Clinical trial NCT03289143
Conditions: Alzheimer's Disease
Keywords: Alzheimer Disease Brain Diseases Dementia Neurodegenerative Diseases Neurocognitive Disorders
Sponsor: Genentech, Inc.
Start date: 2017-10-04; Completion date: 2021-01-15
Enrollment: 457 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a phase II, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of Semorinemab in participants with prodromal to mild Alzheimer's disease. An optional 96-week open-label extension period was available to participants who completed the double-blind treatment period and who, in the judgment of the investigator, would potentially benefit from open-label Semorinemab treatment.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Semorinemab intervention 2: Placebo intervention 3: [18F]GTP1
Intervention descriptions: intervention 1: Participants will receive Semorinemab intravenously (IV). intervention 2: Matching placebo doses of Semorinemab given intravenously (IV). 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_000.pdf: 
 
Official Title: 
A Phase II, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group, Efficacy, and Safety Study of MTAU9937A 
in Patients With Prodromal to Mild Alzheimer's Disease 
NCT Number: 
NCT03289143 
Document Date: 
Protocol Version 4: 11-June 2019 
 
 


PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, 
especially any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) 
and therefore is provided to you in confidence as an investigator, potential investigator, or consultant, 
for review by you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is 
understood that this information will not be disclosed to others without written authorization from 
Roche except to the extent necessary to obtain informed consent from persons to whom the drug 
may be administered.
MTAU9937A—Genentech, Inc.
Protocol GN39763, Version 4
PROTOCOL
TITLE:
A PHASE II, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP, EFFICACY, AND SAFETY 
STUDY OF MTAU9937A IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE
PROTOCOL NUMBER: GN39763
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-001800-31
IND NUMBERS:
129270, 125702
TEST PRODUCTS:
MTAU9937A (RO7105705) and 
[18F]GTP1 (RO6880276)
MEDICAL MONITOR:
 M.D., Ph.D.
SPONSOR:
Genentech, Inc.
APPROVAL DATE:
See electronic date stamp below.
 
11-Jun-2019 20:44:36
Title
Approver's Name
Company Signatory
Date and Time (UTC)


MTAU9937A—Genentech, Inc.
2/Protocol GN39763, Version 4
PROTOCOL HISTORY
Protocol
Associated Country-Specific Protocols
Version
Date Final
Country
Version
Date Final
3
20 August 2018
European Union
3
6 December 2018
European Union (only)
2
12 October 2017
1
31 May 2017





MTAU9937A—Genentech, Inc.
3/Protocol GN39763, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol GN39763, Version 4, encompasses the cumulative changes to the protocol that 
were made to Version 3 (European Union) (6 Dec 2018), which was only applicable to 
E.U. countries, along with global changes specific to this amendment.
Changes specific to Protocol GN39763, Version 4, along with a rationale for each 
change, are summarized below:

Clinical background information on MTAU9937A clinical studies was updated to 
include Study GN40040, an ongoing Phase II study in patients with moderate 
Alzheimer’s disease (Section 1.2.2).

Clinical background information on fluorine-18 Genentech tau probe 1 ([18F]GTP1) 
has been updated to include reference to ongoing clinical Substudies
WN29922/WN39658 and Study GN40040 (Section 1.3.1).

The total number of patients enrolled and the number of clinical sites has been 
updated (Sections 3.1.1, 4.1, and 9.4).

Exclusion criteria have been modified (Section 4.1.2):
-
The exclusion criterion for biologic therapy has been clarified to indicate that 
any investigational biologic therapy (e.g., therapeutic proteins, monoclonal 
antibodies, or other active or passive immunotherapy) is prohibited at screening 
and during the study.
-
The exclusion criterion for systemic immunosuppressive therapy has been 
revised to indicate that short courses (2 weeks) of high-dose corticosteroid 
therapy are permitted, and that chronic therapy (2 weeks) is permitted as long 
as the dose is 7.5 mg/day prednisolone equivalent and the condition being 
treated is not expected to deteriorate significantly during the study period.

The description of the recall time frame for the Caregiver Global Impression of 
Change Scales has been corrected to align with the time frames used for the 
assessment (Section 4.5.7.11). 

Language has been added to clarify that, after withdrawal of consent for 
participation in the Research Biosample Repository (RBR), remaining RBR samples 
will be destroyed or will no longer linked to the patient (Section 4.5.12.6).

Examples of clinically significant magnetic resonance imaging (MRI) abnormalities 
have been provided (Section 5.1.1.2).

Contact information for Medical Monitor supporting E.U. sites has been updated 
(Section 5.4.1).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).


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
Language has been revised to clarify that data posting will not be limited to two 
clinical trial registries and to clarify that redacted Clinical Study Reports are provided
only if requirements of Roche's global policy on data sharing have been met
(Section 9.5).

The window for postbaseline [18F]GTP1 PET scans has been expanded to 14 days,
and further extensions to the allowed window for the Week 73 [18F]GTP1 PET scan 
may be granted on a case-by-case basis by the Medical Monitor. Scheduling of the 
Week 49, Week 169, and Treatment Discontinuation visit [18F]GTP1 PET scans 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 (Appendices 1 and 2).

It has been clarified that if additional coagulation panel tests are required per the 
local standard prior to performing lumbar puncture for cerebrospinal fluid (CSF)
collection, these tests may be performed at the central laboratory or at a local 
laboratory (Appendices 1 and 2). The open-label extension (OLE) schedule of 
activities was corrected to include coagulation laboratory tests at the Week 169 visit 
for patients undergoing optional CSF collection (lumbar puncture) (Appendix 2).
Protocol GN39763, Version 3, was amended to address feedback from European Health 
Authorities resulting in protocol Version 3 (European Union) (6 Dec 2018).  Changes to 
the protocol, along with the rationale for each change, are summarized below:

Study visits during the protocol safety follow-up period were clarified to state that 
patients who discontinue from treatment early will have a treatment discontinuation 
visit (Section 3.1.1.1).

For visits that include both MRI and study medication dosing, it has been clarified 
that although the MRI must be performed prior to study medication dosing, dosing 
can occur following local, real-time assessment and before the site receives the 
central MRI report if no clinically significant new or worsening abnormalities are 
identified (Section 5.1.1.2 and Appendices 1 and 2).

Adverse event reporting was clarified to include reporting of adverse events that 
occur after the protocol defined adverse event reporting interval following the last 
dose of [18F]GTP1 or study drug administration for adverse events leading to 
discontinuation from the study (Section 5.6).

It has been clarified that coagulation studies must be performed within 90 days prior 
to a lumbar puncture or within an interval consistent with the local standard of care, 
whichever is shorter.  Guidance was added that 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 lumbar puncture (LP) is warranted (e.g., continuing aspirin and 
discontinuing thienopyridine derivatives for 12 weeks prior to LP; Appendices 1 
and 2).


MTAU9937A—Genentech, Inc.
5/Protocol GN39763, Version 4
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.
6/Protocol GN39763, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13
PROTOCOL SYNOPSIS .................................................................................... 14
1.
BACKGROUND .......................................................................................... 27
1.1
Background on Alzheimer’s Disease..................................... 27
1.2
Background on MTAU9937A................................................. 28
1.2.1
Non-Clinical Information ........................................................ 28
1.2.2
Clinical Information ................................................................ 29
1.3
Background on [18F]GTP1 ..................................................... 30
1.3.1
Clinical Safety and Tolerability............................................... 30
1.4
Study Rationale and BenefitRisk Assessment..................... 31
2.
OBJECTIVES AND ENDPOINTS ............................................................... 32
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 ........................................................................ 37
3.1.2
Independent Data Monitoring Committee .............................. 41
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 ......................................... 43
3.3.4
Rationale for Requiring Caregiver Participation..................... 43
3.3.5
Rationale for Control Group................................................... 44
3.3.6
Rationale for Pharmacokinetic Sampling............................... 44
3.3.7
Rationale for Use of Clinician and Observer 
Reported Outcome Assessments.......................................... 44
3.3.8
Rationale for Use of Investigational Tau 
Radioligand [18F]GTP1 .......................................................... 44
3.3.9
Rationale for Biomarker Assessments................................... 45


