consent Form at the beginning of screening.  The initial signing 
of an Informed Consent Form, regardless if it is the Early Screening or main Informed 
Consent Form, represents the beginning of the screening period.
On the basis of any initial screening procedures, provided that the patient remains 
eligible, a DVF must be completed by the investigator and submitted to the Sponsor or 
Sponsor delegate.  The DVF must contain results from the MMSE and CDR, along with 
information supportive of an AD diagnosis.  The DVF must be reviewed and approved by 
the Sponsor or Sponsor delegate prior to performing MRI, [18F]GTP1 or amyloid PET 
scans, or LP.  If the DVF is not approved by the Sponsor or Sponsor delegate, the 
patient is not eligible for the study.  Patients who are determined to be not eligible for the 
study may be rescreened at a later date, at the discretion of the Sponsor, if changes 
occur to the patient’s condition or situation that might render the patient eligible to 
participate.  On a case-by-case basis, the Medical Monitor may advise on whether any 
specific screening procedures may not have to be repeated during rescreening.
During the COVID-19 pandemic, extensions to the screening period may be granted on 
a case-by-case basis by the Medical Monitor for patients and clinical sites impacted by 
COVID-19 and/or any associated restrictions.  If screening activities are interrupted and 
later resumed, the Medical Monitor will advise, on a case-by-case basis, whether 
specific screening procedures need to be repeated.  
Double-Blind Treatment
The double-blind treatment period of the study includes a baseline period and a 
double-blind treatment period.  The baseline period lasts up to 15 days; however, 
extensions to the 15-day baseline period, for instance, to complete [18F]GTP1 PET 
imaging, may be granted on a case-by-case basis by the Medical Monitor.  


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If the baseline period is extended to 2 months or longer because of the COVID-19 
pandemic and baseline activities are interrupted and later resumed, the Medical Monitor 
will advise, on a case-by-case basis, whether specific baseline procedures need to be 
repeated prior to Week 1.
The double-blind treatment period consists of Weeks 149 for Cohort 1 and Weeks 161 
for Cohort 2.  Treatment with study drug will be Q2W for the first three doses (i.e., doses 
at Weeks 1, 3, and 5) and Q4W thereafter, up to and including the last double-blind dose 
(up to a total of 13 doses for Cohort 1 and 16 doses for Cohort 2).  There will be no 
administration of study drug at the last visit of the double-blind treatment period.  For 
Cohort 2, if two or more consecutive study drug infusions are missed during the 
double-blind treatment period, study drug administration will be re-initiated with Q2W 
dosing for the next three doses, followed by Q4W dosing thereafter.  Safety, efficacy, 
PK, and biomarker assessments will be performed prior to the first administration of 
study drug and at several postbaseline visits, including the last visit of the double-blind 
treatment period.  See Appendix 1 (Cohort 1) and Appendix 3 (Cohort 2) for details 
regarding study activities during the double-blind treatment period.  Patients who miss
study drug infusions during the double-blind treatment period for reasons related to the 
COVID-19 pandemic may have additional COAs (see Section 4.5.7 ) administered 
remotely (by telephone or video call) at the time of the first missed infusion and at the 
time when in-clinic infusions resume.  Refer to the Study GN40040 remote COA
administration guidance for further details.
Open-Label Extension Period 
An optional 96-week OLE period is available to patients who complete the double-blind 
treatment period and who, in the judgment of the investigator, would potentially benefit 
from open-label MTAU9937A treatment.  For the OLE period, all patients will receive 
MTAU9937A 4500 mg IV beginning at Week 53 (Cohort 1) or Week 65 (Cohort 2).  
See Appendix 2 (Cohort 1) and Appendix 4 (Cohort 2) for details regarding study 
activities during the OLE period.
Safety Follow-Up Period 
All patients must be followed for safety after their final dose of study drug.  Patients not 
entering the OLE period will have a safety follow-up visit 12 weeks after the final dose of 
study drug (i.e., at Week 57 for Cohort 1 or Week 69 for Cohort 2).  Patients entering the 
OLE period will have a safety follow-up visit 12 weeks after the final dose of open-label 
treatment (i.e., at Week 157 for Cohort 1 or Week 169 for Cohort 2).  Patients who 
discontinue from treatment early, in either the double-blind treatment period or in the 
OLE period, will have a treatment discontinuation visit 12 weeks following their final 
treatment dose.  See Appendix 1Appendix 4 for details regarding study activities during 
the safety follow-up period.




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At the time of each review, the IMC will make one of the following recommendations:  
the study continues as planned, treatment is suspended or discontinued for safety 
reasons, the study is stopped for safety reasons, the protocol is to be amended, or 
additional analyses need to be performed.  Recommendations will be made in 
consideration of the totality of the available data.  There are currently no planned interim 
analyses to stop the trial early for either futility or clear signs of efficacy.  Final decisions 
will rest with the Sponsor's study team.
Any outcomes of these reviews that affect study conduct will be communicated in a 
timely manner to the investigators for notification of their respective Institutional Review 
Boards (IRBs) or Ethics Committees (ECs) and health authorities.
Refer to the IMC Charter for additional details.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs or the 
date at which safety follow-up is received from the last patient, whichever occurs later.  
The end of the study is expected to occur up to 45 months after the last patient is 
enrolled.
The entire study, from screening of the first patient to the end of the study, is expected to 
last up to 60 months.  
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for MTAU9937A Dose and Schedule
The potentially efficacious dose of MTAU9937A is not known.  Due to the lack of a fully 
translatable animal model of AD, preclinical experiments do not provide guidance for 
human efficacious dose selection.  In addition, the exploratory PD and efficacy data 
collected in the Phase I study (GN39058) were not intended to guide dose selection. 
The rationale for the 4500 mg Q4W dosing regimen in this study takes into consideration 
the safety profiles from the nonclinical toxicology studies, safety and PK profiles from the 
Phase I study (GN39058), and results from the target engagement modeling exercise.
In the target engagement modeling analysis, simulations were conducted to predict 
percent target (i.e., tau) engagement by MTAU9937A in the interstitial fluid of the brain.  
Results demonstrated that high-target engagement (i.e., > 80%) is predicted for the 
4500 mg dose under various scenarios (e.g., several plasma:brain partitioning ratios and 
MTAU9937A binding affinities).  It should be noted that the extent of target engagement 
required for clinical efficacy is unknown.
The dosing frequency will be Q4W, except during the first month, when a dose of 
MTAU9937A will also be administered to patients on Week 3 to rapidly increase the 
serum concentrations to those achieved at steady state.  For Cohort 2, if two or more 
consecutive study drug infusions are missed during the double-blind treatment period, 
study drug administration will be re-initiated with Q2W dosing for the next three doses, 


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followed by Q4W dosing thereafter.  This brief course of higher frequency dosing, which 
is identical to dosing at the start of the double-blind treatment period, is expected to 
rapidly restore study drug exposure to prior steady-state levels.
3.3.2
Rationale for Patient Population
The patient selection approach is consistent with the NIA-AA Diagnostic Criteria and 
Guidelines for AD as well as with the Qualification Opinion from the European Medicines 
Agency’s Committee for Medicinal Products for Human Use on the use of CSF 
biomarkers and/or PET-amyloid imaging for enrichment of trials in mild to moderate AD 
dementia (2012), and U.S. Food and Drug Administration (FDA) draft guidance for early 
AD (2018).  Although the FDA guidance refers to the early stage of AD in which 
individuals present with mild cognitive impairment, biomarkers of amyloid pathology are 
also expected to add value to patient selection in moderate AD (see Section 3.3.3).
Patients in this study are required to meet standard research criteria for AD (according to 
the NIA-AA Diagnostic Criteria and Guidelines for AD; Appendix 5).  Overall, the 
population will have an MMSE of 1621 points, inclusive, and a CDR-GS of 1 or 2.  
Together, these scores will provide evidence of moderate disease severity.
The rationale for targeting the spread of tau in patients with moderate AD using 
MTAU9937A emerges from the hypothesis that tau pathology appears to continue to 
increase at this stage of the disease (Jack et al. 2013).  Studies that have examined tau 
indices via neuropathology (Nelson et al. 2012), CSF tau levels (Kanai et al. 1998) and 
PET imaging (Ishiki et al. 2015) suggest continued progression of tau pathology in 
patients with AD of at least moderate severity.
To ensure that the patients selected are likely to fulfill the clinical diagnostic criteria for 
moderate AD dementia, evidence of prior decline consistent with AD will be verified 
through observations made by clinician or caregiver and recorded on the DVF.  
Enrollment in this study is subject to adjudication of diagnosis by the Sponsor or 
Sponsor delegates.  The objective of the adjudication process is to ensure that patients 
are enrolled on the basis of objectively ascertained and well-documented diagnosis of 
AD (McKhann et al. 2011).  The Medical Monitor may review anonymized source 
documents and may solicit advice from other qualified Sponsor staff or external, 
independent experts to support and verify a diagnosis of moderate AD.  The scope and 
detailed procedures for the diagnostic verification process will be described in the study 
documents and documented for review on the DVF.
3.3.3
Rationale for Amyloid Enrichment
The rationale for selecting amyloid-positive patients in this study is consistent with 
recently proposed revised diagnostic criteria for AD (McKhann et al. 2011; 
Dubois et al. 2014).  Such biomarker enrichment is important for clinical trials in patients 
with AD because recent results have demonstrated that approximately 20% of patients 
enrolled in trials on the basis of a clinical diagnosis of AD may not have underlying 


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amyloid pathology as assessed by amyloid PET (Doody et al. 2014), including 
approximately 15% of moderate AD patients (Degenhardt et al. 2016).  Cerebral amyloid 
pathology is a required component of AD pathology, and biomarker evidence against 
such pathology makes an underlying neuropathological diagnosis of AD highly unlikely 
(Clark et al. 2012).
For enrollment, biomarker evidence of Adeposition will be assessed either by 
decreased CSF A142 levels (using a pre-specified cutoff point and the Roche 
Diagnostics Elecsys-Amyloid [142] immunoassay) or a centralized visual 
assessment of the brain by amyloid PET imaging.  The Sponsor is proposing to enroll 
patients on the basis of a positive CSF test or PET scan, because both approaches have 
been shown to correlate with the “gold standard” of Apathology at autopsy (Shaw et al. 
2009; Clark et al. 2011; Le Bastard et al. 2013).  Both methods have been widely used in 
the research community, and patients or physicians in the study and in clinical practice 
generally may not have access to both methods.
This approach is in line with emerging evidence that indicates consistency between 
amyloid PET imaging and CSF biomarkers.  Low CSF A142 shows an inverse 
relationship with in vivo Acortical load as measured with Pittsburgh Compound B 
amyloid PET imaging (Fagan et al. 2006; Forsberg et al. 2008; Tolboom et al. 2009).  
There is concordance on the information obtained via amyloid PET imaging and low 
CSF A142 in broad populations across a range of severity of AD (pre-dementia through 
mild to moderate AD; Jagust et al. 2009; Fagan et al. 2011; Landau et al. 2013; Zwan 
et al. 2014).
3.3.4
Rationale for Use of Investigational Tau Radioligand [18F]GTP1
[18F]GTP1 has a favorable safety profile to date (see Section 1.3.1).  Tau imaging using 
the investigational [18F]GTP1 radioligand has been incorporated in this study because it 
provides a unique advantage over conventional CSF biomarker evaluation in that it 
allows for the relationship between the distribution of tau pathology and response to the 
investigational anti-tau therapy to be evaluated. 
Longitudinal [18F]GTP1 PET imaging data will be collected to assess the response of this 
biomarker to the investigational anti-tau therapy, as it has the potential to inform the 
relationship between spatial distribution of tau pathology, cognitive function, and disease 
progression.
3.3.5
Rationale for Biomarker Assessments
Blood and CSF biomarker assessments will be used to verify amyloid-positivity, evaluate 
the relationship between [18F]GTP1 PET and CSF tau measures, demonstrate evidence 
of the biologic activity of MTAU9937A in patients, identify biomarkers that may be 
predictive of response to MTAU9937A, define PK and PD relationships, advance the 
understanding of the mechanism of action of MTAU9937A in patients, and increase the 
knowledge and understanding of disease biology.


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As some of these biomarkers may also have prognostic value, their potential association 
with disease progression will also be explored.
3.3.6
Rationale for Requiring Caregiver Participation
Patients with AD generally require supervision or assistance in their daily activities and 
may lack the insight necessary to provide accurate reports of their functioning.  For this 
reason, caregivers provide essential information for the endpoints evaluated in AD trials.  
A caregiver is defined as a non-paid (i.e., non-health care professional) individual who 
has frequent and sufficient contact with the patient to be able to provide accurate 
information as to the patient’s cognitive and functional abilities. 
3.3.7
Rationale for Control Group
A placebo dose group will be used as a concurrent control in the double-blind treatment 
period of this study.  The placebo-control group will help to establish a baseline safety 
profile, help to identify any adverse events that may be non-study drug related, and 
serve as a comparison group for efficacy measures in the double-blind treatment period 
of the study. 
3.3.8
Rationale for Pharmacokinetic Sampling
A sparse sampling schedule is being used to minimize patient burden and yet provide an 
adequate characterization of the population PK profile of MTAU9937A.  The PK data 
may be compared with available data from other MTAU9937A studies and may be used 
to assess exposure-response relationships for relevant imaging, CSF, plasma PD 
biomarkers, ECG, and efficacy and safety outcomes in patients with moderate AD as 
appropriate. 
3.3.9
Rationale for Use of Clinician and Observer Reported Outcome 
Assessments
COAs provide an understanding of the effect a treatment has on a patient.  A variety of 
observer (caregiver) and clinician-reported outcomes will be collected to characterize the 
efficacy and clinical profile of study treatment.  The primary outcome measures, the 
ADAS-Cog11 and the ADCS-ADL, are validated instruments that have been widely used 
in assessing AD.  Additional observer (caregiver) and clinician reported outcomes will be 
used to evaluate patient cognition, function, and behavior.  Site staff will be provided with 
a standardized rater-training program to certify them to administer the COAs identified in 
this protocol.
To minimize the contribution of potential confounding factors to these cognitive 
assessments, any patient with a current untreated depressive episode (i.e., presence of 
clinically significant depressive symptoms) will be excluded from the study. 


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4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 260 male and female patients with moderate AD, between the ages of 
50 and 85 years, will be enrolled at approximately 50 investigative sites located in 
North America and Europe.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Signed Informed Consent Form by the patient (co-signed by the patient’s legally 
authorized representative, if deemed appropriate by the investigator and/or required 
by the local regulations, guidelines, and IRB/EC)
Patients should be judged by the investigator to have capacity for informed 
consent when signing the Informed Consent Form.  In judging capacity, the 
investigator must confirm that the patient is able to understand the information 
relevant to the decision to participate in the study, appreciate the situation in 
terms of the treatment and research options and their likely outcomes, and 
weigh the potential risks and benefits of participation to arrive at a decision and 
communicate that decision.
If the patient does not fulfill the above criteria, their assent must be obtained 
and full informed consent must be obtained from a legally authorized 
representative.

Ability to comply with the study protocol, in the investigator's judgment

Age between 50 and 85 years, inclusive, at time of signing Informed Consent Form

NIA-AA core clinical criteria for probable AD dementia (see Appendix 5; McKhann 
et al. 2011)

Evidence of the AD pathological process, by a positive amyloid assessment either 
on CSF A142 as measured on Elecsys β-Amyloid(142) Test System OR amyloid 
PET scan by visual read by the core/central PET vendor as specified in the Imaging 
Review Charter
If a patient is amyloid negative based on CSF assessment, they may undergo 
an amyloid PET scan during screening to potentially be enrolled.  The patient 
may undergo an LP for CSF assessment or an amyloid PET scan only one time 
each during screening.
If a patient is amyloid negative based on an amyloid PET scan, they may 
undergo an LP for CSF assessment during screening for potential eligibility.  
The patient may undergo an LP for CSF assessment or an amyloid PET scan 
only one time each during screening.


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Under certain circumstances, a previously acquired amyloid PET scan may be 
used for study inclusion (see Section 4.5.8).  If the previously acquired amyloid 
PET scan is considered valid and is read negative by the core/central PET 
vendor, the patient may undergo CSF assessment for potential eligibility, but 
the patient may not undergo an additional amyloid PET scan for enrollment.

AD dementia of moderate severity, as defined by a screening MMSE score of 
1621 points, inclusive, and a CDR-GS of 1 or 2
MMSE obtained during the screening period for Study GN39763 may be used 
provided this is obtained within 8 weeks of the randomization date for 
Study GN40040 and provided the screen failure was not due to evidence of 
amyloid negativity.

Currently not receiving non-investigational AD medications except for as defined 
below:
If the patient is receiving non-investigational AD medications, the dosing 
regimen must have been stable for 2 months prior to the start of screening.  
There should be no a priori intent to initiate, discontinue, or alter the dose of 
any AD therapy for the duration of the study.  However, following the initiation of 
study drug, standard-of-care symptomatic medications for AD may be initiated, 
dose adjusted, or discontinued as deemed clinically appropriate.

Inclusion subject to Sponsor review of clinical criteria at screening (via the DVF)

Availability of a person (referred to as the “caregiver” throughout this protocol) who 
in the investigator's judgment:
–
Has frequent and sufficient contact with the patient (i.e., 10 hours/week) to be 
able to provide accurate information regarding the patient’s cognitive, 
behavioral, and functional abilities; agrees to provide information at clinic visits 
(for items which require caregiver input for scale completion); signs the 
necessary consent form; and has sufficient cognitive capacity to accurately 
report upon the patient’s behavior and cognitive and functional abilities
–
Is in sufficiently good general health to have a high likelihood of maintaining the 
same level of interaction with the patient and participation in study procedures 
throughout the study duration
Every effort should be made to have the same caregiver participate throughout the 
duration of the study for completing the designated caregiver COAs.

Fluency in the language of the tests administered at the study site

Completion of at least 6 years of formal education after the age of 5 years

Willingness and ability to complete all required aspects of the study (including MRI, 
clinical genotyping, and, if applicable, PET imaging)
The patient should be capable of completing study procedures either alone or 
with the help of caregiver(s).