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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..................... 52
4.3
Study Treatments Relevant to the Study Design................... 53
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............................................................................ 54
4.3.2.1
MTAU9937A and Placebo ..................................................... 54
4.3.2.2
[18F]GTP1 Tau PET Radioligand ........................................... 55
4.3.2.3
Amyloid PET Radioligands .................................................... 55
4.3.3
Investigational Medicinal Product Accountability ................... 55
4.3.4
Continued Access to MTAU9937A ........................................ 56
4.4
Concomitant Therapy ............................................................ 56
4.4.1
Permitted Therapy................................................................. 56
4.4.2
Cautionary Therapy ............................................................... 57
4.4.2.1
Herbal Therapies................................................................... 57
4.4.3
Prohibited Therapy ................................................................ 57
4.5
Study Assessments ............................................................... 57
4.5.1
Informed Consent Forms and Screening Log........................ 57
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 57
4.5.3
Physical Examinations........................................................... 58
4.5.4
Neurological Examinations .................................................... 58
4.5.5
Lumbar Puncture................................................................... 58
4.5.6
Vital Signs.............................................................................. 58
4.5.7
Clinical Outcome Assessments ............................................. 59
4.5.7.1
Mini-Mental State Examination.............................................. 60
4.5.7.2
Clinical Dementia Rating Scale ............................................. 60


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4.5.7.3
Repeatable Battery for the Assessment of 
Neuropsychological Status .................................................... 60
4.5.7.4
Alzheimer’s Disease Assessment Scale–
Cognitive Subscale................................................................ 61
4.5.7.5
Amsterdam Instrumental Activity of Daily Living 
Questionnaire ........................................................................ 61
4.5.7.6
Alzheimer’s Disease Cooperative 
StudyActivities of Daily Living Inventory .............................. 61
4.5.7.7
Alzheimer’s Disease Event Inventory .................................... 61
4.5.7.8
Resource Utilization in DementiaLite 
Questionnaire ........................................................................ 62
4.5.7.9
Columbia-Suicide Severity Rating Scale ............................... 62
4.5.7.10
Diagnostic Classification........................................................ 62
4.5.7.11
Caregiver Global Impression of Change Scales.................... 62
4.5.8
Amyloid and Tau Positron Emission Tomography................. 62
4.5.9
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 64
4.5.10
Electrocardiograms................................................................ 66
4.5.11
Mandatory Samples for Genetic Analysis.............................. 66
4.5.12
Optional Samples for Research Biosample 
Repository ............................................................................. 67
4.5.12.1
Overview of the Research Biosample Repository.................. 67
4.5.12.2
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 68
4.5.12.3
Sample Collection.................................................................. 68
4.5.12.4
Confidentiality........................................................................ 69
4.5.12.5
Consent to Participate in the Research 
Biosample Repository............................................................ 69
4.5.12.6
Withdrawal from the Research Biosample 
Repository ............................................................................. 70
4.5.12.7
Monitoring and Oversight....................................................... 70
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 70
4.6.1
Study Treatment Discontinuation........................................... 70
4.6.2
Patient Discontinuation from Study........................................ 71
4.6.3
Study Discontinuation............................................................ 71


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4.6.4
Site Discontinuation............................................................... 71
5.
ASSESSMENT OF SAFETY....................................................................... 72
5.1
Safety Plan ............................................................................ 72
5.1.1
Potential Risks Associated with MTAU9937A........................ 72
5.1.1.1
Infusion-Related Reactions or Hypersensitivity ..................... 72
5.1.1.2
Neuroimaging Abnormalities.................................................. 72
5.1.1.3
Immunogenicity ..................................................................... 73
5.1.2
Potential Risks Associated with [18F]GTP1 and 
Amyloid PET Radiopharmaceuticals ..................................... 74
5.1.2.1
Infusion-Related Reactions.................................................... 74
5.1.2.2
Radiation Risk ....................................................................... 74
5.1.3
Management of Patients Who Experience 
Specific Adverse Events........................................................ 74
5.1.3.1
Treatment Interruption ........................................................... 74
5.1.3.2
Management Guidelines for Infusion-Related 
Reactions............................................................................... 74
5.1.3.3
Management of Increases in QT Interval............................... 75
5.2
Safety Parameters and Definitions ........................................ 76
5.2.1
Adverse Events ..................................................................... 76
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 76
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 77
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 78
5.3.1
Adverse Event Reporting Period ........................................... 78
5.3.2
Eliciting Adverse Event Information....................................... 78
5.3.3
Assessment of Severity of Adverse Events ........................... 78
5.3.4
Assessment of Causality of Adverse Events ......................... 79
5.3.5
Procedures for Recording Adverse Events............................ 80
5.3.5.1
Infusion-Related Reactions.................................................... 80
5.3.5.2
Diagnosis versus Signs and Symptoms................................. 80
5.3.5.3
Adverse Events That Are Secondary to Other 
Events.................................................................................... 81
5.3.5.4
Persistent or Recurrent Adverse Events................................ 81


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5.3.5.5
Abnormal Laboratory Values ................................................. 82
5.3.5.6
Abnormal Vital Sign Values ................................................... 82
5.3.5.7
Abnormal Liver Function Tests.............................................. 83
5.3.5.8
Deaths ................................................................................... 83
5.3.5.9
Preexisting Medical Conditions.............................................. 84
5.3.5.10
Lack of Efficacy or Worsening of Alzheimer’s 
Disease.................................................................................. 84
5.3.5.11
Hospitalization or Prolonged Hospitalization.......................... 84
5.3.5.12
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 85
5.3.5.13
Clinical Outcome Assessment Data ...................................... 85
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 86
5.4.1
Emergency Medical Contacts................................................ 86
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 87
5.4.2.1
Events That Occur prior to Initiation of Study 
Drug or [18F]GTP1 or an Amyloid Radioligand....................... 87
5.4.2.2
Events That Occur after Initiation of Study Drug 
or [18F]GTP1 or an Amyloid Radioligand ............................... 87
5.4.3
Reporting Requirements for Pregnancies.............................. 88
5.4.3.1
Pregnancies in Female Patients............................................ 88
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 88
5.4.3.3
Congenital Anomalies/Birth Defects and 
Abortions ............................................................................... 88
5.5
Follow-Up of Patients after Adverse Events .......................... 89
5.5.1
Investigator Follow-Up........................................................... 89
5.5.2
Sponsor Follow Up ................................................................ 89
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 89
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 90
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 90
6.1
Determination of Sample Size ............................................... 91
6.2
Summaries of Conduct of Study............................................ 91


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6.3
Summaries of Treatment Group Comparability ..................... 91
6.4
Efficacy Analyses .................................................................. 91
6.4.1
Primary Efficacy Endpoint...................................................... 91
6.4.2
Secondary Efficacy Endpoints............................................... 91
6.5
Safety Analyses..................................................................... 92
6.6
Pharmacokinetic Analyses..................................................... 92
6.7
Immunogenicity Analyses...................................................... 92
6.8
Biomarker Analyses............................................................... 93
6.9
Interim analyses .................................................................... 93
6.9.1
Optional Interim Analysis....................................................... 93
7.
DATA COLLECTION AND MANAGEMENT ............................................... 94
7.1
Data Quality Assurance......................................................... 94
7.2
Electronic Case Report Forms............................................... 95
7.3
Electronic Clinician-Reported Outcome Data ........................ 95
7.4
Source Data Documentation.................................................. 95
7.5
Use of Computerized Systems .............................................. 96
7.6
Retention of Records............................................................. 96
8.
ETHICAL CONSIDERATIONS.................................................................... 97
8.1
Compliance with Laws and Regulations ................................ 97
8.2
Informed Consent.................................................................. 97
8.3
Institutional Review Board or Ethics Committee.................... 98
8.4
Confidentiality........................................................................ 98
8.5
Financial Disclosure .............................................................. 99
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 99
9.1
Study Documentation ............................................................ 99
9.2
Protocol Deviations................................................................ 99
9.3
Site Inspections ................................................................... 100
9.4
Administrative Structure....................................................... 100
9.5
Publication of Data and Protection of Trade 
Secrets ................................................................................ 100
9.6
Protocol Amendments ......................................................... 101


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10. REFERENCES ......................................................................................... 102
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 33
Table 2
Administration of First and Subsequent Infusions of 
MTAU9937A ............................................................................... 55
Table 3
Clinical Outcome Assessments................................................... 59
Table 4
Exploratory Biomarkers............................................................... 65
Table 5
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in WHO Toxicity Grading Scale ..................... 79
Table 6
Causal Attribution Guidance ....................................................... 80
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 40
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................ 107
Appendix 2
Schedule of Activities (Open-Label Extension) ......................... 114
Appendix 3
National Institute on Aging/Alzheimer’s Association Criteria 
for Mild Alzheimer’s Disease..................................................... 119
Appendix 4
National Institute on Aging/Alzheimer’s Association Criteria 
for Prodromal Alzheimer’s Disease (Mild Cognitive 
Impairment due to Alzheimer’s Disease) .................................. 121
Appendix 5
Anaphylaxis Precautions........................................................... 122
Appendix 6
World Health Organization Toxicity Grading Scale ................... 123


MTAU9937A—Genentech, Inc.
13/Protocol GN39763, Version 4
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 
PRODROMAL TO MILD ALZHEIMER’S DISEASE
PROTOCOL NUMBER:
GN39763
VERSION NUMBER:
4
EUDRACT NUMBER:
2017-001800-31
IND NUMBERS:
129270, 125702
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.
16/Protocol GN39763, Version 4
Resource Utilization Objectives
Corresponding Endpoint
To evaluate resource utilization of 
caregivers and patients treated with 
MTAU9937A
Change from baseline in the RUD-Lite at Week 73 
ADA=anti-drug antibody; ADAS-Cog=Alzheimer’s Disease Assessment ScaleCognitive 
Subscale; ADCS-ADL=Alzheimer’s Disease Cooperative Study GroupActivities of Daily Living 
Inventory; CSF=cerebrospinal fluid; C-SSRS=Columbia-Suicide Severity Rating Scale; 
CDR-SB=Clinical Dementia RatingSum of Boxes; GTP1= Genentech tau probe 1; 
iADL=Instrumental Activity of Daily Living; MOA= mechanism of action; MRI=magnetic resonance 
imaging; PET=positron emission tomography; PD=pharmacodynamic; PK=pharmacokinetic; 
RBANS=Repeatable Battery for the Assessment of Neuropsychological Status; RUDResource 
Utilisation in Dementia; WGS=whole genome sequencing.
Study Design
Description of Study
This Phase II, randomized, double-blind, placebo-controlled, parallel-group study will evaluate 
the efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of MTAU9937A 
in patients with prodromal AD (pAD) to mild AD (mAD). 
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 in the double-blind treatment period.  MTAU9937A will be administered Q4W in the 
OLE period.  
Study treatment is defined as study drug plus the PET radioligand used during PET imaging 
procedures ([18F] Genentech tau probe 1 [GTP1] for tau PET imaging and the amyloid 
radioligand for amyloid PET imaging).  
Patients will be randomly assigned to one of three active, IV dose arms (1500 mg, 4500 mg, or 
8100 mg MTAU9937A) or to an IV placebo dose arm in a 2:3:2:3 
(1500 mg:4500 mg:8100 mg:placebo) ratio.  All patients participating in the OLE will receive 
MTAU9937A 4500 mg IV.  To maintain balance in dementia status and APOE status between 
treatment arms, randomization will be stratified by dementia status (pAD vs. mAD) and APOE
status (ApoE4+ vs. ApoE4).  To ensure adequate representations of each diagnostic group, 
the Sponsor may operationally manage the proportion of pAD and mAD patients in the study 
(e.g., no more than approximately 80% of one category).
Patients will be selected on the basis of clinical diagnosis of probable AD (according to the 
National Institute on Aging/Alzheimer’s Association [NIA-AA] Diagnostic Criteria and Guidelines 
for AD) or pAD (according to the NIA-AA Diagnostic Criteria and Guidelines for AD).  pAD is 
defined in this protocol as a clinical diagnosis of mild cognitive impairment (MCI) due to AD 
coupled with evidence of cerebral amyloidosis. 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80 years old at the beginning of screening, meet diagnostic criteria 
for MCI or 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.  Under certain circumstances, a previously acquired amyloid PET scan may be used 
for study inclusion.  If the previously acquired amyloid PET scan is read as amyloid negative by 


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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 Mini-Mental State Examination (MMSE) score 
of 20 points and a Clinical Dementia RatingGlobal Score (CDR-GS) of 0.5 or 1.0.  To confirm 
objective memory impairment, patients must also have a Repeatable Battery for the 
Assessment of Neuropsychological Status (RBANS) Delayed Recall Index of 85 at the time of 
screening.  Patients will be eligible for the study whether or not 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 (including during the 
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.
To monitor patients for safety, the incidence and nature of adverse events, serious adverse 
event, adverse events of special interest, responses on the Columbia-Suicide Severity Rating
Scale (C-SSRS), and abnormalities in standard safety blood and urine tests, ECG, vital signs, 
physical examination, and magnetic resonance imaging (MRI) will be assessed on a regular 
basis by the Sponsor and an unblinded independent Data Monitoring Committee (iDMC). Blood 
samples will be obtained from all patients for the assessment of pharmacokinetics and for the 
measurement of antibodies directed against MTAU9937A and other components of the drug 
product.
Baseline measures of clinical outcome assessments (COAs) (for clinical efficacy) and tau 
biomarkers (for pharmacodynamic [PD] activity) will be obtained prior to the initiation of study 
drug, either during the screening period (e.g., Clinical Dementia RatingSum of Boxes [CDR-
SB]) or during the post-randomization baseline visit (e.g., the Amsterdam Instrumental Activity 
of Daily Living [iADL] or [18F]GTP1 PET imaging).  Assessment of clinical efficacy will be 
determined by changes from baseline to Week 73 on a number of COAs.  Changes from 
baseline to Week 73 on a number of biomarker measurements (e.g., tau burden as measured 
by [18F]GTP1 PET, plasma/CSF analytes) will be used to assess PD activity in this study.  
Assessment of COAs and biomarkers will continue into the OLE period, for those patients 
continuing into the optional OLE period.
All patients must have baseline and longitudinal tau-related biomarker evaluation.  
If [18F]GTP1 PET imaging is available to a patient, based on site availability of [18F]GTP1 PET 
imaging and lack of local restriction to such imaging, the patient must undergo [18F]GTP1 PET 
imaging for tau-related biomarker evaluation.  [18F]GTP1 PET imaging will be performed at the 
baseline visit (after randomization), Week 49, and Week 73 during the double-blind treatment 
period; those patients continuing into the optional OLE period must also have [18F]GTP1 PET 
imaging performed at Week 169.  In addition, for patients undergoing [18F]GTP1 PET imaging, 
optional CSF collection at baseline and postbaseline time points is also encouraged.
For sites where [18F]GTP1 PET imaging is not available, or where local restrictions preclude 
[18F]GTP1 PET imaging, patients must have CSF collected via lumbar puncture (LP) at baseline, 
Week 49, and Week 73 during the double-blind treatment period; those patients continuing into 
the optional OLE period are encouraged to have an LP performed at Week 169.  If an LP was 
performed during screening for the assessment of amyloid positivity, CSF from this LP will be 
used for the baseline measurement; otherwise, an LP must be performed during the baseline 
visit (after randomization).
[18F]GTP1 PET, amyloid PET, and MRI evaluation will use a standard protocol, provided in the 
imaging technical operations manuals.  Screening amyloid PET and MRIs will be read by a 
central reader to determine eligibility.  Screening amyloid CSF analysis will be performed by a 
central laboratory.
PET scans should be performed only if the investigator has determined that the total past and 
planned annual radiation exposure does not exceed local guidelines.  Radiation exposure for 
[18F]GTP1 doses can be found in the [18F]GTP1 Investigator’s Brochure.  Radiation exposure 
for doses of the amyloid radioligands can be found in the local labeling instructions or, 
depending on locality, in the Investigator’s Brochures.


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Number of Patients
This study has enrolled 457 patients and is being conducted at 97 sites in North America, 
Europe, and the Asia-Pacific region.
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 required by the local regulations, guidelines, and independent ethics 
committee or institutional review board)
Patients should be judged by the investigator to be lucid and oriented when giving the 
informed consent.