Adequate visual and auditory acuity, in the investigator’s judgment, to perform the 
neuropsychological testing (eye glasses and hearing aids are permitted)


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
For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures, and agreement to refrain 
from donating eggs, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 9 weeks after the final dose 
of study drug or 4 days after the final dose of [18F]GTP1 radioligand or an 
amyloid radioligand, whichever is longer.  Women must refrain from donating 
eggs during this same period.
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).  The 
definition of childbearing potential may be adapted for alignment with local 
guidelines or requirements.
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male partner sterilization, hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of contraception.

For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below:
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
9 weeks after the final dose of study drug or 4 days after the final dose of 
[18F]GTP1 radioligand or an amyloid radioligand, whichever is longer, to avoid 
exposing the embryo.  Men must refrain from donating sperm during this same 
period.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not acceptable methods of preventing drug 
exposure.


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4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Pregnant or breastfeeding, or intending to become pregnant during the study or 
within 9 weeks after the final dose of study drug or 4 days after the final dose of 
[18F]GTP1 radioligand or an amyloid radioligand, whichever is longer
Women of childbearing potential must have a negative serum pregnancy test 
result during screening and a negative urine pregnancy test result each day of 
dosing or of PET imaging prior to administration of study drug or radioligand.

Inability to tolerate MRI procedures or contraindication to MRI, including, but not 
limited to, presence of pacemakers not compatible with MRI, aneurysm clips, 
artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or 
body that would contraindicate an MRI scan; or any other clinical history or 
examination finding that, in the judgment of the investigator, would pose a potential 
hazard in combination with MRI

Contraindication to PET imaging:  planned, or recent (within 12 months prior to 
screening) exposure to ionizing radiation (including other PET imaging) that in 
combination with the planned administrations of [18F]GTP1 radioligand (if applicable) 
or an amyloid radioligand (if applicable) would result in a cumulative exposure that 
exceeds recommended local guidelines

For patients undergoing LP for confirmation of amyloid positivity: contraindication to 
lumbar dural puncture, including coagulopathy, concomitant anticoagulation (except 
for a platelet inhibitor such as aspirin or clopidogrel), thrombocytopenia (platelet 
count50,000), prior lumbar spinal surgery, significant deformity of the lumbosacral 
region, or other factor that precludes safe LP in the opinion of the investigator

Body mass index40 

Hospitalization during the 4 weeks prior to screening
In jurisdictions where hospitalization status can be classified as observational or 
an inpatient admission, this exclusion criterion specifically refers to an inpatient 
admission.

Planned procedure or surgery during the study that in the investigator’s opinion 
would affect cognitive assessments or otherwise interfere with compliance with the 
protocol

Residence in a skilled nursing facility such as a convalescent home or long-term 
care facility
Residence in an assisted living facility is not exclusionary.
Patients who subsequently require residence in such facilities during the study 
may continue in the study and be followed for efficacy and safety, provided that 
they have a caregiver who meets the minimum requirement.

Blood transfusion within 8 weeks prior to screening or planned transfusion during 
the study


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
Poor peripheral venous access

Any serious medical condition or abnormality in clinical laboratory tests that remains 
abnormal on retest and, in the investigator’s judgment, precludes the patient’s safe 
participation in and completion of the study, or bias the assessment of the clinical or 
mental status of the participant to a significant degree.  Including, but not limited to:
–
Severe chronic kidney disease (Stage 4 or 5, according to National Kidney 
Foundation guidelines)
–
Hypertension not stably controlled by current medication (e.g., sustained 
systolic blood pressure > 160 mmHg or diastolic blood pressure > 95 mmHg)
–
Diabetes not stably controlled by current medication (e.g., hemoglobin A1c 
[HbA1c] 8%, or any history of clinically significant hypoglycemia, 
hyperosmolar syndrome, ketoacidosis, or other significant complication of 
diabetes within 2 years before screening)
–
Heart failure (e.g., New York Heart Association Class II or higher)
–
Clinically significant, abnormal ECG at screening (e.g., evidence of significant 
conduction blockade, or evidence of prior myocardial infarction, unless 
associated with a known myocardial infarction more than 2 years before 
screening)

History of cancer, except as follows:
–
If considered to be cured
–
An appropriately treated carcinoma in situ of the cervix or Stage I uterine 
cancer
–
If there has been no significant clinical progression during the past 5 years, with 
no active anti-cancer therapy or radiotherapy and, in the opinion of the 
investigator, is not likely to progress or require treatment in the ensuing 5 years
–
Prostate cancer or basal cell carcinoma, where there has been no significant 
progression over the previous 2 years

QT interval corrected through use of Fridericia’s formula (QTcF) 470 ms in females 
and >450 ms in males, demonstrated by at least two ECGs 30 minutes apart

Abnormal screening thyroid function tests or tests that remain abnormal on retest or 
require a new treatment or an adjustment of current treatment
Abnormal screening thyroid function tests should be defined as a 
thyroid-stimulating hormone level that is outside the normal range AND either a 
free thyroxine (T4) or a total T4 level that is outside the normal range.
A patient may be rescreened if there is no improvement in cognition in the 
investigator's judgment after 2 months of adequate treatment for thyroid 
function.


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
Screening folic acid or vitamin B12 levels that are sufficiently low or remain low on 
retest such that deficiency requires initiation or alteration of treatment and/or may be 
contributing to cognitive impairment
A patient may be rescreened if there is no improvement in cognition after 
2 months of adequate treatment for folic acid or vitamin B12 deficiency.
Cerebrovascular/Neurologic/Psychiatric Exclusion
Patients who meet any of the following cerebrovascular/neurologic/psychiatric criteria 
will be excluded from study entry:

History of seizures, with the exception of childhood febrile seizures or other remote, 
non-recurrent seizure

History of prior traumatic brain injury graded as moderate or severe, defined as a 
head injury resulting in loss of consciousness lasting 30 minutes or longer, an initial 
Glasgow Coma Scale of 12 or worse at presentation, posttraumatic amnesia or 
confusion lasting 24 hours or longer, or any associated abnormal brain imaging 
finding at presentation

Any evidence of a condition other than AD that may affect cognition, including, but 
not limited to, dementia with Lewy bodies, vascular dementia, Parkinson’s disease, 
corticobasal degeneration, Creutzfeldt-Jakob disease, progressive supranuclear 
palsy, frontotemporal degeneration, Huntington disease, normal pressure 
hydrocephalus, hypoxia, severe sleep apnea or other chronic sleep disturbance, or 
baseline intellectual disability

History of schizophrenia, schizoaffective disorder, major depression, or bipolar 
disorder
A history of major depression is acceptable if patient has had no episode within 
the past year, is considered in remission, or depression is controlled by 
treatment.

At risk of suicide in the opinion of the investigator

Substance abuse, meeting criteria for alcohol, cannabis, phencyclidine, other 
hallucinogen, inhalant, opioid, sedative, hypnotic, anxiolytic, or stimulant use 
disorder of any severity (per the Diagnostic and Statistical Manual of Mental 
Disorders, Version 5) within the past 2 years
Investigators may elect to obtain a urine drug screen if clinically indicated.

History or presence of clinically evident vascular disease potentially affecting the 
brain (e.g., clinically significant carotid, vertebral stenosis, or plaque; aortic 
aneurysm; intracranial aneurysm; cerebral or other intracranial hemorrhage; 
arteriovenous malformation) that, in the opinion of the investigator, has the potential 
to affect cognitive function

History or presence of any stroke with clinical symptoms within the past 2 years, or 
documented history within the last 6 months of an acute event consistent, in the 
opinion of the investigator, with a transient ischemic attack 


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
History of cerebral amyloid angiopathy or MRI evidence of >6 microhemorrhages, 
any macrohemorrhage, or superficial siderosis comprising more than one region or 
a single region >1 cm

History or presence of intracranial tumor that is clinically relevant (e.g., glioma, 
cerebral metastasis) in the opinion of the investigator

Presence of infections that affect brain function or history of infections that resulted 
in neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, viral or bacterial 
meningitis/encephalitis)

History or presence of CNS or systemic autoimmune disorders potentially causing 
progressive neurologic disease with associated cognitive deficits (e.g., multiple 
sclerosis, lupus erythematosus, antiphospholipid antibody syndrome, 
Behçet disease)

MRI evidence of more than two lacunar infarcts, any territorial infarct 1 cm3, or 
significant fluid-attenuated inversion recovery hyperintense lesions in the cerebral 
deep white matter corresponding to a Fazekas deep white matter score of 3 or that 
otherwise may, in the investigator’s opinion, contribute to cognitive dysfunction
Infection and Immune Disorder Exclusion
Patients who meet any of the following infection and immune disorder criteria will be 
excluded from study entry:

Systemically, clinically significantly immunocompromised patients, owing to 
continuing effects of immunosuppressive medication

Positive for hepatitis C virus (HCV) antibody at screening
Patients who have undergone curative treatment for HCV and have serologic 
evidence of sustained undetectable HCV RNA levels may be considered for 
inclusion after discussion with the Medical Monitor.

Positive for hepatitis B surface antigen (HBsAg) at screening

Positive for HIV antibody at screening

Serious infection requiring oral or IV antibiotics within 30 days prior to screening

Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric, human, or humanized antibodies or fusion proteins
The following medications are prohibited for a prespecified duration prior to study start, 
as indicated, and during the entire period of study participation (patients who start these 
medications during the study may be withdrawn from study treatment, except under 
specific circumstances as indicated):

Use of any experimental therapy within 90 days or 5 half-lives prior to screening, 
whichever is greater


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
Use of any passive immunotherapy (immunoglobulin) against tau
An exception will be made for use of MTAU9937A in Genentech 
Study GN39058, as long as the final dose was at least 90 days prior to 
screening.

Use of any passive immunotherapy (immunoglobulin) against A, unless the final 
dose was at least 1 year prior to screening

Use of any active immunotherapy (vaccine) that is under evaluation to prevent or 
postpone cognitive decline

Investigational biologic therapy (e.g., therapeutic proteins, monoclonal antibodies, or 
other active or passive immunotherapy) within 1 year of screening, or any 
expectation to require additional investigational biologic therapy for the duration of 
the trial

Any previous treatment with medications specifically intended to treat Parkinsonian 
symptoms or any other non-AD neurodegenerative disorder within 1 year of 
screening
Certain medications are acceptable if the medicine is for a 
non-neurodegenerative disorder, such as restless leg disorder 
(e.g., pramipexole).

Systemic immunosuppressive therapy within 12 months of screening through the 
entire study period
Short courses (2 weeks) of high-dose corticosteroid therapy are permitted.  
Chronic corticosteroid therapy (> 2 weeks) is permitted if the dose is 
7.5 mg/day prednisolone equivalent and the condition being treated is not 
expected to deteriorate significantly during the study period.

Typical antipsychotic or neuroleptic medication within 6 months of screening, except 
as brief treatment for a non-psychiatric indication (e.g., emesis)

Daily treatment with any of the following classes of medication, except for 
intermittent short-term use, which is permitted except within 2 days or 5 half-lives 
(whichever is longer) prior to any COA.  The investigator should contact the Medical 
Monitor if there are questions regarding permitted medications.
–
Opiates or opioids (including long-acting opioid medication)
–
Benzodiazepines, barbiturates, or hypnotics
–
Any medication with clinically significant centrally-acting antihistamine or 
anticholinergic activity (i.e., those medications with significant levels of blood-
brain barrier penetration that are likely to affect cognition and/or behavior)

Stimulant medications (amphetamine, methylphenidate preparations, or modafinil), 
unless the dose has been stable within the 6 months prior to screening and is 
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4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Patients will be randomly assigned to an active (4500 mg MTAU9937A) or placebo arm 
in a 1:1 ratio.  Randomization of patients will be managed by a central interactive voice 
or web-based response system (IxRS) vendor using stratified permuted block 
randomization.
Study site personnel (with the exception of the unblinded site pharmacist and unblinded 
contract research organization [CRO] monitor) and patients will be blinded to treatment 
assignment during the study.  The Sponsor and its agents will also be blinded to 
treatment assignment, with the exception of individuals who require access to patient 
treatment assignments to fulfill their job roles during a clinical trial.  These roles include 
the unblinding group responsible, clinical supply chain managers, sample handling staff, 
operational assay group personnel, IxRS service provider, Sponsor’s IMC members, and 
CRO monitor.
While PK and ADA samples must be collected from patients assigned to the placebo 
arm to maintain the blinding of treatment assignment, PK and ADA assay results for 
these patients are generally not needed for the safe conduct or proper interpretation of 
this study.  Laboratory personnel responsible for performing study drug PK and ADA 
assays will be unblinded to patients' treatment assignments to identify appropriate 
samples to be analyzed.  PK samples from patients assigned to the placebo arm will not 
be analyzed for study drug PK concentration except by request (e.g., to evaluate a 
possible error in dosing).  Baseline ADA samples will be analyzed for all patients.  
Postbaseline ADA samples from patients assigned to the placebo arm will not be 
analyzed for ADAs except by request.
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  The investigator will be able to break the treatment code by contacting the 
IxRS.


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As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT
TO THE STUDY DESIGN
MTAU9937A is an investigational medicinal product (IMP) in this study.  Depending on 
local classification, the [18F]GTP1 tau PET radioligand and/or the amyloid PET 
radioligand(s) may be considered non-investigational medicinal products or IMPs. 
Refer to the Amyloid Imaging Technical Operations Manual for a list of amyloid PET 
radioligands allowed in this study.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
MTAU9937A and Placebo
MTAU9937A and placebo will be supplied by the Sponsor as sterile liquids in glass vials.  
For information on the formulation and handling of MTAU9937A, see the pharmacy 
manual and the MTAU9937A Investigator’s Brochure.
4.3.1.2
[18F]GTP1 Tau PET Radioligand
[18F]GTP1 radioligand will be provided under contract with a PET imaging vendor in 
accordance with approved national and/or local standards. [18F]GTP1 radioligand will be 
supplied as a sterile non-pyrogenic solution in sterile borosilicate glass vials with gray 
butyl septa and aluminum ring seals.  The final product bears a label with the following 
items:  total activity (mCi), volume (mL), strength (mCi/mL), calibration date and time, 
batch number, study identification, and shelf life.  For information on the formulation and 
handling of [18F]GTP1 radioligand, see the [18F]GTP1 Investigator’s Brochure.
4.3.1.3
Amyloid PET Radioligands
Appropriate amyloid PET radioligands will be provided under contract with a PET 
imaging vendor and/or PET radioligand producers in accordance with approved national 
and/or local standards.  Refer to the local labeling instructions or, depending on locality, 
the Investigator’s Brochures, for details on packaging, formulation, and handling of the 
amyloid PET radioligands.  Depending on locality, additional information may also be 
found in the local labeling information or the Investigator’s Brochure for the particular 
amyloid PET radioligand being used.


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4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1. 
Any dose modification should be noted on the Study Drug Administration eCRF.  Cases 
of accidental overdose or medication error, along with any associated adverse events,
should be reported as described in Section 5.3.5.12.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.3.
During the COVID-19 pandemic, study treatment may be administered in the patient’s 
home or in an approved alternate location.
4.3.2.1
MTAU9937A and Placebo
MTAU9937A and placebo will be prepared and diluted into 100-mL IV bags according to 
the pharmacy manual, and infusions will be administered per the instructions outlined in 
Table 1 and the pharmacy manual.


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Table 1
Administration of First and Subsequent Infusions of MTAU9937A 
(or Placebo)
First Infusion a
Subsequent Infusions

Begin infusion at an initial rate of 0.5 mL/min 
(30 mL/hr).

If no infusion-related or hypersensitivity 
reaction occurs during the first 30 minutes, 
then increase the rate to 1.0 mL/min 
(60 mL/hr). 

If no infusion-related or hypersensitivity 
reaction occurs during the subsequent 
30 minutes, then increase the rate to
3.0 mL/min (180 mL/hr).

If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  The patient should 
be monitored until all infusion-related 
adverse events are Grade 1 or are 
resolved. 
If the reaction resolves, resume the infusion 
at a 50% reduction in rate (i.e., 50% of rate 
being used at the time that the reaction 
occurred).  If the reaction recurs after 
resumption of the infusion, then stop the 
infusion.  For patients who experience 
serious or severe hypersensitivity or 
hypersensitivity-like reactions 
(e.g., hypotension, mucosal involvement), 
the investigator must discuss with the 
Medical Monitor whether to continue study 
drug treatment. 
If the participant experienced an 
infusion-related or hypersensitivity reaction 
during the prior infusion, begin infusion at an 
initial rate of 0.5 mL/min and follow 
instructions for first infusion.
If the participant tolerated the prior infusion 
well (defined by an absence of Grade 2 
reactions during a final infusion rate of 
3.0 mL/min), begin infusion at a rate of 
3.0 mL/min.
If a reaction develops, stop or slow the 
infusion.  Administer medications and 
supportive care in accordance with 
institutional guidelines.  The patient should 
be monitored until all infusion-related 
adverse events are Grade 1 or are resolved.
If the reaction resolves, resume the infusion 
at a 50% reduction in rate (i.e., 50% of rate 
being used at the time that the reaction 
occurred).  If the reaction recurs after 
resumption of the infusion, then stop the 
infusion.  For patients who experience 
serious or severe hypersensitivity or 
hypersensitivity-like reactions 
(e.g., hypotension, mucosal involvement), 
the investigator must discuss with the 
Medical Monitor whether to continue study 
drug treatment.
OLEopen-label extension.
a First infusion instructions apply to the first infusion of MTAU9937A or placebo during the 
double-blind treatment period and the first infusion of MTAU9937A during the OLE period.
4.3.2.2
[18F]GTP1 Tau PET Radioligand
Patients may receive [18F]GTP1 radioligand and undergo a PET scan on multiple 
occasions as described in the schedules of activities in Appendix 1Appendix 4.  Refer 
to the [18F]GTP1 PET Imaging Technical Operations Manual for details on the use of 
[18F]GTP1 radioligand for PET imaging.
4.3.2.3
Amyloid PET Radioligand
All patients enrolled using amyloid PET evaluation will be assessed by PET imaging 
using an appropriate amyloid PET radioligand.  Refer to the Amyloid Imaging Technical 
Operations Manual for details on the use of the amyloid PET radioligands.


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4.3.3
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (MTAU9937A or placebo) and radioligands 
([18F]GTP1 and amyloid radioligands) will be provided by the Sponsor where required by 
local health authority regulations.  The study site will acknowledge receipt of IMPs 
supplied by the Sponsor, using the appropriate documentation mechanism (system or 
paper 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 be returned to the Sponsor with the appropriate 
documentation.  The site’s method of destroying MTAU9937A/placebo must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any MTAU9937A/placebo is destroyed, and MTAU9937A/placebo destruction must be 
documented on the appropriate form.  Radioligands will be disposed of or returned 
according to instructions provided by the PET imaging vendor.
Accurate records of all study treatments received at, dispensed from, returned to, and 
disposed of by the study site should be recorded on the applicable Drug Inventory or 
Dispensing Logs.
4.3.4
Continued Access to MTAU9937A
Currently, the Sponsor (Genentech, a member of the Roche Group) does not have any 
plans to provide Sponsor study drug (MTAU9937A) or any other study treatments or 
interventions to patients who have completed the study.  The Sponsor may evaluate 
whether to continue providing MTAU9937A in accordance with the Roche Global Policy 
on Continued Access to Investigational Medicinal Product, available at the following 
website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 
3 months prior to screening until the final study visit.  However, any agent that targets A
used by the patient at any time during their life is also considered to be a concomitant 
therapy.  All such medications should be reported to the investigator and recorded on 
the appropriate Concomitant Medications eCRF.


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4.4.1
Permitted Therapy 
All participants who use concomitant therapies should continue to use those therapies, 
unless they conflict with the inclusion or exclusion criteria as stated in Sections 4.1.1
and 4.1.2. 
Non-investigational therapies for AD are permissible, provided that the dosing regimen 
has been stable for 2 months prior to screening.  At the time of enrollment, there should 
be no a priori intent to initiate, discontinue, or alter the dose of any AD therapy for the 
duration of the study.  However, following the initiation of study drug, standard-of-care 
symptomatic medications for AD may be initiated, dose adjusted, or discontinued as 
deemed clinically appropriate.
During the OLE, daily treatment with opiates or opioids, benzodiazepines, barbiturates or 
hypnotics, and medications with clinically significant central antihistaminic or 
anticholinergic activity may be permitted upon approval by the Medical Monitor. During 
the OLE, typical antipsychotic and neuroleptic medication is permitted if clinically 
indicated.
4.4.2
Cautionary Therapy
4.4.2.1
Herbal Therapies
Concomitant use of herbal therapies is not recommended because their 
pharmacokinetics, safety profiles, and potential drug-drug interactions are generally 
unknown.  However, herbal therapies may be used during the study at the discretion of 
the investigator.
4.4.3
Prohibited Therapy
Refer to the exclusion criteria (Section 4.1.2) for a list of prohibited therapies and 
exceptions.
4.5
STUDY ASSESSMENTS 
The schedules of activities to be performed during the study are provided in
Appendix 1Appendix 4.  All activities should be performed and documented for each 
patient.  During the COVID-19 pandemic, study visit activities, excluding imaging 
assessments, may be performed in the patient’s home or in an approved alternate 
location.
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and available local laboratory test values are acceptable.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Refer to 
Section 3.1.1.1 regarding the use of the Early Screening Informed Consent Form versus 


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the main Informed Consent Form.  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.
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures); reproductive status; smoking history; 
use of alcohol and drugs of abuse; and recent history (5 years) of non-elective 
hospitalizations, pneumonia, or cardiovascular events will be recorded at baseline.  
In addition, lifetime use of any A-targeting therapies, and all medications 
(e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic 
remedies, nutritional supplements) used by the patient within 3 months prior to initiation 
of screening until the final study visit will be recorded.  Any agent that targets Aused by 
the patient at any time during their life (any time before initiation of screening and while 
on study) will also be recorded.  At the time of each follow-up physical examination, an 
interval medical history should be obtained and any changes in medications and 
allergies should be recorded.
Demographic data will include age, sex, self-reported race/ethnicity (as permitted by 
local regulations), handedness, and years of education.  Demographic data will be 
collected for both the patient and the caregiver, with the exception of handedness, which 
will only be collected for the patient.
As this study is being conducted in multiple geographic regions, it is likely that patients of 
different ethnic origins will be enrolled in the study.  Although there is currently no 
indication that MTAU9937A is metabolized or eliminated differently or that the treatment 
effect would be different in patients with different ethnic origins, collecting this 
information (where permitted by local regulations) is essential to adequately evaluate the 
results of this study (e.g., possible differences in PK exposure [concentration of the drug 
in the blood] or treatment effect).
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, respiratory, and gastrointestinal systems.  In addition, the 
musculoskeletal and genitourinary systems should be examined as clinically indicated.  
Any clinically significant abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 


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Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and 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.
4.5.4
Neurologic Examinations
A complete neurologic examination should include the evaluation of consciousness, 
cranial nerves, motor and sensory system, coordination and gait, and reflexes.  Any 
clinically significant abnormality identified at baseline should be recorded on the General 
Medical History and Baseline Conditions eCRF.  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.
4.5.5
Lumbar Puncture
For patients providing CSF samples, the LP procedure should be performed according 
to standard procedures at the study site using sterile technique and an atraumatic 
needle.  See the laboratory manual for details regarding the collection, processing, and 
storage of CSF.
4.5.6
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, and temperature.
The same arm should be used for all blood pressure measurements.  Pulse rate and 
blood pressure should not be measured unless 15 minutes have passed since the last 
blood draw.  Vital sign assessments should be performed both prior to and after study 
drug administration. 
4.5.7
Clinical Outcome Assessments
The COAs listed in Table 2 will be administered to all patients and/or caregivers enrolled 
in this study.  Clinicians/raters (but not caregivers or patients) will use an electronic 
device to capture COA data.  COA data from the electronic device will be transmitted to 
a centralized database maintained by the electronic device vendor.  The C-SSRS will be 
used to monitor safety (as described below).  All other COAs will only be used as 
assessments of treatment efficacy.


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Table 2
Clinical Outcome Assessments
Clinical Outcome Assessments
Patient
Caregiver
Concept
Mini-Mental State Examination (MMSE)
x
Cognition
Alzheimer’s Disease Assessment ScaleCognitive 
Subscale, 11-item version (ADAS-Cog11)
x
Cognition
Clinical Dementia Rating (CDR) Scale
x
x
Cognition and 
Function
Alzheimer’s Disease Cooperative Study–Activities of 
Daily Living Inventory (ADCS-ADL)
x
Function
Neuropsychiatric Inventory (NPI)
x
Behavioral 
Symptoms
Caregiver Global Impression Scales for Alzheimer’s 
disease (CaGI-Alz)
x
Cognition and 
Function
Columbia-Suicide Severity Rating Scale (C-SSRS)
x
Suicidality
These assessments, translated into the local language as required, will be completed in 
their entirety at specified timepoints during the study.  To ensure instrument validity and 
that data standards meet health authority requirements, questionnaires will be 
administered before the patient, clinician, or caregiver receives any information 
regarding disease status, prior to the performance of non-COA assessments, and prior 
to administration of study drug or radioligand, unless otherwise specified. 
The COA scales and assessments for this study will be provided unless otherwise 
specified.  Whenever possible, there should be consistency in the rater and caregiver 
who complete the scales for each patient throughout the duration of the study.  Potential 
raters should be designated at each site and will receive training and be approved by the 
rating-scale vendor prior to being allowed to administer any cognitive assessments/
rating scales in the study.  Administration of cognitive assessments/rating scales 
(i.e., the COAs) will be performed in accordance with instructions provided in the 
Study GN40040 COA Manual and the training/documentation provided by the 
rating-scale vendor.
In addition, given that multiple outcome measures in this study involve some degree of 
subjective judgment and/or interpretation, the adequacy of patient interviews and ratings 
will be monitored by an endpoint reliability program administered by the rating-scale 
vendor; this is considered to be an essential part of good research methodology.  Prior 
studies have clearly demonstrated that the failure to adequately monitor such ratings can 
substantially increase the risks of failed trials (Becker and Greig 2008; Kobak 2010).
Please see the Study GN40040 COA Manual for instructions on COA administration 
order, specification of list versions to use at each visit, rater roles, restrictions on raters, 
and additional details on COA administration and the endpoint reliability program. 


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Patients who miss study drug infusions during the double-blind treatment period for 
reasons related to the COVID-19 pandemic may have additional COAs administered 
remotely (by telephone or video call) at the time of the first missed infusion and at the 
time when in-clinic study drug infusions resume. COAs that may be administered 
remotely include the CDR, ADCS-ADL, NPI, CaGI-Alz, and C-SSRS.  Refer to the 
Study GN40040 remote COA administration guidance for further details.
4.5.7.1
Mini-Mental State Examination
The MMSE is a brief clinical cognitive examination commonly used to screen for 
dementia and other cognitive deficits (Folstein et al. 1975) that has a total score of 030.  
The MMSE will be administered to patients at screening to determine eligibility for the 
trial, at baseline, and at other postbaseline timepoints.
4.5.7.2
Clinical Dementia Rating Scale
The CDR (Morris 1993) instrument is a semi-structured interview that yields five degrees 
of impairment in performance for each of six categories of cognitively based functioning:  
memory, orientation, judgment and problem solving, community affairs, home and 
hobbies, and personal care.  The CDR interview is administered to both the patient with 
AD and his or her caregiver.  The ratings of degree of impairment obtained for each of 
the six categories of function (the six “boxes”) are synthesized into one global rating of 
dementia (range, 0–3).  A more refined measure of impairment is available by using the 
CDR-SB that is the sum of the six domains and has a range of 018.  Reliability and 
validity have been established, as it has high inter-rater reliability.  The CDR will be used 
as a global assessment of severity of dementia.
4.5.7.3
Alzheimer’s Disease Assessment Scale–Cognitive Subscale, 
11-Item Version
The ADAS-Cog is the most frequently used scale to assess cognition in clinical trials for 
mild to moderate AD (Rozzini et al. 2007; Connor and Sabbagh 2008; Ihl et al. 2012).  
The ADAS-Cog11 (11-item version) will be used.  The ADAS-Cog11 is administered to 
the patient.  Equivalent alternate forms of the word recall and word recognition subtests 
will be used in successive test administrations. 
4.5.7.4
Alzheimer’s Disease Cooperative StudyActivities of Daily 
Living Inventory
The ADCS-ADL (Galasko et al. 1997) is the most widely scale for assessing functional 
outcomes in patients with AD (Vellas et al. 2008).  The ADCS-ADL is administered to 
caregivers and covers both basic activities of daily living (ADL) (e.g., eating and toileting) 
and more complex ADL or instrumental ADL (e.g., using the telephone, managing 
finances, preparing a meal).  Scores range from 0 to 78, with higher scores indicating 
better ADL function.


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4.5.7.5
Neuropsychiatric Inventory
The NPI (Cummings et al. 1994) is a widely used scale that assesses the behavioral 
symptoms in AD, including their frequency, severity, and associated distress.  The NPI is 
administered to caregivers and focuses on 12 common behavioral symptoms that are 
most often reported in AD.  Individual symptom scores range from 0 to 12 and total NPI 
scores range from 0 to 144.
4.5.7.6
Caregiver Global Impression Scales for Alzheimer’s Disease
The CaGI-Alz is comprised of four items to assess the caregiver’s perception of the 
patient’s change in disease severity.  In this study, caregivers will be asked to rate the 
patient’s change in memory and ADL since study treatment started and since the 
previous CaGI-Alz assessment (e.g., the prior 6 months).  All items are rated on a 
7-point Likert-type scale from 1 (very much improved since treatment started/previous 
CaGI-Alz assessment) to 7 (very much worsened since treatment started/previous 
CaGI-Alz assessment).  These items will be used as anchors to determine meaningful 
change on other COAs.
4.5.7.7
Columbia-Suicide Severity Rating Scale
The C-SSRS is an interview-based instrument used to assess baseline incidence of 
suicidal ideation and behavior and to prospectively assess suicidal ideation and behavior 
at postbaseline visits.  Postbaseline assessments will assess suicidal ideation and 
behavior since the previous visit.  The C-SSRS will be used to monitor safety.  It is 
administered to the patient and measures five subtypes of suicidal ideation and behavior 
thought by the FDA to be important to capture in a prospective assessment of suicidality 
(FDA 2012).  If any C-SSRS responses are suggestive of an adverse event, the 
investigator will determine whether the criteria for an adverse event have been met and, 
if so, will report the event on the Adverse Event eCRF.
Patients who are deemed suicidal on the basis of C-SSRS by the investigator will be 
referred for appropriate psychiatric evaluation and management as per local clinical 
practice.
4.5.8
Amyloid and Tau Positron Emission Tomography
Patients who are enrolled using amyloid PET evaluation will be assessed by PET 
imaging at screening and must have a positive amyloid PET scan by central visual read 
(see Section 4.1.1).  Refer to the study overview (Section 3.1.1) and the inclusion criteria 
(Section 4.1.1) for details regarding amyloid PET evaluation.
If a prospective patient has previously received an amyloid PET scan and has not 
received prior amyloid immunotherapy, this prior scan may be used to determine 
eligibility if all of the following requirements are met:


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
The prior amyloid PET scan must have been conducted in accordance to the 
specifications outlined in the appropriate local reference documentation and must 
pass the quality control procedures established by the core/central PET vendor.  
If the prior scan does not pass the quality control procedures or cannot be reliably 
read by the core/central PET vendor, the prior scan is not considered valid.

Relevant prior data must be the original, raw scan images themselves, not the 
resulting clinical reading.  Images need to be sent to the imaging vendor for central 
review (see instructions for transferring in the Amyloid Imaging Technical 
Operations Manual).

Images must be presented to the study reader(s) in the same format and 
undifferentiated in any way from images that would result from a newly acquired 
scan in this study.
The study reader(s) must conduct a new, independent reading of the prior amyloid scan, 
following the same process as for a newly acquired scan (see the Amyloid Imaging 
Technical Operations Manual), to determine eligibility.  The study reader(s) should not 
reference any prior reading of a previously acquired scan.
Patients who undergo tau PET imaging will receive [18F]GTP1 radioligand and undergo a 
PET scan on multiple occasions as described in the schedules of activities in 
Appendix 1Appendix 4.
If occurring at the same visit, amyloid PET or [18F]GTP1 PET scans must be performed 
after administration of COAs.  Only one PET scan should be performed on a given day.
Positron Emission Tomography Imaging Procedures 
The Sponsor in conjunction with the CRO will prepare and distribute detailed imaging 
technical operations manuals for image acquisition, reconstruction procedures, and 
parameters for each center prior to the start of the study. All imaging data will be 
transferred to the imaging vendor for quality control and image analysis as documented 
in the PET Technical Operations Manual or other image transfer instructions.
Detailed methodology, including scanning procedures, is included in the [18F]GTP1 PET 
Imaging Technical Operations Manual.
4.5.9
Laboratory, Biomarker, and Other Biological Samples
Samples for the following laboratory tests will be sent to the study site's local laboratory 
for analysis:

Pregnancy test
All women of childbearing potential will have a serum pregnancy test at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits prior to dosing.  If a urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test.  Pregnancy tests must be negative prior to dosing 
with study drug or [18F]GTP1.


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Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (absolute counts of neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, and other cells)

Chemistry panel (serum or plasma):  bicarbonate or total carbon dioxide 
(if considered standard of care for the region), sodium, potassium, chloride, 
magnesium, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total and direct bilirubin, ALP, ALT, AST, gamma glutamyl transpeptidase, 
and creatine kinase.  
Glomerular filtration rate should also be calculated from creatinine using the 
Cockcroft-Gault formula.

Coagulation:  INR, aPTT, and PT

Lipids:  cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides

Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood)
Microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria) should be performed if the dipstick is abnormal. 

Viral serology (at screening only):  HIV, HBsAg, total hepatitis B core antibody, and 
HCV antibody

Additional analytes (at screening only):  HbA1c (glycosylated hemoglobin), B12, folic 
acid, thyroid-stimulating hormone, and T4
Results from laboratory tests obtained prior to obtaining informed consent and within 
90 days prior to the start of screening may be used.  Such tests do not need to be 
repeated for screening.
The following samples will be sent to the Sponsor or a designee for analysis:

CSF samples for PK analysis (MTAU9937A)

Serum samples for PK analysis (MTAU9937A)

Serum samples for immunogenicity analysis (ADAs)

Blood sample for determination of ApoE4 status

Blood and CSF samples for exploratory research on biomarkers
Exploratory biomarker research may include, but will not be limited to, analyses of 
soluble tau, neurofilament light chain, and genetic markers associated with AD, 
neurodegeneration, and neuro-inflammation.  Research may involve extraction of DNA,
to enable whole genome sequencing (WGS), and analysis of single nucleotide 
polymorphisms (SNPs), but only at participating sites (see Section 4.5.11).


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These samples will be used to further the Sponsor’s understanding of AD and the 
response to treatment and may also be used to support the development of biomarker 
and diagnostic assays.  For sampling procedures, storage conditions, and shipment 
instructions, see the laboratory manual.
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.12), biological samples will be destroyed 
when the final Clinical Study Report has been completed, with the following exceptions:

Serum samples collected for PK analysis and/or immunogenicity analysis may be 
needed for additional PK and ADA assay development and validation, and 
additional immunogenicity characterization; these samples will be destroyed no later 
than 5 years after the final Clinical Study Report has been completed.