Age between 50 and 80 years, inclusive, at time of signing Informed Consent Form

NIA-AA core clinical criteria for probable AD dementia or pAD (consistent with the NIA-AA 
diagnostic criteria and guidelines for MCI) 

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 to potentially be enrolled.  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 to potentially enrollment, but the patient may not undergo an additional 
amyloid PET scan for enrollment.

mAD symptomatology, as defined by a screening MMSE score of 20 points and CDR-GS 
of 0.5 or 1

Abnormal memory function at screening as demonstrated by an RBANS Delayed Recall 
Index 85

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 is subject to 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 to be able to provide accurate 
information regarding the patient’s cognitive and functional abilities, agrees to provide 
information at clinic visits (which require partner input for scale completion), signs the 
necessary consent form, and has sufficient cognitive capacity to accurately report upon 
the patient’s behavior and cognitive and functional abilities
Is in sufficiently good general health to have a high likelihood of maintaining the same 
level of interaction with the patient and participation in study procedures throughout the 
study duration


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Every effort should be made to have same caregiver participate throughout the duration of 
the study, for the purpose of 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 aspects of the study (including MRI, LP [if applicable], 
clinical genotyping, and PET imaging [if applicable]); 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)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use of contraceptive methods with a failure rate of 1% per 
year during the treatment period and for 9 weeks after the last dose of study drug or 4 days 
after the last dose of [18F]GTP1 or an amyloid radioligand, whichever is longer
A woman is considered to be of childbearing potential if she is postmenarcheal, has not 
reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, 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 female partners of childbearing potential or pregnant female partners, men must 
remain abstinent or use a condom during the treatment period and for 9 weeks after the 
last dose of study drug or 4 days after the last dose of [18F]GTP1 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 contraception.
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 last dose of study drug or 4 days after the last dose of [18F]GTP1 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


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
A patient must be able to undergo either PET imaging or lumbar dural puncture, or both, and 
patients with contraindications to both procedures are ineligible.
For patients undergoing PET imaging:  Planned, or recent (within 12 months prior to 
screening) exposure to ionizing radiation that in combination with the planned 
administrations of [18F]GTP1 or an amyloid radioligand would result in a cumulative 
exposure that exceeds recommended local guidelines
For patients undergoing LP:  contraindication to lumbar dural puncture, including 
coagulopathy, concomitant anticoagulation (except for a platelet inhibitor such as 
aspirin or clopidogrel), thrombocytopenia, 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 regions 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, 
except if current residence is in a section of the facility where no assistance is provided for 
basic activities of daily living
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 using Fridericia’s formula 470 ms in females and >450 ms in males, 
demonstrated by at least two ECGs 30 minutes apart


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
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 are defined as a thyroid-stimulating hormone 
(TSH) level outside the normal range and either a free thyroxine (T4) or a total T4 level 
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 
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’s 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 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.
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
History or presence of central nervous system or systemic autoimmune disorders potentially 
causing progressive neurologic disease with associated cognitive deficits (e.g., multiple 
sclerosis, lupus erythematosus, antiphospholipid antibody syndrome, Behçet disease)

MRI evidence of 1) more than two lacunar infarcts, 2) any territorial infarct 1 cm3, or 
3) 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
Infections and Immune Disorders
Patients who meet any of the following infections and immune disorders criteria will be excluded 
from study entry:

Systemically, clinically significantly immunocompromised patients, owing to continuing 
effects of immune-suppressing medication

Positive for hepatitis C virus antibody at screening

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 pre-specified duration prior to study start, as 
indicated, and during the entire period of study participation (patients who start these medications 
during the study may be withdrawn from study treatment, 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, except use of 
MTAU9937A in Genentech Study GN39058, as long as the last dose was at least 90 days 
prior to screening.

Use of any passive immunotherapy (immunoglobulin) against A, unless the last 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 neurodegenerative disorder within 1 year of screening 
Certain medications are acceptable if the patient is taking the medicine for a 
non-neurodegenerative disorder, such as restless leg disorder (e.g., pramipexole)

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 as long as the dose is 7.5 mg/day 
prednisolone equivalent and the condition being treated is not expected to deteriorate 
significantly during the study period.

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.
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
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.
Atypical antipsychotics
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 43 months after the last patient is enrolled.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 63 months.
Investigational Medicinal Products
Test Product (Investigational Drug)
Study treatment is defined as study drug plus the PET radioligand used during PET imaging 
procedures ([18F]GTP1 for tau PET imaging, and the amyloid radioligand for amyloid PET 
imaging).  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 
investigational medicinal products.
Study drug (MTAU9937A or placebo) will be administered IV in the double-blind treatment 
period, and MTAU9937A will be administered IV in the optional OLE period.  Study drug 
administration will occur Q2W for the first three doses of the double-blind treatment period and 
every 4 weeks (Q4W) thereafter in the double-blind treatment period.  Patients will receive
1500 mg, 4500 mg, or 8100 mg MTAU9937A IV or a placebo IV.  MTAU9937A will be 
administered Q4W in the OLE period.  All patients participating in the OLE will receive 
MTAU9937A 4500 mg IV.
[18F]GTP1 and amyloid radioligands will be used for tau PET and amyloid PET imaging, 
respectively.  For each PET imaging procedure, a single dose of the relevant radioligand will be 
injected prior to the PET scan.  Details for radioligand doses and administration are provided in 
the Technical Operations Manuals for the various radioligands.
Statistical Methods
Primary Analysis
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 primary efficacy Clinical Dementia RatingSum of Boxes (CDR-SB) measurement.  
For the efficacy analysis, patients will be grouped according to the treatment assigned at 
randomization.  The primary efficacy endpoint is change in CDR-SB score from baseline to 
Week 73.  The difference in mean change from baseline to Week 73 between MTAU9937A-
and placebo-treated patients will be estimated using an analysis of covariance model adjusting 
for ApoE4 status and baseline clinical status (i.e., prodromal AD vs. mild AD dementia).  
Confidence intervals as well as least squares estimates will be used to aid in interpretation of 
study results. 
The safety analysis will be based on all randomized patients who receive at least one dose of 
either MTAU9937A or placebo, or GTP1.  Patients will be grouped according to MTAU9937A 
treatment actually received.  All adverse events that occur after informed consent is given will 


MTAU9937A—Genentech, Inc.
24/Protocol GN39763, Version 4
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.  Dose-limiting adverse events and adverse events of special interest 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.

A primary analysis will occur after the last patient has completed the Week 73 assessment. 

A final analysis will occur after the last patient has finished the OLE and completed the 
Week 169 assessment.
Determination of Sample Size  
This study has enrolled 457 patients, randomized to one of three active IV dose arms or to an IV 
placebo dose arm in a 2:3:2:3 ratio.  The prior projected sample size of 360 patients provides 
reasonable precision for estimating a clinically significant treatment effect on CDR-SB scores
when MTAU9937A is compared with placebo. Assuming an observed 0.6-point difference in 
mean CDR-SB decline between the 4500 mg MTAU9937A arm and placebo at Week 73, a 
standard deviation across patients of 2, and a 25% dropout rate, a 90% confidence interval on 
the population treatment effect point estimate for the CDR-SB is approximately 0.081.12.
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct an interim efficacy analysis.  The rationale for conducting an interim analysis 
will be on the basis of factors and information external to this study such as new, emergent data 
from other clinical trials.  
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis will be 
conducted by an external statistical group and reviewed by the iDMC.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC charter. 
The decision to conduct an optional interim analysis, along with the rationale and timing, will be 
documented in the protocol.  Statistical details for the interim analysis will be contained within 
the Statistical Analysis Plan (SAP).  A substantial protocol amendment (in the European Union) 
or the SAP (other jurisdictions) will be submitted to relevant health authorities, as appropriate,
prior to the conduct of the interim analysis.  The iDMC charter will also be updated to document 
potential recommendations the iDMC can make to the Sponsor as a result of this analysis and 
the iDMC charter will be submitted to relevant Health Authorities.  All documents submitted to 
health authorities would be simultaneously submitted to the study master file to further 
document this information appropriately.  The Clinical Study Report will also document that such 
an interim analysis occurred.
If the interim analysis plan allows for early assessment of efficacy, the type I error rate will be 
controlled to ensure statistical validity is maintained.  Specifically, the Lan-DeMets -spending 
function that approximates the O’Brien-Fleming boundary will be applied to determine the 
critical value for stopping for positive efficacy at the interim analysis.  Additional criteria for 
recommending that the study be stopped for positive efficacy may be added to the iDMC charter.  
If the study continues beyond the interim analysis, the critical value at the final analysis would 
be adjusted accordingly to maintain the overall type I error rate, per standard Lan-DeMets 
methodology.  The select efficacy endpoints provided to the iDMC as part of ongoing safety 
review do not enable and are not considered sufficient for a formal interim analysis to assess
early efficacy or futility.
If the interim analysis plan allows for early assessment of futility, the threshold for declaring 
futility will include an assessment of the predictive probability that the primary endpoint will 
achieve statistical significance.  An interim analysis that might lead to stopping the study for 
futility will not occur before at least 50% of the information has been accumulated for the 
primary endpoint.


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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-Cog
Alzheimer’s Disease Assessment ScaleCognitive Subscale
ADCS-ADL
Alzheimer’s Disease Cooperative Study GroupActivities of Daily Living 
Inventory
ADL
activities of daily living
AUC
area under the concentrationtime curve
CaGI-Alz
Caregiver Global Impression of Change 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 Practices
GTP1
Genentech tau probe 1
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HV
healthy volunteer
iADL
Instrumental Activity of Daily Living 
ICH
International Conference on Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (application)


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Abbreviation
Definition
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LP
lumbar puncture
mAD
mild AD
MCI
mild cognitive impairment
MMSE
Mini-Mental State Examination
MRI
magnetic resonance imaging
NIA-AA
National Institute on Aging/Alzheimer’s Association
NIMP
Non-investigational medical product
OLE
open-label extension
pAD
prodromal AD
PD
pharmacodynamic
PET
positron emission tomography
PK
pharmacokinetic
Q2W
every 2 weeks
Q4W
every 4 weeks
QTcF
QT interval corrected using Fridericia’s formula
RBANS
Repeatable Battery for the Assessment of Neuropsychological Status
RBR
Research Biosample Repository
RUD
Resource Utilization in Dementia
SAP
Statistical Analysis Plan
SNP
single nucleotide polymorphism
T4
thyroxine
TK
toxicokinetic
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
URTI
upper respiratory tract infection
WES
whole exome sequencing
WGS
whole genome sequencing
YTE
heavy chain with M249Y, S251T, and T253E mutations


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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 
4.5 million individuals in the United States and 26.6 million worldwide (Hebert et al. 2003; 
Brookmeyer et al. 2007).  The disease is characterized pathologically by the 
accumulation 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 scale (CDR; 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 neuron 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 AD patients 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.


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1.2
BACKGROUND ON MTAU9937A
1.2.1
Non-Clinical 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 Practices
(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 [AUC] 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).
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 data show that MTAU9937A was well tolerated by 
cynomolgus monkeys following 27 weekly IV doses up to 300 mg/kg with no 


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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), this ongoing Phase II study (GN39763), and an ongoing 
Phase II study in patients with moderate AD (GN40040).
Study GN39058 was a randomized, placebo-controlled, double-blind, 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.  The study 
consisted of a single-ascending dose part (6 IV cohorts, with doses from 225 mg to 
16,800 mg, and one SC cohort at 1200 mg) and a multiple-dose part (2 IV cohorts each 
receiving 8400 mg IV once weekly 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 four doses of 8400 mg IV once a week (except for 1 HV, who was mistakenly 
given a first dose of 4200 mg, followed by three doses of 8400 mg).
Study GN40040 is a randomized, double-blind, Phase II study that aims to assess the 
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. 
This study will include approximately 260 patients from approximately 50 sites in 
North America and Europe. Patients will be randomized to MTAU9937A (4500 mg) or 
placebo administered IV in a 1:1 ratio.  
MTAU9937A has been generally well tolerated in HVs and patients with AD (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) or weekly (8400 mg 4 doses) IV or single (1200 mg) SC 


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administration to HVs and to patients with mild-to-moderate AD.  Upon IV administration, 
MTAU9937A exhibited biphasic disposition, and the 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.  An assessment of 
dose proportionality demonstrated that serum pharmacokinetics increased proportionally 
with the dose after a single-dose IV administration.  MTAU9937A was detected in the 
cerebrospinal fluid (CSF), suggesting penetration into the CNS.
Refer to the MTAU9937A Investigator's Brochure for further details on clinical studies, 
including the numbers of patients that have been exposed to MTAU9937A.
1.3
BACKGROUND ON [18F]GTP1
Tau protein has been identified as one of the key pathological features of AD (Grundke 
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 positron emission tomography (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.
Fluorine-18 Genentech tau probe 1 ([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 two additional Phase I studies: 
a test re-test study (e0048) with 5 patients with AD and 5 elderly HVs, and a radiation 
dosimetry study (e0049) with 6 HVs.  In addition, [18F]GTP1 is currently being evaluated 
in a Phase I longitudinal natural history study (Study GN30009; clinicaltrials.gov identifier 
NCT02640092).
[18F]GTP1 is also being evaluated in longitudinal PET-imaging substudies of Phase III 
trials of the anti-Aantibodies crenezumab (Studies BN29552 and BN29553; 
clinicaltrials.gov identifiers NCT02670083 and NCT03114657, respectively), and 
gantenerumab (Studies WN29922 and WN39658; clinicaltrials.gov identifiers 
NCT03444870 and NCT03443973, respectively).
1.3.1
Clinical Safety and Tolerability
Available safety data from the completed and ongoing clinical studies (completed: 
Studies e0040, e0048, e0049; ongoing: Study GN30009, Substudies
BN29552/BN29553, Substudies WN29922/WN39658, Study GN39763, and 


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Study GN40040) with [18F]GTP1 show that exposure to [18F]GTP1 and imaging
procedures are generally well tolerated.  One serious adverse event has been reported:  
a urinary tract infection in Study GN30009, assessed as not related to [18F]GTP1 by the 
investigator.  There have been no deaths, no adverse events of special interest, no 
hypersensitivity reactions, and no systemic infusion-related reactions reported. 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 among patients with AD, and 
MTAU9937A may fill that gap by targeting a key pathological protein believed to underlie 
the degenerative process.  Study GN39763 is a proof-of-concept study, using clinical 
outcome assessments (COAs), a novel tau imaging technology, and other biomarkers to 
test the hypothesis that MTAU9937A administration to patients with AD improves clinical 
outcome and stops or slows cell-to-cell spread and propagation of tau pathology in the 
brain.
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 weekly IV doses of up to 
300 mg/kg.  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.  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).
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 (GN39763).  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) and suicidality monitoring (see Section 4.5.7), and regular safety review
by an unblinded, independent Data Monitoring Committee (iDMC; Section 3.1.2).


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Because of high unmet need for disease-modifying treatments for 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 will be used in this study to evaluate the effect of MTAU9937A on tau burden 
as measured by tau PET in patients with AD.  Measures based on PET imaging with 
[18F]GTP1 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 is expected to be well tolerated by patients with AD in this study.  
There are no known risks to [18F]GTP1; potential risks of [18F]GTP1 are described in 
Section 5.1.2.
The benefitrisk of [18F]GTP1 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 efficacy, safety, pharmacokinetics, and pharmacodynamics 
of MTAU9937A in patients with prodromal AD (pAD) or mild AD (mAD), ages 5080, 
who are amyloid positive by CSF or amyloid PET. Specific objectives and 
corresponding endpoints for the study are outlined in Table 1.