Blood samples collected for WGS and SNP (see Section 4.5.11)

Whole blood, plasma, and CSF samples collected for exploratory biomarker 
research will be stored 10 years after the study results have been reported
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis, including data on mutations, will be subject to the 
confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.10
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedules of activities (see Appendix 1Appendix 4), and may be obtained at 
unscheduled timepoints as indicated.  Results obtained prior to obtaining informed 
consent and within 90 days prior to the start of screening may be used.  Such tests do 
not need to be repeated for screening.
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
On the day of the first administration of study drug, ECG should be performed 04 hours 
before the start of infusion and 030 minutes after the end of infusion.  Subsequent 
ECGs at other visits should be performed 030 minutes after the end of infusion.  All 
ECGs are to be obtained prior to other procedures scheduled at that same time 


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(e.g., vital sign measurements, blood draws) and a large rich meal should be avoided 
within 3 hours before the ECG recording (a snack or light meal is acceptable).  
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.
If at a particular postdose timepoint the QTcF is 500 ms and/or 60 ms longer than the 
baseline value, another ECG must be recorded, ideally within the next 5 minutes, and 
ECG monitoring should continue until QTcF has stabilized on two successive ECGs.  
The Medical Monitor should be notified.  Standard-of-care treatment may be instituted 
per the discretion of the investigator.  If a PK sample is not scheduled for that timepoint, 
an unscheduled PK sample should be obtained.  A decision regarding study drug 
discontinuation should be made, as described in Section 5.1.3.3.  The investigator 
should also evaluate the patient for potential concurrent risk factors (e.g., electrolyte 
abnormalities, co-medications known to prolong the QT interval, severe bradycardia).
4.5.11
Samples for Whole Genome and SNP Sequencing 
(at Participating Sites Only)
At participating sites, blood samples will be collected for DNA extraction to enable WGS 
and analysis of SNPs that are predictive of response to study drug, are associated with 
progression to a more severe disease state, are associated with susceptibility to 
developing adverse events, or can increase the knowledge and understanding of 
disease biology and drug safety.  Research may aim to distinguish germline mutations 
from somatic mutations.  The samples may be sent to one or more laboratories for 
analysis.
Collection and submission of WGS and SNP samples is contingent upon the review and 
approval of the exploratory research by each site's IRB/EC and, if applicable, an 
appropriate regulatory body.  If a site has not been granted approval for WGS or SNP 
sampling, this section of the protocol (Section 4.5.11) will not be applicable at that site.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and SNP analyses provide a comprehensive characterization of the genome and, 
along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches or new methods for monitoring efficacy and 
safety or predicting which patients are more likely to respond to a drug or develop 
adverse events.  Data will be analyzed in the context of this study but will also be 
explored in aggregate with data from other studies.  The availability of a larger dataset 
will assist in identification and characterization of important biomarkers and pathways to 
support future drug development.


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For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Blood samples collected for WGS and SNP analyses are to be stored until they are no 
longer needed or until they are exhausted.  However, the storage period will be in 
accordance with the IRB/EC-approved Informed Consent Form and applicable laws 
(e.g., health authority requirements).
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Patient medical information associated with WGS and SNP samples is confidential and 
may be disclosed to third parties only as permitted by the Informed Consent Form 
(or separate authorization for use and disclosure of personal health information) signed 
by the patient, unless permitted or required by law.
Given the complexity and exploratory nature of the WGS and SNP analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
4.5.12
Optional Samples for Research Biosample Repository
4.5.12.1
Overview of the Research Biosample Repository
The Research Biosample Repository (RBR) is a centrally administered group of facilities 
used for the long-term storage of human biological specimens, including body fluids, 
solid tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The 
collection, storage, and analysis of RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.
Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be used to achieve the following 
objectives:

To study the association of biomarkers with efficacy or disease progression

To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation

To increase knowledge and understanding of disease biology and drug safety


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
To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.12) 
will not be applicable at that site.
4.5.12.3
Sample Collection
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to MTAU9937A, tau,
diseases, or drug safety:

Any blood, serum, plasma, and CSF remaining after planned analyses
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic mutations via WGS, whole exome sequencing (WES), or other genomic 
analysis methods.  Genomics is increasingly informing researcher's understanding of 
disease pathobiology.  WGS and WES provide a comprehensive characterization of the 
genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or predicting which patients are more likely to 
respond to a drug or develop adverse events.
Data generated from RBR samples will be analyzed in the context of this study but will 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.  
RBR samples are to be stored until they are no longer needed or until they are 
exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements).


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4.5.12.4
Confidentiality
RBR samples and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient 
and/or authorized legal representative (if applicable), unless permitted or required by 
law.
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication.
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise.
4.5.12.5
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research.
4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed or will no longer be linked to the patient.  However, if RBR samples 
have been tested prior to withdrawal of consent, results from those tests will remain as 
part of the overall research data.  If a patient wishes to withdraw consent to the testing of 


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his or her RBR samples during the study, the investigator must inform the Medical 
Monitor in writing of the patient's wishes through use of the appropriate RBR Subject 
Withdrawal Form and must enter the date of withdrawal on the RBR Research Sample 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the trial is closed.  A patient's withdrawal from 
Study GN40040 does not, by itself, constitute withdrawal of specimens from the RBR.  
Likewise, a patient's withdrawal from the RBR does not constitute withdrawal from 
Study GN40040.
If a patient wishes to withdraw consent to the testing of his or her specimens after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address:
global_rcr-withdrawal@roche.com
4.5.12.7
Monitoring and Oversight
RBR samples will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for a treatment discontinuation visit 12 weeks (7 days)
after the final dose of study drug (see Appendix 1Appendix 4 for additional details).


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4.6.2
Patient Discontinuation from Study
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

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study but have not withdrawn consent.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a patient requests to be 
withdrawn from the study, this request must be documented in the source documents 
and signed by the investigator.  Patients who withdraw from the study will not be 
replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
MTAU9937A is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with MTAU9937A in completed and 
ongoing studies.  Important potential safety risks for patients receiving MTAU9937A are 
outlined below.  Refer to the MTAU9937A Investigator's Brochure for a complete 
summary of safety information.
[18F]GTP1 radioligand is not approved by any health authority, and clinical development 
is ongoing.  The safety plan for participants in this study is based on clinical experience 
with [18F]GTP1 radioligand in completed and ongoing studies, and the safety experience 
to date is detailed in the [18F]GTP1 Investigator’s Brochure.
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  Ongoing review of 
unblinded safety data will be performed by an IMC (see Section 3.1.2).  External experts 
may be consulted.  In addition, guidelines for managing adverse events, including 
criteria for dosage modification and treatment interruption or discontinuation, are 
provided below.
5.1.1
Potential Risks Associated with MTAU9937A 
5.1.1.1
Infusion-Related Reactions or Hypersensitivity
Monoclonal antibodies such as MTAU9937A may be associated with a potential immune 
response in clinical trials, such as hypersensitivity or hypersensitivity-like reactions, 
including severe, anaphylactic reactions (see Appendix 6 for precautions).  Study sites 
will be prepared to manage any hypersensitivity or hypersensitivity-like events.
All participants will be monitored for infusion-related reactions, hypersensitivity, or 
hypersensitivity-like reactions during the infusion and immediately afterward (see 
Section 5.1.3.2 for additional instructions on monitoring and management of 
infusion-related reactions).
5.1.1.2
Neuroimaging Abnormalities
The occurrence of imaging abnormalities believed to represent cerebral vasogenic 
edema and microhemorrhage have been reported in association with the investigational
use of immunotherapy targeting the Apeptide, possibly by interacting with A
deposited in or around blood vessels and eliciting an immune response.  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 (Salloway et al. 2009; Sperling et al. 2012). 


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Tau pathology occurs primarily intracellularly in the cytoplasm of diseased neurons 
(Braak et al. 2006), and soluble extracellular tau is found in the CSF (Blennow and 
Zetterberg 2009).  Unlike A, tau is not known to deposit in vascular structures, and 
administration of an antibody against the tau protein is not anticipated to cause 
vasogenic edema or microhemorrhage.  Moreover, MTAU9937A has an IgG4 backbone, 
which is associated with reduced effector function.  Nevertheless, in this study, the 
following will be performed to monitor for potential neuroimaging abnormalities:

All patients will have an MRI at screening and at several postbaseline timepoints 
(see Appendix 1Appendix 4).  MRI must be performed prior to any dosing on the 
corresponding study visit and must be read locally in real time for the evaluation of 
any new, clinically significant abnormality prior to the dose being given.  However, if 
no such abnormalities are identified in the local MRI interpretation, the dose may be 
given prior to the receipt of the central MRI report. In case of an abnormality 
identified by the central MRI reading, the investigator should assess the clinical 
significance of it and proceed as described below.

During the COVID-19 pandemic, if study-associated MRIs cannot be obtained, the 
patient should be monitored for any signs or symptoms suggestive of new, clinically 
significant neurologic abnormalities. If no new, clinically significant abnormalities 
are observed, study drug may be administered without an MRI, but a subsequent 
unscheduled study-associated MRI should be obtained as local conditions allow. 
If new, clinically significant neurologic abnormalities are observed, study drug 
should be withheld and the patient should be referred for appropriate follow-up and 
medical treatment, including, if appropriate, an MRI. Preliminary analyses of 
unblinded safety data from Studies GN39763 and GN40040 suggest that rates of 
MRI abnormalities in these studies are consistent with background rates reported in 
this patient population (Carlson et al. 2011; Caunca et al. 2016).

All patients will regularly undergo neurologic examinations to evaluate for any 
neurologic signs or symptoms.  In case of findings suggestive of a new, clinically 
significant CNS disturbance or lesion, patients must undergo an MRI examination as 
soon as possible. 

All MRIs will be read locally in real time for the evaluation of any clinically significant 
new or worsening abnormality.  Study drug will be withheld at the corresponding 
study visit if, in the investigator’s judgment, any clinically significant new or 
worsening MRI abnormality (e.g., symptomatic or asymptomatic intracranial tumor, 
cerebral infarct [lacunar or territorial], cerebral hemorrhage [macrohemorrhage, 
microhemorrhage, superficial siderosis], vasogenic edema, sulcal effusion) is 
observed.  Restarting study drug treatment can occur only after discussion with the 
Medical Monitor.

Regardless of severity, all events of a clinically significant new or worsening MRI 
abnormality that occur at any time after receiving study drug are considered to be 
adverse events of special interest and must be reported in an expedited manner.


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5.1.1.3
Immunogenicity
MTAU9937A is a pan-tau IgG4 monoclonal antibody engineered to contain Fc mutations 
(YTE) that enhance binding to FcRn and have been shown to slow peripheral antibody 
clearance in humans.  ADAs to MTAU9937A in humans may be associated with 
changes in MTAU9937A exposure, reductions in treatment efficacy, or safety findings 
such as hypersensitivity reactions.  In the Phase I study (GN39058), there was no 
evidence of treatment emergent ADAs. Immunogenicity in this Phase II study 
(GN40040) will be evaluated using validated immunoassays and by assessing the 
incidence of ADAs after treatment relative to their prevalence at baseline.
5.1.2
Potential Risks Associated with [18F]GTP1 and Amyloid PET 
Radiopharmaceuticals
5.1.2.1
Infusion-Related Reactions 
All participants will be monitored for infusion-related reactions both during the infusion 
and immediately afterward.  Infusion-related reactions should be treated as per 
institutional guidelines.  In the event that a participant experiences an infusion-related 
reaction, the infusion should be halted.
5.1.2.2
Radiation Risk
[18F]GTP1 and amyloid PET radioligands, similar to other radiopharmaceuticals, 
contribute to a patient’s overall long-term cumulative radiation exposure.  Long-term 
cumulative radiation exposure is associated with an increased risk of cancer.  Safe 
handling of [18F]GTP1 and amyloid PET radioligands should be ensured to protect 
patients and health care workers from unintentional radiation exposure.
Radiation exposure for [18F]GTP1 radioligand doses can be found in the [18F]GTP1 
Investigator’s Brochure.  Radiation exposure for the amyloid tracers can be found in 
the local labeling instructions or, depending on locality, the Investigator’s Brochures.  
See the local labeling instructions or, depending on locality, the Investigator’s Brochure, 
in addition to consulting with the local PET imaging center for additional radiation 
exposure due to potential head computed tomography (attenuation correction) scans 
acquired in conjunction with PET imaging.
Refer to local guidelines for recommended annual radiation exposure.
5.1.3
Management of Patients Who Experience Specific Adverse 
Events
5.1.3.1
Treatment Interruption
MTAU9937A (or placebo) treatment may be temporarily suspended in patients who 
experience toxicity considered to be related to study drug.  If more than two doses of 
MTAU9937A (or placebo) have been withheld because of toxicity, the patient should be 
discontinued from MTAU9937A (or placebo), unless resumption of treatment is approved 
following investigator discussion with the Medical Monitor. 


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MTAU9937A (or placebo) treatment may be suspended for reasons other than toxicity 
(e.g., surgical procedures) with Medical Monitor approval.  The investigator and the 
Medical Monitor will determine the acceptable length of treatment interruption.
5.1.3.2
Management Guidelines for Infusion-Related Reactions
In the event that a participant experiences a mild infusion-related reaction, the infusion 
may be halted.  Once the reaction has resolved, the infusion rate will be resumed at half 
of the most recently used rate (e.g., from 60 mL/hr [1.0 mL/min] to 30 mL/hr 
[0.5 mL/min]; see Section 4.3.2.1).  Patients who experience a moderate to severe 
infusion-related reaction (e.g., fever or chills) should have their infusion stopped 
immediately and should receive aggressive symptomatic treatment.  The patient should 
be monitored until all infusion-related adverse events are Grade 1 or are resolved.  The 
infusion should not be restarted before all symptoms have disappeared, and then it 
should be restarted at half the initial rate.  The infusion should not be resumed if there is 
a second occurrence at the same visit or if the patient experiences any of the following:  
mucosal tissue involvement, airway compromise, or symptomatic hypotension with 
systolic blood pressure 90 mmHg measured in the supine position.  In the case of any 
serious or severe infusion-related reaction, the investigator must discuss with the 
Medical Monitor whether to continue study drug treatment (see Section 4.3.2.1 for 
further details).
In the event of an infusion-related reaction, unscheduled ADA and PK serum samples 
should be collected at the following three timepoints:  as close to investigator-determined 
onset of the event as feasible, at investigator-determined resolution of the event, and 
30 days after the resolution of the event.
For patients who experience a serious or severe hypersensitivity or hypersensitivity-like 
reaction (e.g., hypotension, mucosal involvement), the investigator must discuss with the 
Medical Monitor whether to continue study drug treatment (see Section 4.3.2.1 for 
further details).
5.1.3.3
Management of Increases in QT Interval
Study drug should be discontinued in patients who develop any of the following, unless 
there is a clear alternative cause for the changes:

Sustained (at least two ECG measurements 30 minutes apart) QTcF that is 
500 ms and 60 ms longer than the baseline value

Sustained absolute QTcF that is 515 ms 

An episode of torsades de pointes or a new ECG finding of clinical concern
Of note, if there is a new intraventricular conduction block, the increase in QRS complex 
duration should be subtracted from the QTcF change, because this represents an 
increase in QTcF unrelated to alterations in repolarization.  Also of note, it is not 
uncommon to record arrhythmias such as non-sustained ventricular tachycardia, 


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supraventricular tachycardia, pauses, or atrial fibrillation in HVs receiving placebo during 
periods of extended ECG monitoring.  Therefore, it is critical that expert cardiology 
advice be sought to confirm any ECG changes and to ascertain the likelihood of a 
drug-induced arrhythmia versus the background occurrence of this arrhythmia.  In such 
a situation, saving all available ECG data is highly suggested.
Management of patients with sustained QTcF prolongation should include close 
monitoring, with ECGs repeated at least hourly until two successive ECGs show 
resolution of the findings, correction of any electrolyte abnormalities, and possible 
discontinuation of other concomitant medications that are known to prolong the QT 
interval.  Consultation with a cardiologist or electrophysiologist is recommended, to help 
in the management of such patients.
In rare circumstances, it may be acceptable to resume study drug, at a lower dose, 
provided that any ECG abnormalities have resolved and the patient is appropriately 
monitored.  Clinical judgment should be applied.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.3.5.9 and 
Section 5.3.5.10 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline


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
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug or [18F]GTP1 radioligand or an amyloid 
radioligand

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug or [18F]GTP1 radioligand or an amyloid radioligand

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events; see Section 5.3.3); 
the event itself may be of relatively minor medical significance (such as severe 
headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).


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5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.3.5.7)

Suspected transmission of an infectious agent by the study drug or [18F]GTP1
radioligand, 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 or [18F]GTP1 radioligand is suspected.

Treatment-emergent clinically significant MRI abnormalities (see Section 5.1.1.2)

Severe (Grade 3) infusion-related reactions
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.45.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.
After informed consent has been obtained but prior to initiation of study drug 
(MTAU9937A or placebo, or [18F]GTP1 radioligand or an amyloid radioligand), only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).


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After initiation of study drug or [18F]GTP1 radioligand or an amyloid radioligand, 
all adverse events will be reported until 12 weeks after the final dose of study drug or 
4 days after the final dose of [18F]GTP1 radioligand or an amyloid radioligand, whichever 
is longer. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?" 
5.3.3
Assessment of Severity of Adverse Events
The WHO toxicity grading scale (see Appendix 7) will be used for assessing adverse 
event severity.  Table 3 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale.
Table 3
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in WHO Toxicity Grading Scale
Grade
Severity
1
Mild; transient or mild discomfort (48 hours); no medical intervention or 
therapy require
2
Moderate; mild to moderate limitation in activity; some assistance may be 
needed; no or minimal medical intervention or therapy required
3
Severe; marked limitation in activity; some assistance usually required; 
medical intervention or therapy required; hospitalization possible
4
Life-threatening; extreme limitation in activity; significant assistance required; 
significant medical intervention or therapy required, hospitalization or hospice 
care probable
Notes:  Developed by the Division of Microbiology and Infectious Diseases.
Regardless of severity, some events may also meet seriousness criteria.  Refer to definition of a 
serious adverse event (see 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 an 
adverse event is considered to be related to the study drug or [18F]GTP1 radioligand or 
an amyloid radioligand (if [18F]GTP1 radioligand or the amyloid radioligand is considered 
to be an IMP), indicating "yes" or "no" accordingly.  The following guidance should be 
taken into consideration (see also Table 4):

Temporal relationship of event onset to the initiation of study drug or [18F]GTP1 
radioligand or an amyloid radioligand

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug or reintroduction of study drug (as applicable)

Known association of the event with the study drug, [18F]GTP1 radioligand or an 
amyloid radioligand, 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 4
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug or [18F]GTP1 radioligand or an 
amyloid radioligand 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 or [18F]GTP1 radioligand or an amyloid radioligand, 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 or [18F]GTP1 radioligand or an amyloid radioligand; and/or 
the adverse event abates or resolves upon discontinuation of the study drug or 
[18F]GTP1 radioligand or an amyloid radioligand or dose reduction and, if applicable, 
reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug or 
[18F]GTP1 radioligand or an amyloid radioligand (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 or 
[18F]GTP1 radioligand or an amyloid radioligand (e.g., cancer diagnosed 2 days after 
first dose of study drug or [18F]GTP1 radioligand or an amyloid radioligand).