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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 efficacy, safety and tolerability, pharmacokinetics, and 
pharmacodynamics of MTAU9937A in patients with pAD to mAD.
The study consists of a screening period, a double-blind treatment period, an optional 
OLE period, and a safety follow-up period (see Figure 1 for the study schema and in 
Appendix 1 and Appendix 2 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 in the double-blind treatment period.  MTAU9937A 
will be administered Q4W in the OLE period.
Study treatment is defined as study drug plus the PET radioligand used during PET 
imaging procedures ([18F]GTP1 for tau PET imaging and the amyloid radioligand for 
amyloid PET imaging).  See Section 4.3 for a description of the study treatments used in 
this study.
This study has enrolled 457 patients at 97 sites in North America, Europe, and the 
Asia-Pacific region.  Patients will be randomly assigned to one of three active, IV dose
arms (1500 mg, 4500 mg, or 8100 mg MTAU9937A) or to an IV placebo dose arm in a 
2:3:2:3 (1500 mg:4500 mg:8100 mg:placebo) ratio.  All patients participating in the OLE 
will receive MTAU9937A 4500 mg IV.  To maintain balance in dementia status and 
APOE status between treatment arms, randomization will be stratified by dementia 
status (pAD vs. mAD) and APOE status (ApoE4+ vs. ApoE4).  To ensure adequate 
representations of each diagnostic group, the Sponsor may operationally manage the 
proportion of pAD and mAD patients in the study (e.g., no more than approximately 80% 
of one category).
Patients will be selected on the basis of clinical diagnosis of probable AD (according to
the National Institute on Aging/Alzheimer’s Association [NIA-AA] Diagnostic Criteria and
Guidelines for AD; see Appendix 3; McKhann et al. 2011) or pAD (according to the 
NIA-AA Diagnostic Criteria and Guidelines for AD; see Appendix 4; Albert et al. 2011). 
pAD is defined in this protocol as a clinical diagnosis of mild cognitive impairment (MCI) 
due to AD (see Appendix 4; Albert et al. 2011) coupled with evidence of cerebral 
amyloidosis (see below). Clinical diagnosis for each patient must be supported by 
information provided on a Diagnostic Verification Form (DVF), which must be reviewed 


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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.
Eligible patients must be 5080 years old at the beginning of screening, meet diagnostic 
criteria for MCI (Albert et al. 2011) or 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 of 20 points and a Clinical 
Dementia RatingGlobal Score (CDR-GS) of 0.5 or 1.0.  To confirm objective memory 
impairment, patients must also have a Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS) Delayed Recall Index of 85 at the time of 
screening.  Patients will be eligible for the study whether or not 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 (including during the 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.
See Section 4.1 for further details of the inclusion and exclusion criteria.
To monitor patients for safety, the incidence and nature of adverse events, serious 
adverse events, adverse events of special interest, responses on the Columbia-Suicide 
Severity Rating Scale (C-SSRS), and abnormalities in standard safety blood and urine 
tests, ECG, vital signs, physical examination, and MRI will be assessed on a regular 
basis by the Sponsor and an unblinded iDMC.  Blood samples will be obtained from all 
patients for the assessment of pharmacokinetics and for the measurement of antibodies 
directed against MTAU9937A and other components of the drug product.
Baseline measures of COAs (for clinical efficacy) and tau biomarkers (for PD activity) will 
be obtained prior to the initiation of study drug, either during the screening period 


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(e.g., Clinical Dementia RatingSum of Boxes [CDR-SB]) or during the post-
randomization baseline visit (e.g., the Amsterdam Instrumental Activity of Daily Living
[iADL] or [18F]GTP1 PET imaging) (see Appendix 1 for details). Assessment of clinical 
efficacy will be determined by changes from baseline to Week 73 on a number of COAs. 
Changes from baseline to Week 73 on a number of biomarker measurements (e.g., tau
burden as measured by [18F]GTP1 PET, plasma/CSF analytes) will be used to assess 
PD activity in this study. Assessment of COAs and biomarkers will continue into the 
OLE period, for those patients continuing into the optional OLE period.
All patients must have baseline and longitudinal tau-related biomarker evaluation.  
If [18F]GTP1 PET imaging is available to a patient, based on site availability of 
[18F]GTP1 PET imaging and lack of local restriction to such imaging, the patient must 
undergo [18F]GTP1 PET imaging for tau-related biomarker evaluation.  [18F]GTP1 PET 
imaging will be performed at the baseline visit (after randomization), Week 49, and 
Week 73 during the double-blind treatment period; those patients continuing into the 
optional OLE period must also have [18F]GTP1 PET imaging performed at Week 169.  
In addition, for patients undergoing [18F]GTP1 PET imaging, optional CSF collection at 
baseline and postbaseline time points is also encouraged.
For sites where [18F]GTP1 PET imaging is not available, or where local restrictions 
preclude [18F]GTP1 PET imaging, patients must have CSF collected via lumbar puncture 
(LP) at baseline, Week 49, and Week 73 during the double-blind treatment period; those 
patients continuing into the optional OLE period are encouraged to have an LP
performed at Week 169.  If an LP was performed during screening for the assessment of 
amyloid positivity, CSF from this LP will be used for the baseline measurement; 
otherwise, an LP must be performed during the baseline visit (after randomization).
[18F]GTP1 PET, amyloid PET, and MRI evaluation will use a standard protocol, provided 
in the imaging technical operations manuals.  Screening amyloid PET and MRIs will be
read by a central reader to determine eligibility (see Section 4.1.2).  Screening amyloid 
CSF analysis will be performed by a central laboratory.
PET scans should be performed only if the investigator has determined that the total 
past and planned annual radiation exposure does not exceed local guidelines.  Radiation 
exposure for [18F]GTP1 doses can be found in the [18F]GTP1 Investigator’s Brochure.  
Radiation exposure for doses of the amyloid radioligands can be found in the local 
labeling instructions or, depending on locality, in the Investigator’s Brochures.
3.1.1.1
Study Periods
A schedule of activities is provided in Appendix 1 and Appendix 2, describing in detail 
the procedures and assessments of the various study periods.


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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 Mini-Informed Consent Form may 
be signed that covers only medical history, MMSE, and RBANS, and 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.
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, RBANS, and CDR, 
along with information supportive of a pAD or mAD 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, by the DVF or other screening procedures, 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.
See Appendix 1 for details regarding screening activities. On a case-by-case basis, the 
Medical Monitor may advise whether any specific screening procedures need to be 
repeated at the time of a rescreening.
Double-Blind Treatment Period
The double-blind treatment period of the study includes a baseline visit (of up to 15 days; 
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), a 68-week treatment 
period (Weeks 169), and an efficacy assessment period (baseline to Week 73). 
Treatment with study drug will occur Q2W for the first three doses (i.e., doses at 
Weeks 1, 3, and 5) and Q4W thereafter, up to and including the Week 69 dose (for a 
total of 19 doses).  There will be no administration of study drug at the Week 73 visit.  
Safety, efficacy, PK, and biomarker assessments will be performed at baseline (during 
screening, the baseline visit, or at the Week 1 visit, prior to initiation of study drug) and at 
several postbaseline visits, including the Week 73 visit. See Appendix 1 for details 
regarding study activities during the double-blind treatment period.
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.  Safety and efficacy assessments during the OLE period will 


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be performed at a schedule similar to that of the double-blind treatment period. The 
procedure(s) performed for tau-based biomarker evaluation during the OLE period 
([18F]GTP1 PET imaging and/or LP) should match the procedure(s) performed during the 
double-blind treatment period; LP will remain optional, but encouraged, for any patient 
who continues with longitudinal [18F]GTP1 PET imaging and had a screening or baseline 
LP.  See Appendix 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 last dose of 
study drug (i.e., at Week 81).  Patients entering the OLE period will have a safety 
follow-up visit 12 weeks after the last dose of open-label treatment (i.e., at Week 181). 
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 last treatment dose.  See Appendix 1 and Appendix 2 for details regarding 
study activities during the safety follow-up period.