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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. Causality assessment for [18F]GTP1 radioligand or an 
amyloid radioligand is only applicable for events within 4 days after radioligand 
exposure, as per the adverse event reporting period for radioligands defined in
Section 5.3.1.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Infusion-Related Reactions
Adverse events that occur during or within 24 hours after administration of study drug or 
[18F]GTP1 radioligand or an amyloid radioligand and are judged to be related to study 
drug infusion or [18F]GTP1 radioligand or an amyloid radioligand should be captured as a 
diagnosis (e.g., “infusion-related reaction” or “anaphylactic reaction”) on the Adverse 
Event eCRF.  If possible, avoid ambiguous terms such as “systemic reaction.”  
Associated signs and symptoms should be recorded on the dedicated Infusion-Related 
Reaction eCRF.  If a patient experiences both a local and systemic reaction to the same 
dose of study drug, [18F]GTP1 radioligand, or an amyloid radioligand infusion, each 
reaction should be recorded separately on the Adverse Event eCRF with signs and 
symptoms recorded separately on the dedicated Infusion-Related Reaction eCRF. 
5.3.5.2
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.


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
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  Details regarding any increases in severity will be captured on the Adverse 
Event Intensity or Grade Changes eCRF.  If the event becomes serious, it should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning that the 
event became serious; see Section 5.4.2 for reporting instructions).  The Adverse Event 
eCRF should be updated by changing the event from "non-serious" to "serious," 
providing the date that the event became serious, and completing all data fields related 
to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 


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It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5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 whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).


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5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.4.2).
5.3.5.8
Deaths
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.3.1), regardless of relationship to study drug or [18F]GTP1 radioligand or 
an amyloid radioligand, must be recorded on the Adverse Event eCRF and immediately 
reported to the Sponsor (see Section 5.4.2).  This includes death attributed to 
progression of AD.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of AD, "Alzheimer’s Disease progression" should 
be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.


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5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.10
Lack of Efficacy or Worsening of Alzheimer’s Disease
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as adverse events.  These data will be 
captured as efficacy assessment data only.  In most cases, the expected pattern of 
progression will be based on decline in clinical efficacy measures.  In rare cases, the 
determination of clinical progression will be based on symptomatic deterioration.  
However, every effort should be made to document progression through use of objective 
criteria.  If there is any uncertainty as to whether an event is due to disease progression, 
it should be reported as an adverse event.
5.3.5.11
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours


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5.3.5.12
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For 
MTAU9937A (or matching placebo), [18F]GTP1 radioligand, and amyloid radioligand 
adverse events associated with special situations should be recorded as described 
below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.
In addition, all special situations associated with MTAU9937A (or matching placebo), 
[18F]GTP1 radioligand, and amyloid radioligand, regardless of whether they result in an 
adverse event, should be recorded on the Adverse Event eCRF as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.


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As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.13
Clinical Outcome Assessment Data
Adverse event reports will not be derived from COA data by the Sponsor, and safety 
analyses will not be performed using COA data, except for the C-SSRS.  If any 
responses suggestive of a possible adverse event are identified during administration of 
the C-SSRS, the investigator will determine whether the criteria for an adverse event 
have been met, and if so, will report the event on the Adverse Event eCRF.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug or [18F]GTP1 radioligand or an 
amyloid radioligand:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC.


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5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Primary Medical Monitor:
, M.D. (IQVIA North America 
and Latin America)
Telephone Nos.:
United States: 
International: 
Secondary Medical Monitor:
, M.D., Ph.D. 
(Genentech North America)
Telephone No.:
IQVIA Emergency Medical Contact Telephone Nos.:
 or 
 (United States)
Alternate Medical Monitor contact information: 
Medical Monitor supporting E.U. sites:
, M.D. (IQVIA Slovakia)
Telephone Nos.:
Office: 
Mobile: 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Initiation of Study Drug or 
[18F]GTP1 Radioligand or an Amyloid Radioligand 
After informed consent has been obtained but prior to initiation of study drug or 
[18F]GTP1 radioligand or an amyloid radioligand, only serious adverse events caused by 
a protocol-mandated intervention should be reported.  The paper Clinical Trial Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form provided to 
investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), by scanning and 
emailing the form using the email address provided below:
Email address:
GenentechEDC@IQVIA.com
5.4.2.2
Events That Occur after Initiation of Study Drug or [18F]GTP1 
Radioligand or an Amyloid Radioligand 
After initiation of study drug or [18F]GTP1 radioligand or an amyloid radioligand, 
serious adverse events and adverse events of special interest will be reported until 
12 weeks after the final dose of study drug or 4 days after the final dose of [18F]GTP1 
radioligand or an amyloid radioligand, whichever is longer.  Investigators should record 
all case details that can be gathered immediately (i.e., within 24 hours after learning of 
the event) on the Adverse Event eCRF and submit the report via the electronic data 
capture (EDC) system.  A report will be generated and sent to Safety Risk Management 
by the EDC system.


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In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), by scanning and emailing the form using the 
email address provided in Section 5.4.2.1.  Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system.
Instructions for reporting serious adverse events that occur 12 weeks after the final 
dose of study treatment or 4 days after the final dose of [18F]GTP1 radioligand or an 
amyloid radioligand, whichever is longer, are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 9 weeks after the final 
dose of study drug or 4 days after the final dose of [18F]GTP1 radioligand or an amyloid 
radioligand, whichever is longer.  A paper Clinical Trial Pregnancy Reporting Form 
should be completed and submitted to the Sponsor or its designee immediately (i.e., no 
more than 24 hours after learning of the pregnancy), by scanning and emailing the form 
using the email address provided in Section 5.4.2.1.  Pregnancy should not be recorded 
on the Adverse Event eCRF.  The investigator should discontinue study drug and 
counsel the patient, discussing the risks of the pregnancy and the possible effects on the 
fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  Any 
serious adverse events associated with the pregnancy (e.g., an event in the fetus, an 
event in the mother during or after the pregnancy, or a congenital anomaly/birth defect in 
the child) should be reported on the Adverse Event eCRF.  In addition, the investigator 
will submit a paper Clinical Trial Pregnancy Reporting Form when updated information 
on the course and outcome of the pregnancy becomes available.  
5.4.3.2
Pregnancies in Female Partners of Male Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
9 weeks after the final dose of study drug or 4 days after the final dose of [18F]GTP1 
radioligand or an amyloid radioligand, whichever is longer.  A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), by 
scanning and emailing the form using the email address provided in Section 5.4.2.1.  
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male patient exposed to study drug.  When permitted by 
the site, the pregnant partner would need to sign an Authorization for Use and 
Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If after the authorization has been signed, the investigator would submit a paper Clinical 
Trial Pregnancy Reporting Form when updated information on the course and outcome 
of the pregnancy becomes available.  An investigator who is contacted by the male 


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patient or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician.
5.4.3.3
Congenital Anomalies/Birth Defects and Abortions
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or [18F]GTP1 radioligand or an amyloid radioligand or the female partner of a male 
patient exposed to study drug or [18F]GTP1 radioligand or an amyloid radioligand 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).
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2).
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity 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).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.
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 [18F]GTP1 radioligand or 
an amyloid radioligand or trial-related procedures until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.


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5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, the
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
12 weeks after the final dose of study drug or 4 days after the final dose of [18F]GTP1 
radioligand or an amyloid radioligand, whichever is longer), if the event is believed to be 
related to prior study drug or [18F]GTP1 radioligand or an amyloid radioligand treatment.  
If a patient discontinues the study due to an adverse event after 12 weeks after the final 
dose of study drug or after 4 days after the final dose of [18F]GTP1 radioligand or an 
amyloid radioligand, whichever is longer, the adverse event(s) leading to study 
discontinuation should be reported.  These events should be reported through use of the 
Adverse Event eCRF.  However, if the EDC system is not available, the investigator 
should report these events directly to the Sponsor or its designee, either by faxing or by 
scanning and emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or email address provided to 
investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

MTAU9937A Investigator's Brochure 

[18F]GTP1 Investigator's Brochure

Investigator’s Brochure or prescribing information for specific amyloid radioligand 
used 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.


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Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The efficacy analyses will be based on the modified intent-to-treat population, which is 
defined as all randomized patients who receive at least one dose of study drug and have 
at least one postbaseline ADAS-Cog11 and/or ADCS-ADL measurement.  For the 
efficacy analysis, patients will be grouped according to the treatment assigned at 
randomization.
The safety analysis will be based on all randomized patients who receive at least one 
dose of either MTAU9937A or placebo.  Patients will be grouped according to 
MTAU9937A treatment actually received.

A primary analysis will occur after the last patient has completed the assessments 
for the last visit of the double-blind treatment period (Week 49 for Cohort 1 or
Week 61 for Cohort 2). 

A final analysis will occur after the last patient has completed the OLE and 
completed the assessments for the last visit of the OLE period (Week 145 for Cohort 
1 or Week 157 for Cohort 2).
6.1
DETERMINATION OF SAMPLE SIZE
This study will enroll approximately 260 patients randomized to either an IV active dose 
arm or to an IV placebo dose arm in a 1:1 ratio.  This sample size provides 
approximately 80% power to detect a 35% relative reduction in mean ADAS-Cog11 
change from baseline when MTAU9937A is compared with placebo assuming an 
average decline of 6 points for placebo-treated patients, a standard deviation across 
patients of 7.5, a 10% dropout rate, and a two-sided 0.2 significance level.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue (early discontinuation of treatment or 
early termination from the study), complete the double-blind treatment period (through 
Week 49 for Cohort 1 or Week 61 for Cohort 2), and continue into the OLE 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 major 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 score will be summarized with means, standard deviations, medians, 
and ranges for continuous variables and with frequencies and proportions for categorical 
variables, as appropriate.  Summaries will be presented by treatment arm and overall. 


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6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoints
The co-primary efficacy endpoints are change in ADAS-Cog11 and ADCS-ADL scores 
from baseline to the last visit of the double-blind treatment period (Week 49 for Cohort 1
or Week 61 for Cohort 2).  The difference in mean change from baseline to the last visit 
of the double-blind treatment period between MTAU9937A- and placebo-treated patients 
will be estimated using an analysis of covariance model adjusting for ApoE4 status 
(ApoE4+ vs. ApoE4), screening MMSE (1618 vs. 1921), baseline [18F]GTP1 PET 
standard uptake value ratio, age, baseline ADAS-Cog11 or ADCS-ADL scores, and if 
appropriate, the number of missed study drug infusions during the double-blind 
treatment period due to the COVID-19 pandemic.  Confidence intervals, as well as least 
squares estimates, will be used to aid in interpretation of study results.
6.4.2
Secondary Efficacy Endpoints
The secondary endpoints are change in CDR-SB and MMSE scores from baseline to the 
last visit of the double-blind treatment period (Week 49 for Cohort 1 or Week 61 for 
Cohort 2).  Secondary efficacy endpoints will be analyzed in the same manner as the 
primary endpoint.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of either MTAU9937A or placebo, or GTP1, with patients grouped 
according to treatment arm.  Patients will be analyzed according to actual MTAU9937A 
treatment received.
All adverse events that occur after informed consent is given will be summarized by 
mapped term, appropriate thesaurus level, and toxicity grade.  In addition, all serious 
adverse events, including deaths and events leading to discontinuation, will be listed 
separately and summarized.
Laboratory data will be summarized by descriptive statistics by treatment group.  
In addition, all laboratory abnormalities will be summarized by grade using the WHO 
grading scale. 
Adverse events of special interest and neuroimaging abnormalities will be listed and 
summarized by treatment group.
Vital signs (pulse rate, blood pressure, body temperature, and respiratory rate), weight, 
and other disease-specific data will be summarized by descriptive statistics by treatment 
group.  Changes from baseline will be summarized by treatment group.
Detailed statistical methods will be outlined in the Data Analysis Plan. 


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6.6
PHARMACOKINETIC ANALYSES
Individual and mean serum MTAU9937A concentrationtime data will be tabulated and 
plotted by treatment group and/or cohort, as appropriate, and Cmax and minimal 
concentration will be reported.  Estimates for PK parameters will be tabulated and 
summarized by descriptive statistics (e.g., mean, standard deviation, minimum, 
and maximum) for patients completing the study without missed doses, as appropriate.  
Individual and mean MTAU9937A CSF concentration–time data will be tabulated by 
treatment group.  Additional PK analyses will be conducted as appropriate.
6.7
IMMUNOGENICITY ANALYSES
Baseline prevalence and postbaseline incidence of ADA to MTAU9937A will be 
summarized.  ADA response and potential effect of ADA response to relevant clinical 
safety and activity endpoints will be assessed for evaluable patients.
The immunogenicity analyses will include patients with at least one predose and one 
postdose ADA assessment, with patients grouped according to treatment arm.
The number and proportion of ADA-positive patients and ADA-negative patients during 
both the treatment and follow-up period will be summarized by treatment group.  
Patients are considered to have treatment-emergent ADAs if they are ADA negative at 
baseline but develop an ADA response following study drug administration, or if they are 
ADA positive at baseline and the titer of one or more postbaseline samples is at least 
4-fold greater (i.e., 0.60 titer unit) than the titer of the baseline sample.  Patients are 
considered to be ADA negative if they are ADA negative at baseline and all postbaseline 
samples are negative or treatment unaffected if they are ADA positive at baseline but do 
not have any postbaseline samples with a titer that is at least 4-fold greater than the titer 
of the baseline sample.
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported via descriptive statistics.
6.8
BIOMARKER ANALYSES
Exploratory analyses will be conducted to evaluate the effect of MTAU9937A on 
exploratory biomarkers such as those listed in Section 2.5.  Exploratory biomarkers may 
be analyzed before and after dosing with MTAU9937A to determine the relationship 
between PK exposure and exploratory biomarker levels.  In addition, relationships
amongst biomarkers may be assessed.
WGS and SNP data will be analyzed in the context of this study and explored in 
aggregate with data from other studies to increase researchers’ understanding of 
disease pathobiology and guide the development of new therapeutic approaches.


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6.9
INTERIM ANALYSES
6.9.1
Optional Interim Analysis
Given the hypothesis generating nature of this study, the Sponsor may conduct up to 
two interim analyses of efficacy.  The decision to conduct such an interim analysis and 
its timing will be documented in the Sponsor’s study master file prior to the conduct of 
the interim analysis.  The Clinical Study Report will also document that such an interim 
analysis occurred.  The interim analysis, should it occur, will be performed and 
interpreted by members of the Sponsor study team and management who would then be 
unblinded to treatment group (MTAU9937A or placebo).
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data, imaging data, 
sample information, and sample analysis data as well as COA data listed in Table 2
(see Section 4.5.7) will be sent directly to the Sponsor, using the Sponsor’s standard 
procedures to handle and process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required.


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7.3
ELECTRONIC CLINICIAN-REPORTED OUTCOME DATA
An electronic device will be used to capture COA data.  The device is designed for entry 
of data in a way that is attributable, secure, and accurate, in compliance with FDA 
regulations for electronic records (21 CFR Part 11).  The data will be transmitted to a 
centralized database maintained by the electronic device vendor.
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor’s standard procedures.
Once the study is complete, MedAvante-Prophase will generate PDF files of all 
assessments grouped by patient for each site.  The PDF files, audio-recorded study 
interviews, site queries, and study audit trail will be stored and transferred to Sponsor as 
defined in the data transfer specification.  The investigator will receive patient data for 
the site in a password-protected, machine-readable format that must be kept with the 
study records as source data.  Sites should extract the data as soon as possible after 
receiving it. Acknowledgement of receipt of the data is required.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.


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Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change.
7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper COA data (if applicable), Informed Consent 
Forms, laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for 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.
The Sponsor will retain study data for 25 years after the final Clinical Study Report has 
been completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 


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Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws.
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as Early Screening or Caregiver Informed Consent Form, if applicable) will 
be provided to each site.  If applicable, it will be provided in a certified translation of the 
local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/ECapproved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient and/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 and/or their legally authorized representative 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.


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A copy of each signed Consent Form must be provided to the patient and/or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient 
and/or their legally authorized representative, unless permitted or required by law.


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Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Roche policy on study data publication 
(see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  
In addition, redacted clinical study reports and other summary reports will be provided
upon request.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct 
of the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 


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policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This study will be sponsored and managed by Genentech, Inc., a member of the Roche 
group.  The Sponsor will provide clinical operations management, data management, 
and medical monitoring oversight.  A CRO will provide study and site management, 
medical and site monitoring, along with safety reporting support.  Overall procedures for 
quality assurance of clinical study data are described in the Roche and CRO standard 
operating procedures. 
Approximately 50 sites globally will participate to enroll approximately 260 patients.  
Randomization and drug distribution will occur through an IxRS system.  EDC will be 
used for data collection. 
Central facilities will be used for certain study assessments throughout the study 
(e.g., COAs, imaging, LP, specified laboratory tests, biomarker and PK analyses), as 
specified in Section 4.5.
An IMC will be employed to monitor and evaluate patient safety throughout the study.
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Trials 
Data at the following web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf


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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
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Appendix 1
Cohort 1 Schedule of Activities
Assessment
SRN 
Days 56 
to 1
Double-Blind Treatment Period
Move to OLE, 
if applicable
Safety 
Follow-Upa Unplanned 
Visitb
Tx 
DCa
Infusion/Dose Number
Baseline c
1
2
3
4
5
6
7
8
9
10
11
12
13




Week
1 
3 d
5 
9
13
17
21
25
29
33
37
41
45
49 e
57


(Visit window in days)
(3) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5)
(7)

(7)
Informed consent
x f
See Appendix 2 for OLE, if patient continues
Medical history, AD history, 
personal status, and 
demographics g
x
MMSE h
x
x
x
x
x
x i
CDR h
x
x
x
x
x
x i
Diagnostic verification h
x
ADAS-Cog11 h
x
x
x
x
x
x
x i
ADCS-ADL h
x
x
x
x
x
x
x i
NPI h
x
x
x
x
x i
CaGI-Alz h
x
x
x
x i
C-SSRS h
x
x
x
x
x
x
x
x
x
Vital signs j
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x i
Weight
x
x
x
x
x
x
Height
x
Complete physical examination k
x
x
x
x
x
Limited physical examination l
x 
x
x
x
x
Neurologic examination
x
x
x
x
x
x
x
x
x
x
MRI m
x
x
x
x i
Amyloid PET m, n
x


Appendix 1: Cohort 1 Schedule of Activities
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Assessment
SRN 
Days 56 
to 1
Double-Blind Treatment Period
Move to OLE, 
if applicable
Safety 
Follow-Upa Unplanned 
Visitb
Tx 
DCa
Infusion/Dose Number
Baseline c
1
2
3
4
5
6
7
8
9
10
11
12
13




Week
1 
3 d
5 
9
13
17
21
25
29
33
37
41
45
49 e
57


(Visit window in days)
(3) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5)
(7)

(7)
[18F]GTP1 PET m
x
x
See Appendix 2 for OLE, if patient continues
x i
ECG o
x p
x
x
x
x i
Hematology q
x p
x
x
x
x
x
x
x
x
Chemistry, lipids, coagulation r
x p
x
x
x
x
x
x
x
x
HbA1c, B12, folic acid, TSH, T4
x p
Viral serology s
x p
Pregnancy test t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis u
x p
x
x
x
x
x
x
x
Study drug administration
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK sample v
x
x
x
x 
x 
x 
x
x 
x i
Serum ADA sample v, w
x
x
x
x
x
x i
Blood sample for APOE
x
Blood sample for WGS/SNP x
x
Blood sample for biomarkers v
x 
x
x
x
x
x
x
x
x i
CSF sample for PK and 
biomarkers (if applicable) n
x
x y
x
x i
Concomitant medications z
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events aa
x aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x aa


Appendix 1: Cohort 1 Schedule of Activities
MTAU9937A—Genentech, Inc.
111/Protocol GN40040, Version 5
[18F]GTP1fluorine-18 Genentech tau probe 1; A-amyloid; ADAlzheimer’s disease; ADAanti-drug antibody; ADAS-Cog11Alzheimer’s 
Disease Assessment ScaleCognitive Subscale, 11-item version; ADCS-ADLAlzheimer’s Disease Cooperative Study–Activities of Daily Living 
Inventory; C-SSRSColumbia-Suicide Severity Rating Scale; CaGI-AlzCaregiver Global Impression Scales for Alzheimer’s disease; 
CDRClinical Dementia Rating; COAclinical outcome assessment; CSFcerebrospinal fluid; DCdiscontinuation; DVFDiagnostic 
Verification Form; eCRFelectronic Case Report Form; HbA1chemoglobin A1c; HBsAghepatitis B surface antigen; HCVhepatitis C virus;
LPlumbar puncture; MMSEMini-Mental State Examination; MRImagnetic resonance imaging; NPINeuropsychiatric Inventory; 
OLEopen-label extension; PET positron emission tomography; PK=pharmacokinetic; SNPsingle nucleotide polymorphism; SRNscreening; 
T4thyroxine; TSHthyroid-stimulating hormone; Tx treatment; WGSwhole genome sequencing. 
Notes:  All postbaseline study visits must be scheduled in reference to the first dosing day (Week 1 visit).  All activities/assessments in a given 
study visit must be performed within 5 days of the scheduled visit, unless otherwise specified (e.g., [18F]GTP1 PET scans).  On study drug 
administration visits that span multiple days, study drug administration must occur on the last day.
On study drug administration days:
-  All assessments must be performed prior to dosing, unless otherwise specified
-  Pre-infusion laboratory samples should be drawn 0–4 hours before the start of infusion, unless otherwise specified
-  Post-infusion laboratory samples should be drawn 030 minutes after the end of infusion, unless otherwise specified
During the COVID-19 pandemic, study visit activities, excluding imaging assessments, can be performed in the patient’s home or in an approved 
alternate location.  Selected COAs can be administered remotely (by telephone or video call), as outlined in the Study GN40040 remote COA 
administration guidance.  Deviations from the schedule of activities will be documented as COVID-19related protocol deviations.
a Patients who complete the double-blind treatment period and who do not enroll into the OLE treatment period will return to the clinic for a 
treatment completion visit (safety follow-up) at Week 57 (7 days).  Patients who discontinue study drug (MTAU9937A or placebo) prematurely 
in the double-blind treatment period will return to the clinic for a treatment discontinuation visit 12 weeks (7 days) after the final dose of 
study drug.
b Visit not specified by the protocol.  Additional assessments (possibly including PK sample collection) should be performed as clinically 
indicated.  Patients who miss study drug infusions during the double-blind treatment period for reasons related to the COVID-19 pandemic may 
have additional COAs administered remotely (by telephone or video call) at the time of the first missed infusion and at the time when in-clinic 
study drug infusions resume. Refer to the Study GN40040 COA Manual and remote COA administration guidance for specific COA 
assessments to be administered and order of administration.


Appendix 1: Cohort 1 Schedule of Activities
MTAU9937A—Genentech, Inc.
112/Protocol GN40040, Version 5
c The baseline visit period must begin after enrollment (randomization) and may be split over multiple visit days; the first and last visit days of the 
baseline period must be separated by no more than 14 days from each other (e.g., the baseline visit period may start on a Monday and end on 
the Monday 2 weeks later).  All COA assessments during the baseline visit period should be performed as close to the last visit day of the 
baseline period as possible.  COA assessments, [18F]GTP1 PET scan, and LP from the baseline visit period may be performed on the same 
day that study drug is first administered (on the Week 1 visit), but they must be performed prior to dosing.  All activities specified for the Week 1 
visit (the first dosing visit) must be performed on the same day and must occur no later than 15 days after the baseline visit period begins 
(e.g., if the first baseline visit period day is a Monday, then the first dosing of study drug must occur no later than the Tuesday 2 weeks later).  
Extensions to the 15-day baseline visit period (e.g., to complete [18F]GTP1 PET imaging) may be granted on a case-by-case basis by the 
Medical Monitor.
d At this visit, all activities/assessments must be performed within 3 days of the scheduled visit.
e At Week 49, patients will move to OLE or will be scheduled for a treatment completion visit (safety follow-up).
f
Informed consent must be documented before any study-specific screening procedure is performed.  Informed consent with the Early 
Screening Informed Consent Form permits MMSE, medical history, AD history, personal status, and demographics.  Informed consent with the 
main Informed Consent Form is required for all other study-specific screening procedures.
g Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures); reproductive 
status; smoking history; use of alcohol and drugs of abuse; recent history (5 years) of non-elective hospitalizations, pneumonia or 
cardiovascular events; lifetime use of any A-targeting therapies; and all medications (e.g., prescription drugs, over-the-counter drugs, 
vaccines, herbal/homeopathic remedies, nutritional supplements) used by the patient within 3 months prior to the initiation of screening.  
Demographics include age, sex, self-reported race/ethnicity (as permitted by local regulations), handedness, and years of education.  
Demographics of caregiver will also be collected with exception of handedness.
h Refer to the Study GN40040 COA Manual for instructions on COA administration order, specification of list versions to use at each visit, rater 
roles, restrictions on raters, and additional details on COA administration and the endpoint reliability program.  At all visits, all COA 
questionnaires/scales (excluding the DVF) will be rater administered before the patient, rater, or caregiver receives any information on disease 
status, prior to LPs scheduled in the visit, and prior to the administration of study drug.  In addition, on any given day when COAs are 
performed, all COAs (with the exception of the DVF and the C-SSRS) must be performed prior to non-COA assessments, study drug, and 
[18F]GTP1 radioligand or amyloid radioligand unless otherwise specified.  For details on permitted concomitant medication use prior to COA 
assessments, see Section 4.1.2.
i
Only perform assessment if discontinuation visit is ≥16 weeks after last assessment for this instrument or procedure.  However, if the patient 
discontinues study drug because of an infusion-related reaction, concurrent ADA and PK samples will also be collected at 12 weeks after the 
final administration of the study drug.  An [18F]GTP1 scan should only be performed if at least 24 weeks has elapsed since any previous 
[18F]GTP1 scan and local annual radiation limits have not been exceeded.


Appendix 1: Cohort 1 Schedule of Activities
MTAU9937A—Genentech, Inc.
113/Protocol GN40040, Version 5
j
Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Vital 
sign assessments should be performed just prior to study drug administration.  On study drug treatment visits, vital signs should be collected 
04 hours prior to infusion and 6090 minutes after completion of infusion.  Vital signs should also be assessed within 1 hour prior to injection 
of [18F]GTP1 or initiation of the LP procedure and within 1 hour after injection of [18F]GTP1 or the completion of the LP procedure.  Record 
abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or 
worsened clinically significant abnormalities on the Adverse Event eCRF.
k Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, respiratory, and gastrointestinal systems.  
In addition, the musculoskeletal and genitourinary systems should be examined as clinically indicated.  Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
l
Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.
m If MRI, amyloid PET, or [18F]GTP1 PET scan occurs at the same visit as COAs, neuroimaging must be performed after administration of COAs 
(with the exception of the DVF and the C-SSRS).  Only one PET scan should be performed on a given day.  Postbaseline [18F]GTP1 PET 
scans should be performed 14 days of the scheduled visit; however, extensions to [18F]GTP1 PET scan windows may be granted on a 
case-by-case basis by the Medical Monitor.  Week 49 visit or treatment discontinuation visit [18F]GTP1 PET scan dates may be coordinated by 
the [18F]GTP1 distribution network on the basis of tracer availability and may be scheduled outside the 14-day window around the scheduled 
visit if appropriate extenuating circumstances arise. If, at any time, local restrictions for radiation exposure disallow performing a [18F]GTP1 
PET scan within this window, the site should contact the Sponsor to discuss alternative timing.  The MRI should be performed and assessed 
locally and in real time prior to any study drug dosing at the corresponding study visit.  Study drug should be withheld if there are clinically 
significant new or clinically significant worsened MRI abnormalities identified in the local MRI interpretation.  However, if no such abnormalities 
are identified, the dose may be given prior to receipt of the central MRI report (see Section 5.1.1.2).  During the COVID-19 pandemic, if an MRI 
cannot be obtained, the patient should be monitored for any signs or symptoms suggestive of new, clinically significant neurologic 
abnormalities.  If no new, clinically significant abnormalities are observed, study drug may be administered without an MRI, but a subsequent 
unscheduled study-associated MRI should be obtained as local conditions allow.  If new, clinically significant neurologic abnormalities are 
observed, study drug should be withheld and the patient should be referred for appropriate follow-up and medical treatment, including, if 
appropriate, an MRI.


Appendix 1: Cohort 1 Schedule of Activities
MTAU9937A—Genentech, Inc.
114/Protocol GN40040, Version 5
n If an amyloid PET scan is used to confirm amyloid positive eligibility, an LP will not need to be performed as part of screening.  If an LP is 
performed at screening to confirm eligibility, an amyloid PET scan is not needed.  If a patient is amyloid negative based on one of the two 
modalities (CSF assessment or amyloid PET), then the patient may undergo assessment with the other modality during screening; amyloid 
positivity by either modality is sufficient for eligibility (see Section 4.5.8).  All subsequent LPs are optional for exploratory CSF biomarker 
collection.
o On the day of the first administration of study drug, ECGs should be performed 04 hours before the start of infusion and 030 minutes after 
the end of infusion.  Week 5 ECGs should be performed 030 minutes after the end of infusion.  All ECGs are to be obtained prior to other 
procedures scheduled at that same time (e.g., vital sign measurements, blood draws).
p Results obtained prior to obtaining informed consent and within 90 days prior to the start of screening may be used; such tests do not need to 
be repeated for screening.
q Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (absolute counts of neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, and other cells).
r
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, magnesium, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, 
ALT, AST, gamma glutamyl transpeptidase, and creatine kinase.  Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides.  Coagulation panel includes INR, aPTT, and PT; the coagulation panel should be measured at screening and within 90 days prior 
to any LP or within an interval consistent with the local standard of care, whichever is shorter. If required per local standard of care, additional 
coagulation panel tests may be performed at central laboratory or at a local laboratory.  For patients taking multiple anti-platelet medications, 
the investigator should determine (per local standards of care) whether the temporary discontinuation of one or more anti-platelet medications 
prior to LP is warranted (e.g., continuing aspirin and discontinuing thienopyridine derivatives for 12 weeks prior to LP).
s Viral serology panel includes HIV, HBsAg, total hepatitis B core antibody, and HCV antibody.
t
All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at baseline and 
specified subsequent visits prior to dosing.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Pregnancy 
tests must be negative prior to dosing with study drug or [18F]GTP1.
u Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood).  Microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria) should be performed if the dipstick is abnormal.
v Serum PK samples should be taken 04 hours before the start of infusion and 030 minutes after the end of infusion.  Serum ADA and blood 
biomarker samples should be taken 04 hours before the start of infusion.


Appendix 1: Cohort 1 Schedule of Activities
MTAU9937A—Genentech, Inc.
115/Protocol GN40040, Version 5
w Immunogenicity samples should be obtained prior to study drug administration to measure antibody development to MTAU9937A.  In the event 
of an infusion-related reaction, unscheduled ADA and PK serum samples should be collected at the following three timepoints:  as close to 
investigator-determined onset of the event as feasible, at investigator-determined resolution of the event, and 30 days after the resolution of the 
event.
x Not applicable for a site that has not been granted approval for WGS/SNP.
y If sample was collected at screening, baseline collection is not needed.  If a CSF sample was not collected at screening, the patient may have 
an optional CSF sample collected at baseline.  Collection should occur prior to dosing.
z Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 3 months prior to screening until the final study visit (see Section 4.5.2).  Any agent that 
targets Aused by the patient at any time during their life is also considered to be a concomitant therapy (see Section 4.4).
aa 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.  After initiation of study drug or [18F]GTP1 radioligand or amyloid radioligand, all adverse events will be 
reported until 12 weeks after the final dose of study drug or 4 days after the last dose of [18F]GTP1 or an amyloid radioligand, whichever is 
longer.  During this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior study drug or [18F]GTP1 radioligand or amyloid 
radioligand treatment (see Section 5.6).  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 [18F]GTP1 radioligand or an amyloid radioligand or 
trial-related procedures until a final outcome can be reported.


MTAU9937A—Genentech, Inc.
116/Protocol GN40040, Version 5
Appendix 2
Cohort 1 Schedule of Activities (Open-Label Extension)
Open-Label Treatment Period
Unplanned 
Visit a
Safety FU b
Tx DC b
Week 53
57 61 65 69 73 77
81 85 89 93 97 101 105 109 113 117 121 125 129 133 137 141 145

157 
Infusion/Dose Number 14 15 16 17 18 19 20 21 22 23 24 25
26
27
28
29
30
31
32
33
34
35
36
37



ADAS-Cog11 c
x
x
x
x d
ADCS-ADL c
x
x
x
x d
CDR c
x
x
x
x d
NPI c
x
x
x
x d
MMSE c
x
x
x
x d
C-SSRS c
x
x
x
x
x
x
x
x
x
x
CaGI-Alz c
x
x
x
x d
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
Complete physical 
examination f
x
x
x
x
x
x
Limited physical 
examination g
x
x
x
x
x
Neurologic examination
x
x
x
x
x
x
x
x
x
x
x
MRI h
x
x
x
x i
ECG
x j
Hematology k
x
x
x


Appendix 2: Cohort 1 Schedule of Activities (Open-Label Extension)
MTAU9937A—Genentech, Inc.
117/Protocol GN40040, Version 5
Open-Label Treatment Period
Unplanned 
Visit a
Safety FU b
Tx DC b
Week 53
57 61 65 69 73 77
81 85 89 93 97 101 105 109 113 117 121 125 129 133 137 141 145

157 
Infusion/Dose Number 14 15 16 17 18 19 20 21 22 23 24 25
26
27
28
29
30
31
32
33
34
35
36
37



Chemistry and lipids l
x
x
x
Coagulation m
x
x
Pregnancy test n
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis o
x
x
x
Study drug administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK sample p
x
Serum ADA sample p, q
x
Blood sample for 
biomarkers p
x
x
x
x d
CSF sample for PK and 
biomarkers (if applicable) r
x
x
x i
Concomitant medications s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x s
x s
Adverse events t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x t
x t
ADAanti-drug antibody; ADAS-Cog11Alzheimer’s Disease Assessment ScaleCognitive Subscale, 11-item version; ADCS-ADLAlzheimer’s 
Disease Cooperative Study Group–Activities of Daily Living Inventory; C-SSRSColumbia-Suicide Severity Rating Scale; CaGI-AlzCaregiver 
Global Impression discontinuation; eCRFelectronic Case Report Form; F/Ufollow-up; LPlumbar puncture; MMSEMini-Mental State 
Examination; MRImagnetic resonance imaging; NPINeuropsychiatric Inventory; OLEopen-label extension; PKpharmacokinetic; 
Txtreatment. 