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3.1.2
Independent Data Monitoring Committee
To monitor patients for safety, the incidence and nature of adverse events, serious 
adverse events, and adverse events of special interest, responses on the C-SSRS, and 
abnormalities in standard safety blood and urine tests, ECG, vital signs, physical 
examination, and MRI will be assessed on a regular basis, approximately every 
34 months, by an unblinded iDMC.  The unblinded iDMC may also receive select 
summary statistics of COA endpoints.
At each safety review meeting, the iDMC will meet in a closed session to recommend 
whether the study should continue without modification, continue with minor modification, 
continue with substantial modification, suspend enrollment or treatment, or be
terminated.  There are currently no planned interim analyses to stop the trial early for 
either futility or clear signs of efficacy.  Details of the iDMC will be provided in the iDMC 
Charter.
The Sponsor will also monitor all safety data continuously on a blinded basis.
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 43 months after the last patient is enrolled.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 63 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. 
Therefore, this study will evaluate three doses of MTAU9937A in order to explore 
dose/exposure-response relationships for efficacy, pharmacodynamics, safety, and 
tolerability.
The rationale for the three proposed dosing regimens of 1500, 4500, and 8100 mg Q4W 
in this study take into account 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.  The 8100-mg IV Q4W dose, the highest dose level of 
MTAU9937A, is justified on the basis of a 1.3- to 1.4-fold safety margin between the 
highest mean exposure (based on both Cmax and AUC) in the multiple-dose portion of 
the Phase I study and the predicted steady-state exposure in this study at the 8100-mg 
dose. The favorable safety profile of MTAU9937A to date in Study GN39058 supports 


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doses up to 8100 mg IV (see Section 1.2.2).  In addition, simulations incorporating 
model-based PK variability predict that these three doses will have minimal overlap with 
regard to PK exposure.
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 three
doses 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.
3.3.2
Rationale for Patient Population
The patient selection approach is consistent with the NIA-AA research diagnostic criteria 
and guidelines for AD as well as with the Qualification Opinion from the European 
Medicines Agency’s Committee for Medicinal Products for Human Use on the use of 
CSF biomarkers 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 (2013). Although the FDA guidance refers to the early stage of AD in which 
individuals present with MCI, biomarkers of amyloid pathology are expected to add value 
to patient selection in mAD studies (see Section 3.3.3).
Patients in this study are also required to meet standard research criteria for mAD 
(according to the NIA-AA research criteria and guidelines for AD; Appendix 3) or pAD 
(according to the NIA-AA research criteria and guidelines for MCI; Appendix 4).  Patients 
with pAD will present with documented objective evidence of deficit in at least 
one cognitive domain.  Patients with mAD will present with documented deficits in at 
least two cognitive domains and in functional decline.  Overall, the population will have 
an MMSE of20 points and a CDR-GS of between 0.5 and 1.0.  The MMSE score 
provides evidence of mild disease severity, and the CDR-GS score indicates that the 
patients have noticeable amnestic (pAD) or cognitive and functional deficits (mAD). 
To ensure that the patients selected are likely to decline over the length of the study, 
two approaches have been included.  The first is that all patients have to demonstrate 
amnestic deficits as measured by the Delayed Recall index of the RBANS (see 
Section 4.5.7.3).  The Delayed Recall index of 85 has been selected, corresponding to 
one standard deviation below population-based normative data.
The second approach to ensure decline is to verify that there is evidence of prior decline 
through observations made by clinician or caregiver and recorded on the DVF.  
Enrollment into this study is subject to adjudication of diagnosis by the Sponsor or 


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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) or pAD symptomatology sufficient to meet the appropriate criteria
specified in Albert 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 this adjudication process.  The scope and detailed 
procedures for the diagnostic verification process will be described in the study 
documents and documented for review on the 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 AD 
patients 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 
amyloid pathology as assessed by amyloid PET (Doody et al. 2014). 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 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. 


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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.
3.3.5
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.
3.3.6
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 pAD to mAD, as 
appropriate.
3.3.7
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, CDR-SB, is a 
validated instrument that has been widely used in assessing AD. Additional observer 
(caregiver) and clinician reported outcomes will be used to evaluate patient cognition, 
function, and behavior, as well as health resource usage during the course of the study. 
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 potential confounds to these cognitive assessments, any patient with a 
current untreated depressive episode (i.e., presence of depressive symptoms) will be 
excluded from the study.  Current treatment for depression will be documented in the 
electronic Case Report Form (eCRF).
3.3.8
Rationale for Use of Investigational Tau Radioligand [18F]GTP1
Tau pathology is a required finding in autopsy-confirmed AD. Patients in this study will 
have the option of biomarker measurements of tau in CSF or measurement of tau with 
the investigational PET radioligand [18F]GTP1 (or both). Tau measurements will be 
collected at baseline but will not serve as an eligibility criterion for patient enrichment 
because correlations between these measurements and underlying pathology are not 
yet sufficiently understood. Tau imaging using the investigational [18F]GTP1 PET 
radioligand has been incorporated in this study because it provides an opportunity to 


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evaluate the relationship between baseline levels and distribution of tau pathology, and 
response to the investigational anti-tau therapy. Use of [18F]GTP1 PET has unique 
advantages, a favorable safety profile to date (see Section 1.3.1), and the potential to 
inform the relationship between spatial distribution of tau pathology, cognitive function,
and disease progression.
3.3.9
Rationale for Biomarker Assessments
Biomarker assessments will be used to verify amyloid-positivity for enrichment (see 
Section 3.3.3), 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, support selection of a recommended dosing regimen, and increase the 
knowledge and understanding of disease biology.
Blood samples will be collected at baseline for DNA extraction to enable analysis using 
methods such as whole genome sequencing (WGS) to identify common and rare genetic 
variants that may be 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.
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches.  Data will be analyzed in the context of this study but will also be explored 
in aggregate with data from other studies.  The availability of a larger dataset will assist 
in identification of important pathways, guiding the development of new targeted agents.
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study has enrolled 457 male and female patients with pAD to mAD, between the 
ages of 50 and 80 years, at 97 investigative sites located in North America, Europe, and
the Asia-Pacific region.
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 required by the local regulations, guidelines, and 
independent ethics committee [EC] or Institutional Review Board [IRB])
Patients should be judged by the investigator to be lucid and oriented when 
giving the informed consent.

Age between 50 and 80 years, inclusive, at time of signing Informed Consent Form


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
NIA-AA core clinical criteria for probable AD dementia (see Appendix 3; McKhann 
et al. 2011) or pAD (consistent with the NIA-AA diagnostic criteria and guidelines for 
MCI; Appendix 4; Albert 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 to potentially be enrolled.  
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 (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 to potentially enrollment, but 
the patient may not undergo an additional amyloid PET scan for enrollment.

mAD symptomatology, as defined by a screening MMSE score of20 points and 
CDR-GS of 0.5 or 1

Abnormal memory function at screening as demonstrated by an RBANS Delayed 
Recall Index85

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 is subject to 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 to be able to provide 
accurate information regarding the patient’s cognitive and functional abilities, 
agrees to provide information at clinic visits (which require partner input for 
scale completion), signs the necessary consent form, and has sufficient 
cognitive capacity to accurately report upon the patient’s behavior and cognitive 
and functional abilities
Is in sufficiently good general health to have a high likelihood of maintaining the 
same level of interaction with the patient and participation in study procedures 
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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 aspects of the study (including MRI, LP
[if applicable], clinical genotyping, and PET imaging [if applicable])
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)

For women of childbearing potential:  agreement to remain abstinent (refrain from 
heterosexual intercourse) or use of contraceptive methods with a failure rate of 
1% per year during the treatment period and for 9 weeks after the last dose of
study drug or 4 days after the last dose of [18F]GTP1 or an amyloid radioligand, 
whichever is longer
A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (12 continuous months of 
amenorrhea with no identified cause other than menopause), and has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
Examples of contraceptive methods with a failure rate of 1% per year include 
bilateral tubal ligation, male sterilization, 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 female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for 
9 weeks after the last dose of study drug or 4 days after the last dose of 
[18F]GTP1 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 contraception.