Appendix 2: Cohort 1 Schedule of Activities (Open-Label Extension)
MTAU9937A—Genentech, Inc.
118/Protocol GN40040, Version 5
Notes:  All postbaseline study visits must be scheduled in reference to the first dosing day (Week 1 visit).  All activities/assessments in a given 
study visit must be performed within 5 days of the scheduled visit, unless otherwise specified.  On study drug administration visits that span 
multiple days, study drug administration must occur on the last day.  On study drug administration days, all assessments must be performed 
prior to dosing, unless otherwise specified. 
During the COVID-19 pandemic, study visit activities, excluding imaging assessments, can be performed in the patient’s home or in an approved 
alternate location.  Selected COAs can be administered remotely (by telephone or video call), as outlined in the Study GN40040 remote COA 
administration guidance.  Deviations from the schedule of activities will be documented as COVID-19related protocol deviations.
a Visit not specified by the protocol.  Additional assessments (possibly including PK sample collection) should be performed as clinically 
indicated.
b Patients who complete the OLE treatment period will return to the clinic for a treatment completion visit (safety follow-up) at Week 157 
(7 days).  Patients who discontinue study drug prematurely in the OLE treatment period will return to the clinic for a treatment discontinuation 
visit 12 weeks (7 days) after the final dose of study drug.
c Refer to the Study GN40040 COA Manual for instructions on COA administration order, specification of list versions to use at each visit, rater 
roles, restrictions on raters, and additional details on COA administration and the endpoint reliability program.  At all visits, all COA 
questionnaires/scales will be rater administered before the patient, rater, or caregiver receives any information on disease status, prior to LPs 
scheduled in the visit, and prior to the administration of study drug.  In addition, on any given day when COAs are performed, all COAs (with 
the exception of the C-SSRS) must be performed prior to non-COA assessments and study drug, unless otherwise specified.  For details on 
permitted concomitant medication use prior to COA assessments, see Section 4.1.2.
d Only perform assessment if discontinuation visit is 16 weeks after last assessment for this instrument.
e Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Vital 
sign assessments should be performed just prior to study drug administration.  On study drug treatment visits, vital signs should be collected 
04 hours prior to infusion and 6090 minutes after completion of infusion.  Vital signs should also be assessed within 1 hour prior to initiation 
of the LP procedure and within 1 hour after completion of the LP procedure.  Record abnormalities observed at baseline on the General 
Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF.
f
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, respiratory, and gastrointestinal systems.  
In addition, the musculoskeletal and genitourinary systems should be examined as clinically indicated.  Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
g Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF.


Appendix 2: Cohort 1 Schedule of Activities (Open-Label Extension)
MTAU9937A—Genentech, Inc.
119/Protocol GN40040, Version 5
h If MRI occurs at the same visit as COAs, neuroimaging must be performed after administration of COAs (with the exception of the C-SSRS).  
The MRI should be performed and assessed locally and in real time prior to any study drug dosing at the corresponding study visit.  Study 
drug should be withheld if there are clinically significant new or clinically significant worsened MRI abnormalities identified in the local 
interpretation.  However, if no such abnormalities are identified, the dose may be given prior to receipt of the central MRI report (see 
Section 5.1.1.2).  During the COVID-19 pandemic, if an MRI cannot be obtained, the patient should be monitored for any signs or symptoms 
suggestive of new, clinically significant neurologic abnormalities.  If no new, clinically significant abnormalities are observed, study drug may 
be administered without an MRI, but a subsequent unscheduled study-associated MRI should be obtained as local conditions allow.  If new, 
clinically significant neurologic abnormalities are observed, study drug should be withheld and the patient should be referred for appropriate 
follow-up and medical treatment, including, if appropriate, an MRI.  
i
Only perform assessment if discontinuation visit is 24 weeks after last assessment for this instrument. 
j
Perform assessment if clinically indicated.
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (absolute counts of neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).
l
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, magnesium, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, 
ALT, AST, gamma glutamyl transpeptidase, and creatine kinase.  Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides.
m Coagulation panel includes INR, aPTT, and PT; the coagulation panel should be measured within 90 days prior to any LP or within an interval 
consistent with local standard of care, whichever is shorter.  If required per local standard of care, additional coagulation panel tests may be 
performed at central laboratory or at a local laboratory.  For patients taking multiple anti-platelet medications, the investigator should 
determine (per local standards of care) whether the temporary discontinuation of one or more anti-platelet medications prior to LP is warranted 
(e.g., continuing aspirin and discontinuing thienopyridine derivatives for 12 weeks prior to LP).  The Week 145 coagulation laboratory tests 
are only applicable to patients participating in the optional CSF collection (lumbar puncture).
n For women of childbearing potential, urine pregnancy tests will be performed at specified visits prior to dosing.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test.  Pregnancy tests must be negative prior to dosing with study drug.
o Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood).  Microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria) should be performed if the dipstick is abnormal.
p Serum PK samples should be taken 04 hours before the start of infusion and 030 minutes after the end of infusion.  Serum ADA and blood 
biomarker samples should be taken 04 hours before the start of infusion.


Appendix 2: Cohort 1 Schedule of Activities (Open-Label Extension)
MTAU9937A—Genentech, Inc.
120/Protocol GN40040, Version 5
q Immunogenicity samples should be obtained prior to study drug administration to measure antibody development to MTAU9937A.  In the 
event of an infusion-related reaction, unscheduled ADA and PK serum samples should be collected at the following three timepoints:  as close 
to investigator-determined onset of the event as feasible, at investigator-determined resolution of the event, and 30 days after the resolution of 
the event.
r
All LPs in the OLE are optional for exploratory CSF biomarker collection, regardless of whether prior CSF collection has occurred.
s Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 3 months prior to screening until the final study visit (see Section 4.5.2).  Any agent 
that targets Aused by the patient at any time during their life is also considered to be a concomitant therapy (see Section 4.4).
t
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.  After initiation of study drug, all adverse events will be reported until 12 weeks after the final dose of study 
drug.  During this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the 
investigator becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).  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.


MTAU9937A—Genentech, Inc.
121/Protocol GN40040, Version 5
Appendix 3
Cohort 2 Schedule of Activities
Assessment
SRN 
Days 56 
to 1
Double-Blind Treatment Period
Move to OLE if applicable
Safety 
Follow-Up a
Unplanned 
Visit b
Supplemental 
Dose c
Tx DC a
Infusion/Dose Number
Baseline d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16





Week
1 
3 e
5 
9
13
17
21
25
29
33
37
41
45
49
53
57
61 f
69



(Visit window in days)
(3) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5)
(7)

(3) (7)
Informed consent
x g
See Appendix 4 for OLE, if patient continues
Medical history, AD history, 
personal status, and 
demographics h
x
MMSE i
x
x
x
x
x
x
x j
CDR i
x
x
x
x
x
x
x j
Diagnostic verification i
x
ADAS-Cog11 i
x
x
x
x
x
x
x
x j
ADCS-ADL i
x
x
x
x
x
x
x
x j
NPI i
x
x
x
x
x
x j
CaGI-Alz i
x
x
x
x
x j
C-SSRS i
x
x
x
x
x
x
x
x
x
x
Vital signs k
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x j
Weight
x
x
x
x
x
x
x
Height
x
Complete physical examination l
x
x
x
x
x
x
Limited physical examination m
x 
x
x
x
x
Neurologic examination
x
x
x
x
x
x
x
x
x
x
x


Appendix 3: Cohort 2 Schedule of Activities
MTAU9937A—Genentech, Inc.
122/Protocol GN40040, Version 5
Assessment
SRN 
Days 56 
to 1
Double-Blind Treatment Period
Move to OLE if applicable
Safety 
Follow-Up a
Unplanned 
Visit b
Supplemental 
Dose c
Tx DC a
Infusion/Dose Number
Baseline d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16





Week
1 
3 e
5 
9
13
17
21
25
29
33
37
41
45
49
53
57
61 f
69



(Visit window in days)
(3) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5)
(7)

(3) (7)
MRI n
x
x
x
See Appendix 4 for OLE, if patient continues
x j
Amyloid PET n, o
x
[18F]GTP1 PET n
x
x
x j
ECG p
x q
x
x
x
x j
Hematology r
x q
x
x
x
x
x
x
x
x
x
Chemistry, lipids, coagulation s
x q
x
x
x
x
x
x
x
x
x
HbA1c, B12, folic acid, TSH, T4
x q
Viral serology t
x q
Pregnancy test u
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis v
x q
x
x
x
x
x
x
x
x
Study drug administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK sample w
x
x
x
x 
x 
x 
x
x
x 
x j
Serum ADA sample w, x
x
x
x
x
x
x
x j
Blood sample for APOE
x
Blood sample for WGS/SNP y
x
Blood sample for biomarkers w
x 
x
x
x
x
x
x
x
x
x j
CSF sample for PK and 
biomarkers (if applicable) o
x
x z
x
x j


Appendix 3: Cohort 2 Schedule of Activities
MTAU9937A—Genentech, Inc.
123/Protocol GN40040, Version 5
Assessment
SRN 
Days 56 
to 1
Double-Blind Treatment Period
Move to OLE if applicable
Safety 
Follow-Up a
Unplanned 
Visit b
Supplemental 
Dose c
Tx DC a
Infusion/Dose Number
Baseline d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16





Week
1 
3 e
5 
9
13
17
21
25
29
33
37
41
45
49
53
57
61 f
69



(Visit window in days)
(3) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5) (5)
(7)

(3) (7)
Concomitant medications aa
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Adverse events bb
x bb
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x bb
[18F]GTP1fluorine-18 Genentech tau probe 1; A-amyloid; ADAlzheimer’s disease; ADAanti-drug antibody; ADAS-Cog11Alzheimer’s Disease 
Assessment ScaleCognitive Subscale, 11-item version; ADCS-ADLAlzheimer’s Disease Cooperative Study–Activities of Daily Living Inventory; 
C-SSRSColumbia-Suicide Severity Rating Scale; CaGI-AlzCaregiver Global Impression Scales for Alzheimer’s disease; CDRClinical Dementia 
Rating; COAclinical outcome assessment; CSFcerebrospinal fluid; DCdiscontinuation; DVFDiagnostic Verification Form; eCRFelectronic Case 
Report Form; HbA1chemoglobin A1c; HBsAghepatitis B surface antigen; HCVhepatitis C virus; LPlumbar puncture; MMSEMini-Mental State 
Examination; MRImagnetic resonance imaging; NPINeuropsychiatric Inventory; OLEopen-label extension; PET positron emission tomography; 
PKpharmacokinetic; Q2W every 2 weeks; Q4W every 4 weeks; SNPsingle nucleotide polymorphism; SRNscreening; T4thyroxine; 
TSHthyroid-stimulating hormone; Tx treatment; WGSwhole genome sequencing. 
Notes:  All postbaseline study visits must be scheduled in reference to the first dosing day (Week 1 visit).  All activities/assessments in a given study 
visit must be performed within 5 days of the scheduled visit, unless otherwise specified (e.g., [18F]GTP1 PET scans).  On study drug administration 
visits that span multiple days, study drug administration must occur on the last day.
On study drug administration days:
-  All assessments must be performed prior to dosing, unless otherwise specified
-  Pre-infusion laboratory samples should be drawn 0–4 hours before the start of infusion, unless otherwise specified
-  Post-infusion laboratory samples should be drawn 030 minutes after the end of infusion, unless otherwise specified
During the COVID-19 pandemic, study visit activities, excluding imaging assessments, can be performed in the patient’s home or in an approved 
alternate location.  Selected COAs can be administered remotely (by telephone or video call), as outlined in the Study GN40040 remote COA 
administration guidance.  Deviations from the schedule of activities will be documented as COVID-19related protocol deviations.


Appendix 3: Cohort 2 Schedule of Activities
MTAU9937A—Genentech, Inc.
124/Protocol GN40040, Version 5
a Patients who complete the double-blind treatment period and who do not enroll into the OLE treatment period will return to the clinic for a treatment 
completion visit (safety follow-up) at Week 69 (7 days).  Patients who discontinue study drug (MTAU9937A or placebo) prematurely in the 
double-blind treatment period will return to the clinic for a treatment discontinuation visit 12 weeks (7 days) after the final dose of study drug.
b Visit not specified by the protocol.  Additional assessments (possibly including PK sample collection) should be performed as clinically indicated.  
Patients who miss study drug infusions during the double-blind treatment period for reasons related to the COVID-19 pandemic may have additional 
COAs administered remotely (by telephone or video call) at the time of the first missed infusion and at the time when in-clinic study drug infusions 
resume.  Refer to the Study GN40040 COA Manual and remote COA administration guidance for specific COA assessments to be administered and 
order of administration.
c For patients who miss two or more consecutive study drug infusions during the double-blind treatment period, study drug administration will be 
re-initiated with Q2W dosing for the next three doses (followed by Q4W dosing thereafter).  Upon re-initiation of study drug administration, a single 
supplemental dose visit will be added 2 weeks (3 days) after administration of the first dose.
d The baseline visit period must begin after enrollment (randomization) and may be split over multiple visit days; the first and last visit days of the 
baseline period must be separated by no more than 14 days from each other (e.g., the baseline visit period may start on a Monday and end on the 
Monday 2 weeks later).  All COA assessments during the baseline visit period should be performed as close to the last visit day of the baseline 
period as possible.  COA assessments, [18F]GTP1 PET scan, and LP from the baseline visit period may be performed on the same day that study 
drug is first administered (on the Week 1 visit), but they must be performed prior to dosing.  All activities specified for the Week 1 visit (the first dosing 
visit) must be performed on the same day and must occur no later than 15 days after the baseline visit period begins (e.g., if the first baseline visit 
period day is a Monday, then the first dosing of study drug must occur no later than the Tuesday 2 weeks later).  Extensions to the 15-day baseline 
visit period (e.g., to complete [18F]GTP1 PET imaging) may be granted on a case-by-case basis by the Medical Monitor.
e At this visit, all activities/assessments must be performed within 3 days of the scheduled visit.
f
At Week 61, patients will move to OLE or will be scheduled for a treatment completion visit (safety follow-up).
g Informed consent must be documented before any study-specific screening procedure is performed.  Informed consent with the Early Screening 
Informed Consent Form permits MMSE, medical history, AD history, personal status, and demographics.  Informed consent with the main Informed 
Consent Form is required for all other study-specific screening procedures.
h Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies and procedures); reproductive 
status; smoking history; use of alcohol and drugs of abuse; recent history (5 years) of non-elective hospitalizations, pneumonia or cardiovascular 
events; lifetime use of any A-targeting therapies; and all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal/homeopathic 
remedies, nutritional supplements) used by the patient within 3 months prior to the initiation of screening.  Demographics include age, sex, 
self-reported race/ethnicity (as permitted by local regulations), handedness, and years of education.  Demographics of caregiver will also be collected 
with exception of handedness.


Appendix 3: Cohort 2 Schedule of Activities
MTAU9937A—Genentech, Inc.
125/Protocol GN40040, Version 5
i
Refer to the Study GN40040 COA Manual for instructions on COA administration order, specification of list versions to use at each visit, rater roles, 
restrictions on raters, and additional details on COA administration and the endpoint reliability program.  At all visits, all COA questionnaires/scales 
(excluding the DVF) will be rater administered before the patient, rater, or caregiver receives any information on disease status, prior to LPs 
scheduled in the visit, and prior to the administration of study drug.  In addition, on any given day when COAs are performed, all COAs (with the 
exception of the DVF and the C-SSRS) must be performed prior to non-COA assessments, study drug, and [18F]GTP1 radioligand or amyloid 
radioligand unless otherwise specified.  For details on permitted concomitant medication use prior to COA assessments, see Section 4.1.2.
j
Only perform assessment if discontinuation visit is ≥16 weeks after last assessment for this instrument or procedure.  However, if the patient 
discontinues study drug because of an infusion-related reaction, concurrent ADA and PK samples will also be collected at 12 weeks after the final 
administration of the study drug.  An [18F]GTP1 scan should only be performed if at least 24 weeks has elapsed since any previous [18F]GTP1 scan 
and local annual radiation limits have not been exceeded.
k Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Vital sign 
assessments should be performed just prior to study drug administration.  On study drug treatment visits, vital signs should be collected 04 hours 
prior to infusion and 6090 minutes after completion of infusion.  Vital signs should also be assessed within 1 hour prior to injection of [18F]GTP1 or 
initiation of the LP procedure and within 1 hour after injection of [18F]GTP1 or the completion of the LP procedure.  Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
l
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, respiratory, and gastrointestinal systems.  
In addition, the musculoskeletal and genitourinary systems should be examined as clinically indicated.  Record abnormalities observed at baseline on 
the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the 
Adverse Event eCRF.
m Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
n If MRI, amyloid PET, or [18F]GTP1 PET scan occurs at the same visit as COAs, neuroimaging must be performed after administration of COAs (with 
the exception of the DVF and the C-SSRS).  Only one PET scan should be performed on a given day.  Postbaseline [18F]GTP1 PET scans may be 
performed prior to or after study treatment administration.  Postbaseline [18F]GTP1 PET scans should be performed 14 days of the scheduled visit; 
however, extensions to the [18F]GTP1 PET scan windows may be granted on a case-by-case basis by the Medical Monitor.  Week 61 visit or
treatment discontinuation visit [18F]GTP1 PET scan dates may be coordinated by the [18F]GTP1 distribution network on the basis of tracer availability 
and may be scheduled outside the 14-day window around the scheduled visit if appropriate extenuating circumstances arise.  The Week 61 
[18F]GTP1 PET scan is not required if a [18F]GTP1 PET scan originally scheduled for Week 49 has been performed.  If, at any time, local restrictions 
for radiation exposure disallow performing a [18F]GTP1 PET scan within this window, the site should contact the Sponsor to discuss alternative 
timing.  The MRI should be performed and assessed locally and in real time prior to any study drug dosing at the corresponding study visit.  


Appendix 3: Cohort 2 Schedule of Activities
MTAU9937A—Genentech, Inc.
126/Protocol GN40040, Version 5
n (Cont.) Study drug should be withheld if there are clinically significant new or clinically significant worsened MRI abnormalities identified in the local 
MRI interpretation.  However, if no such abnormalities are identified, the dose may be given prior to receipt of the central MRI report (see 
Section 5.1.1.2).  During the COVID-19 pandemic, if an MRI cannot be obtained, the patient should be monitored for any signs or symptoms 
suggestive of new, clinically significant neurologic abnormalities.  If no new, clinically significant abnormalities are observed, study drug may be 
administered without an MRI, but a subsequent unscheduled study-associated MRI should be obtained as local conditions allow.  If new, clinically 
significant neurologic abnormalities are observed, study drug should be withheld and the patient should be referred for appropriate follow-up and 
medical treatment, including, if appropriate, an MRI.
o If an amyloid PET scan is used to confirm amyloid positive eligibility, an LP will not need to be performed as part of screening.  If an LP is performed 
at screening to confirm eligibility, an amyloid PET scan is not needed.  If a patient is amyloid negative based on one of the two modalities (CSF 
assessment or amyloid PET), then the patient may undergo assessment with the other modality during screening; amyloid positivity by either 
modality is sufficient for eligibility (see Section 4.5.8).  All subsequent LPs are optional for exploratory CSF biomarker collection.
p On the day of the first administration of study drug, ECGs should be performed 04 hours before the start of infusion and 030 minutes after the end 
of infusion.  Week 5 ECGs should be performed 030 minutes after the end of infusion.  All ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws).
q Results obtained prior to obtaining informed consent and within 90 days prior to the start of screening may be used; such tests do not need to be 
repeated for screening.
r
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (absolute counts of neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, and other cells).
s Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, potassium, 
chloride, magnesium, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, ALT, AST, gamma 
glutamyl transpeptidase, and creatine kinase.  Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides.  Coagulation 
panel includes INR, aPTT, and PT; the coagulation panel should be measured at screening and within 90 days prior to any LP or within an interval 
consistent with the local standard of care, whichever is shorter. If required per local standard of care, additional coagulation panel tests may be 
performed at central laboratory or at a local laboratory.  For patients taking multiple anti-platelet medications, the investigator should determine (per 
local standards of care) whether the temporary discontinuation of one or more anti-platelet medications prior to LP is warranted (e.g., continuing 
aspirin and discontinuing thienopyridine derivatives for 12 weeks prior to LP).
t
Viral serology panel includes HIV, HBsAg, total hepatitis B core antibody, and HCV antibody.
u All women of childbearing potential will have a serum pregnancy test at screening.  Urine pregnancy tests will be performed at baseline and specified 
subsequent visits prior to dosing.  If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  Pregnancy tests must be 
negative prior to dosing with study drug or [18F]GTP1.


Appendix 3: Cohort 2 Schedule of Activities
MTAU9937A—Genentech, Inc.
127/Protocol GN40040, Version 5
v Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood).  Microscopic examination (sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, bacteria) should be performed if the dipstick is abnormal.
w Serum PK samples should be taken 04 hours before the start of infusion and 030 minutes after the end of infusion.  Serum ADA and blood 
biomarker samples should be taken 04 hours before the start of infusion.
x Immunogenicity samples should be obtained prior to study drug administration to measure antibody development to MTAU9937A.  In the event of an 
infusion-related reaction, unscheduled ADA and PK serum samples should be collected at the following three timepoints:  as close to 
investigator-determined onset of the event as feasible, at investigator-determined resolution of the event, and 30 days after the resolution of the 
event.
y Not applicable for a site that has not been granted approval for WGS/SNP.
z If sample was collected at screening, baseline collection is not needed.  If a CSF sample was not collected at screening, the patient may have an 
optional CSF sample collected at baseline.  Collection should occur prior to dosing.
aa Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient in 
addition to protocol-mandated treatment from 3 months prior to screening until the final study visit (see Section 4.5.2).  Any agent that targets A
used by the patient at any time during their life is also considered to be a concomitant therapy (see Section 4.4).
bb 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.  After initiation of study drug or [18F]GTP1 radioligand or amyloid radioligand, all adverse events will be reported until 
12 weeks after the final dose of study drug or 4 days after the last dose of [18F]GTP1 or an amyloid radioligand, whichever is longer.  During this 
period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator becomes aware of any 
serious adverse event that is believed to be related to prior study drug or [18F]GTP1 radioligand or amyloid radioligand treatment (see Section 5.6).  
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 [18F]GTP1 radioligand or an amyloid radioligand or trial-related procedures until a final outcome can be 
reported. 


MTAU9937A—Genentech, Inc.
128/Protocol GN40040, Version 5
Appendix 4
Cohort 2 Schedule of Activities (Open-Label Extension)
Open-Label Treatment Period
Unplanned 
Visit a
Safety FU b
Tx DC b
Week 65
69
73
77
81
85
89
93
97
101
105
109 113 117 121 125 129 133 137 141 145 149 153 157

169 
Infusion/Dose Number 17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40



ADAS-Cog11 c
x
x
x
x d
ADCS-ADL c
x
x
x
x d
CDR c
x
x
x
x d
NPI c
x
x
x
x d
MMSE c
x
x
x
x d
C-SSRS c
x
x
x
x
x
x
x
x
x
x
CaGI-Alz c
x
x
x
x d
Vital signs e
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Weight
x
x
x
x
x
x
Complete physical 
examination f
x
x
x
x
x
x
Limited physical 
examination g
x
x
x
x
x
Neurologic examination
x
x
x
x
x
x
x
x
x
x
x
MRI h
x
x
x
x i
ECG
x j
Hematology k
x
x
x


Appendix 4: Cohort 2 Schedule of Activities (Open-Label Extension)
MTAU9937A—Genentech, Inc.
129/Protocol GN40040, Version 5
Open-Label Treatment Period
Unplanned 
Visit a
Safety FU b
Tx DC b
Week 65
69
73
77
81
85
89
93
97
101
105
109 113 117 121 125 129 133 137 141 145 149 153 157

169 
Infusion/Dose Number 17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40



Chemistry and lipids l
x
x
x
Coagulation m
x
x
Pregnancy test n
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis o
x
x
x
Study drug administration
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Serum PK sample p
x
Serum ADA sample p, q
x
Blood sample for 
biomarkers p
x
x
x
x d
CSF sample for PK and 
biomarkers (if applicable) r
x
x
x i
Concomitant medications s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x s
x s
Adverse events t
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x t
x t
ADAanti-drug antibody; ADAS-Cog11Alzheimer’s Disease Assessment ScaleCognitive Subscale, 11-item version; ADCS-ADLAlzheimer’s 
Disease Cooperative Study Group–Activities of Daily Living Inventory; C-SSRSColumbia-Suicide Severity Rating Scale; CaGI-AlzCaregiver 
Global Impression discontinuation; eCRFelectronic Case Report Form; F/Ufollow-up; LPlumbar puncture; MMSEMini-Mental State 
Examination; MRImagnetic resonance imaging; NPINeuropsychiatric Inventory; OLEopen-label extension; PKpharmacokinetic; 
Txtreatment. 


Appendix 4: Cohort 2 Schedule of Activities (Open-Label Extension)
MTAU9937A—Genentech, Inc.
130/Protocol GN40040, Version 5
Notes:  All postbaseline study visits must be scheduled in reference to the first dosing day (Week 1 visit).  All activities/assessments in a given 
study visit must be performed within 5 days of the scheduled visit, unless otherwise specified.  On study drug administration visits that span 
multiple days, study drug administration must occur on the last day.  On study drug administration days, all assessments must be performed prior 
to dosing, unless otherwise specified. 
During the COVID-19 pandemic, study visit activities, excluding imaging assessments, can be performed in the patient’s home or in an approved 
alternate location.  Selected COAs can be administered remotely (by telephone or video call), as outlined in the Study GN40040 remote COA 
administration guidance.  Deviations from the schedule of activities will be documented as COVID-19related protocol deviations.
a Visit not specified by the protocol.  Additional assessments (possibly including PK sample collection) should be performed as clinically indicated.
b Patients who complete the OLE treatment period will return to the clinic for a treatment completion visit (safety follow-up) at Week 169 (7 days).  
Patients who discontinue study drug prematurely in the OLE treatment period will return to the clinic for a treatment discontinuation visit 
12 weeks (7 days) after the final dose of study drug.
c Refer to the Study GN40040 COA Manual for instructions on COA administration order, specification of list versions to use at each visit, rater 
roles, restrictions on raters, and additional details on COA administration and the endpoint reliability program.  At all visits, all COA 
questionnaires/scales will be rater administered before the patient, rater, or caregiver receives any information on disease status, prior to LPs 
scheduled in the visit, and prior to the administration of study drug.  In addition, on any given day when COAs are performed, all COAs (with the 
exception of the C-SSRS) must be performed prior to non-COA assessments and study drug, unless otherwise specified.  For details on 
permitted concomitant medication use prior to COA assessments, see Section 4.1.2.
d Only perform assessment if discontinuation visit is 16 weeks after last assessment for this instrument.
e Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  Vital 
sign assessments should be performed just prior to study drug administration.  On study drug treatment visits, vital signs should be collected 
04 hours prior to infusion and 6090 minutes after completion of infusion.  Vital signs should also be assessed within 1 hour prior to initiation of 
the LP procedure and within 1 hour after completion of the LP procedure.  Record abnormalities observed at baseline on the General Medical 
History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant abnormalities on the Adverse Event 
eCRF.
f
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatologic, respiratory, and gastrointestinal systems.  
In addition, the musculoskeletal and genitourinary systems should be examined as clinically indicated.  Record abnormalities observed at 
baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.
g Perform a limited, symptom-directed examination at specified timepoints or as clinically indicated.  Record new or worsened clinically significant 
abnormalities on the Adverse Event eCRF.


Appendix 4: Cohort 2 Schedule of Activities (Open-Label Extension)
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h If MRI occurs at the same visit as COAs, neuroimaging must be performed after administration of COAs (with the exception of the C-SSRS).  The 
MRI should be performed and assessed locally and in real time prior to any study drug dosing at the corresponding study visit.  Study drug 
should be withheld if there are clinically significant new or clinically significant worsened MRI abnormalities identified in the local interpretation.  
However, if no such abnormalities are identified, the dose may be given prior to receipt of the central MRI report (see Section 5.1.1.2).  During 
the COVID-19 pandemic, if an MRI cannot be obtained, the patient should be monitored for any signs or symptoms suggestive of new, clinically 
significant neurologic abnormalities.  If no new, clinically significant abnormalities are observed, study drug may be administered without an MRI, 
but a subsequent unscheduled study-associated MRI should be obtained as local conditions allow.  If new, clinically significant neurologic 
abnormalities are observed, study drug should be withheld and the patient should be referred for appropriate follow-up and medical treatment, 
including, if appropriate, an MRI.
i
Only perform assessment if discontinuation visit is 24 weeks after last assessment for this instrument.
j
Perform assessment if clinically indicated.
k Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, and differential count (absolute counts of neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).
l
Chemistry panel (serum or plasma) includes bicarbonate or total carbon dioxide (if considered standard of care for the region), sodium, 
potassium, chloride, magnesium, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total and direct bilirubin, ALP, 
ALT, AST, gamma glutamyl transpeptidase, and creatine kinase.  Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, and 
triglycerides.
m Coagulation panel includes INR, aPTT, and PT; the coagulation panel should be measured within 90 days prior to any LP or within an interval 
consistent with local standard of care, whichever is shorter.  If required per local standard of care, additional coagulation panel tests may be 
performed at central laboratory or at a local laboratory.  For patients taking multiple anti-platelet medications, the investigator should determine 
(per local standards of care) whether the temporary discontinuation of one or more anti-platelet medications prior to LP is warranted 
(e.g., continuing aspirin and discontinuing thienopyridine derivatives for 12 weeks prior to LP).  The Week 157 coagulation laboratory tests are 
only applicable to patients participating in the optional CSF collection (lumbar puncture).
n For women of childbearing potential, urine pregnancy tests will be performed at specified visits prior to dosing.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test.  Pregnancy tests must be negative prior to dosing with study drug.
o Urinalysis includes dipstick (pH, specific gravity, glucose, protein, ketones, blood).  Microscopic examination (sediment, RBCs, WBCs, casts, 
crystals, epithelial cells, bacteria) should be performed if the dipstick is abnormal.
p Serum PK samples should be taken 04 hours before the start of infusion and 030 minutes after the end of infusion.  Serum ADA and blood 
biomarker samples should be taken 04 hours before the start of infusion.


Appendix 4: Cohort 2 Schedule of Activities (Open-Label Extension)
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132/Protocol GN40040, Version 5
q Immunogenicity samples should be obtained prior to study drug administration to measure antibody development to MTAU9937A.  In the event 
of an infusion-related reaction, unscheduled ADA and PK serum samples should be collected at the following three timepoints:  as close to 
investigator-determined onset of the event as feasible, at investigator-determined resolution of the event, and 30 days after the resolution of 
the event.
r
All LPs in the OLE are optional for exploratory CSF biomarker collection, regardless of whether prior CSF collection has occurred.
s Medication (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a 
patient in addition to protocol-mandated treatment from 3 months prior to screening until the final study visit (see Section 4.5.2).  Any agent that 
targets Aused by the patient at any time during their life is also considered to be a concomitant therapy (see Section 4.4).
t
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.  After initiation of study drug, all adverse events will be reported until 12 weeks after the final dose of study drug.  
During this period, all deaths, regardless of cause, should be reported.  After this period, the Sponsor should be notified if the investigator 
becomes aware of any serious adverse event that is believed to be related to prior study drug treatment (see Section 5.6).  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.


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Appendix 5
National Institute on AgingAlzheimer’s Association Criteria for 
Alzheimer’s Disease Dementia
NIA-AA category
Description
Probable Dementia: 
core Clinical Criteria
Meets criteria for 
dementia and in 
addition, has the 
following 
characteristics:
A. Insidious onset.  Symptoms have a gradual onset over months to 
years, not sudden over hours or days;
B. Clear-cut history of worsening of cognition by report or observation; 
and
C. The initial and most prominent cognitive deficits are evident on 
history and examination in one of the following categories.
a. Amnestic presentation:  It is the most common syndromic 
presentation of AD dementia.  The deficits should include 
impairment in learning and recall of recently learned information.  
There should also be evidence of cognitive dysfunction in at least 
one other cognitive domain, as defined earlier in the text.
b. Non-amnestic presentations:
Language presentation: The most prominent deficits are in 
word-finding, but deficits in other cognitive domains should be 
present.
Visuospatial presentation:  The most prominent deficits are in 
spatial cognition, including object agnosia, impaired face 
recognition, simultanagnosia, and alexia.  Deficits in other 
cognitive domains should be present.
Executive dysfunction:  The most prominent deficits are impaired 
reasoning, judgment, and problem solving.  Deficits in other 
cognitive domains should be present.
D. The diagnosis of probable AD dementia should not be applied when 
there is evidence of (a) substantial concomitant cerebrovascular 
disease, defined by a history of a stroke temporally related to the 
onset or worsening of cognitive impairment; or the presence of 
multiple or extensive infarcts or severe white matter hyperintensity 
burden; or (b) core features of Dementia with Lewy bodies other 
than dementia itself; or (c) prominent features of behavioral variant 
frontotemporal dementia; or (d) prominent features of semantic 
variant primary progressive aphasia or nonfluent/agrammatic variant 
primary progressive aphasia; or (e) evidence for another concurrent, 
active neurological disease, or a non-neurological medical 
comorbidity or use of medication that could have a substantial effect 
on cognition.


Appendix 5: National Institute on AgingAlzheimer’s Association Criteria for Alzheimer’s 
Disease Dementia
MTAU9937A—Genentech, Inc.
134/Protocol GN40040, Version 5
NIA-AA category
Description
Probable AD 
dementia with 
increased level of 
certainty
Probable AD dementia with documented decline
In persons who meet the core clinical criteria for probable AD dementia, 
documented cognitive decline increases the certainty that the condition 
represents an active, evolving pathologic process, but it does not 
specifically increase the certainty that the process is that of AD 
pathophysiology.
Probable AD dementia with documented decline is defined as follows: 
evidence of progressive cognitive decline on subsequent evaluations 
based on information from informants and cognitive testing in the 
context of either formal neuropsychological evaluation or standardized 
mental status examinations.
Probable AD dementia in a carrier of a causative AD genetic mutation
In persons who meet the core clinical criteria for probable AD dementia, 
evidence of a causative genetic mutation (in APP, PSEN1, or PSEN2), 
increases the certainty that the condition is caused by AD pathology.  
The workgroup noted that carriage of the ɛ4 allele of the 
apolipoprotein E gene was not sufficiently specific to be considered in 
this category.
Probable AD 
dementia with 
evidence of the AD 
pathophysiological 
process
AD dementia is part of a continuum of clinical and biological 
phenomena.  AD dementia is fundamentally a clinical diagnosis.  To 
make a diagnosis of AD dementia with biomarker support, the core 
clinical diagnosis of AD dementia must first be satisfied.
Relevant biomarkers include amyloid-β(CSF or PET); tau (CSF or PET) 
AD=Alzheimer’s disease; CSF=cerebrospinal fluid; NIA-AA=National Institute on 
Aging/Alzheimer’s Association; PET=positron emission tomography.
REFERENCE
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to 
Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers 
Dement 2011;7:2639. 


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Appendix 6
Anaphylaxis Precautions 
The following equipment is needed in the event of a suspected anaphylactic reaction 
during study drug infusion:

Monitoring devices:  ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer

Oxygen

Epinephrine for intravenous, intramuscular, and endotracheal administration in 
accordance with institutional guidelines

Antihistamines

Corticosteroids

Intravenous infusion solutions, tubing, catheters, and tape
The following are the procedures to follow in the event of a suspected anaphylactic 
reaction during study drug infusion:

Stop the study drug infusion. 

Call for additional medical assistance.

Maintain an adequate airway.

Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible.

Administer antihistamines, epinephrine, or other medications as required by 
participant status and as directed by the physician in charge.

Continue to observe the participant and document observations.

Draw serum samples for immunogenicity testing.

Ask participant to return for washout immunogenicity sample (12 weeks after last 
dose) if appropriate.  


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Appendix 7
World Health Organization Toxicity Grading Scale for 
Determining Severity of Adverse Events


Appendix 7: World Health Organization Toxicity Grading Scale for Determining Severity of 
Adverse Events
MTAU9937A—Genentech, Inc.
137/Protocol GN40040, Version 5


Appendix 7: World Health Organization Toxicity Grading Scale for Determining Severity of 
Adverse Events
MTAU9937A—Genentech, Inc.
138/Protocol GN40040, Version 5


Appendix 7: World Health Organization Toxicity Grading Scale for Determining Severity of 
Adverse Events
MTAU9937A—Genentech, Inc.
139/Protocol GN40040, Version 5