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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 last dose of study drug or 4 days after the last dose of 
[18F]GTP1 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

A patient must be able to undergo either PET imaging or lumbar dural puncture, or 
both, and patients with contraindications to both procedures are ineligible.
For patients undergoing PET imaging: Planned, or recent (within 12 months 
prior to screening) exposure to ionizing radiation that in combination with the 
planned administrations of [18F]GTP1 or an amyloid radioligand would result in 
a cumulative exposure that exceeds recommended local guidelines
For patients undergoing LP: Contraindication to lumbar dural puncture, 
including coagulopathy, concomitant anticoagulation (except for a platelet 
inhibitor such as aspirin or clopidogrel), thrombocytopenia, 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 regions 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, except if current residence is in a section of the facility where no 
assistance is provided for basic activities of daily living (ADL)
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
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 using 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 are defined as a thyroid-stimulating 
hormone (TSH) level outside the normal range and either a free thyroxine (T4)
or a total T4 level 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 
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’s 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 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 central nervous system or systemic autoimmune disorders 
potentially causing progressive neurologic disease with associated cognitive deficits 
(e.g., multiple sclerosis, lupus erythematosus, antiphospholipid antibody syndrome, 
Behçet disease)

MRI evidence of 1) more than two lacunar infarcts, 2) any territorial infarct 1 cm3, 
or 3) 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
Infections and Immune Disorders
Patients who meet any of the following infections and immune disorders criteria will be 
excluded from study entry:

Systemically, clinically significantly immunocompromised patients, owing to 
continuing effects of immune-suppressing medication

Positive for hepatitis C virus (HCV) antibody at screening

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 pre-specified duration prior to study start, 
as indicated, and during the entire period of study participation (patients who start these 
medications during the study may be withdrawn from study treatment, 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, except use of
MTAU9937A in Genentech Study GN39058, as long as the last dose was at least 
90 days prior to screening.

Use of any passive immunotherapy (immunoglobulin) against A, unless the last 
dose was at least 1 year prior to screening.


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
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 neurodegenerative disorder within 1 year of screening 
Certain medications are acceptable if the patient is taking the medicine for a 
non-neurodegenerative disorder, such as restless leg disorder 
(e.g., pramipexole).

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 as long as the dose is
7.5 mg/day prednisolone equivalent and the condition being treated is not 
expected to deteriorate significantly during the study period.

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.
Atypical antipsychotics
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
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Patients will be randomly assigned to one of three active, IV dose arms (1500, 
4500, or 8100 mg MTAU9937A) or to an IV placebo dose arm in a 2:3:2:3 
(1500mg:4500 mg: 8100 mg:placebo) ratio.  Randomization of patients will be managed 
by a central interactive voice or Web-based response system (IxRS) vendor using 
stratified permuted block randomization.  The randomization will be stratified by 
dementia status (pAD vs. mAD) and APOE status (ApoE4+ vs. ApoE4).


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Patients, study site personnel who will evaluate patient status, contract research 
organization (CRO) personnel who will review CRFs, other Sponsor agents (with the 
exception of the IxRS vendor), and the Sponsor will remain blinded to treatment 
assignment.  The unblinded site pharmacist and the unblinded CRO monitor will be 
unblinded to treatment assignment.
The iDMC and independent data coordinating center vendor will be unblinded to 
treatment assignment.
Although PK samples must be collected from participants assigned to placebo to 
maintain the blinding of treatment assignment, PK assay results for the placebo 
participants are generally not needed for the safe conduct or proper interpretation of this 
trial.  Laboratory personnel responsible for performing PK assays will be unblinded to 
participants’ treatment assignments to identify appropriate PK samples to be analyzed.  
Samples from participants assigned to the placebo arm will not be analyzed except by 
request (e.g., to evaluate a possible error in dosing).
If unblinding is necessary for immediate patient management (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.
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 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 (NIMPs) or 
IMPs.  Refer to the Amyloid Imaging Technical Operations Manual for a list of amyloid
PET radioligands allowed in this study.


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4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
MTAU9937A and Placebo
MTAU9937A will be supplied by the Sponsor as a sterile liquid in 20-mL 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 will be provided under contract with a PET imaging vendor in accordance with 
approved national and/or local standards. [18F]GTP1 will be supplied as a sterile 
non-pyrogenic solution in sterile borosilicate glass vials with gray butyl septa and 
aluminum ring seals. The vial is contained within an outer lead or tungsten shield ("pig") 
to protect from gamma radiation.  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, see the [18F]GTP1 Investigator’s Brochure and the [18F]GTP1
PET Imaging Technical Operations Manual.
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.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.1.
Any overdose or incorrect administration of MTAU9937A or [18F]GTP1 or an amyloid 
radioligand (if they are considered IMPs) should be noted on the Study Drug 
Administration eCRF.  Adverse events associated with an overdose or incorrect 
administration of any of the study treatments should be recorded on the Adverse Event 
eCRF.
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.3.
4.3.2.1
MTAU9937A and Placebo
MTAU9937A 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 2 and the pharmacy manual.


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Table 2
Administration of First and Subsequent Infusions of MTAU9937A
First Infusion
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.
4.3.2.2
[18F]GTP1 Tau PET Radioligand
Patients who undergo tau PET imaging will receive [18F]GTP1 and undergo a PET scan 
on multiple occasions as described in the schedule of activities in Appendix 1 and 
Appendix 2.  Refer to the [18F]GTP1 PET Imaging Technical Operations Manual for 
details on the use of [18F]GTP1.
4.3.2.3
Amyloid PET Radioligands
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.
4.3.3
Investigational Medicinal Product Accountability
IMPs required for completion of this study (MTAU9937A or placebo) and radiotracers 
(which may be IMPs or NIMPs) will be provided by the Sponsor where required by local 
health authority regulations.  The study site will acknowledge receipt of IMPs, using the 


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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 will be returned to the Sponsor with the appropriate 
documentation.  The site’s method of MTAU9937A/placebo destruction 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 
Web site:
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 the start of 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.
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.


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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 schedule of activities to be performed during the study is provided in Appendix 1
and Appendix 2.  All activities must be performed and documented for each patient. 
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).  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;
and 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, 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.


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Demographic data will include age, sex, self-reported race/ethnicity, and years of 
education.  Demographic data will be collected for both the patient and the caregiver.
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, dermatological, respiratory, and gastrointestinal systems.  In addition, 
the musculoskeletal and genitourinary systems should be examined as clinically 
indicated.  Any abnormality identified at baseline should be recorded on the General 
Medical History and Baseline Conditions eCRF.
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
Neurological Examinations
A complete neurologic examination should include the evaluation of consciousness, 
cranial nerves, motor and sensory system, coordination and gait, and reflexes.  Changes 
from baseline abnormalities should be recorded at each subsequent neurologic 
examination.  New or worsened abnormalities should be recorded as adverse events on 
the Adverse Event eCRF if considered clinically significant in the investigator’s judgment.
4.5.5
Lumbar Puncture
For patients consenting to LP, 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.


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The same arm should be used for all blood pressure measurements. Pulse rate and 
blood pressure should not be measured unless 15 minutes have passed since the last 
blood draw. Vital sign assessments should be performed just prior to study drug 
administration.
4.5.7
Clinical Outcome Assessments
The COAs listed in Table 3 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.
Table 3
Clinical Outcome Assessments
Clinical Outcome Assessments
Concept
Mini-Mental State Examination (MMSE)
Cognition
Clinical Dementia Rating Scale (CDR)
Cognition and Function
Repeatable Battery for the Assessment of Neuropsychological 
Status (RBANS)
Cognition
Alzheimer’s Disease Assessment ScaleCognitive Subscale 
(ADAS-Cog 13)
Cognition
Amsterdam Instrumental Activity of Daily Living Questionnaire 
(iADL)
Function
Alzheimer’s Disease Cooperative Study Group–Activities of 
Daily Living Inventory (ADCS-ADL)
Function
Alzheimer’s Disease Event Inventory (ADEI)
Significant events
Resource Utilization in DementiaLite (RUD-lite)
Resource utilization
Columbia-Suicide Severity Rating Scale (C-SSRS)
Suicidality
Diagnostic Classification
Diagnosis
Caregiver Global Impression of Change Scales for Alzheimer's 
disease (CaGI-Alz)
Cognition and Function
The questionnaires, 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 
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 


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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 done in accordance with instructions provided in the GN39763 
COA Manual and the training/documentation provided by the rating-scale vendor.
In addition, given that the primary outcome measure in this study involves subjective 
judgment, 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 GN39763 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.
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), which has a total score 
of 030.  The MMSE will be administered to patients at screening to determine eligibility 
for the trial and at other timepoints postbaseline. 
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 their caregiver informant.  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 
Sum of Boxes (CDR-SB).  Reliability and validity have been established, as has high 
inter-rater reliability.  This will be used as a global assessment of severity of dementia.
4.5.7.3
Repeatable Battery for the Assessment of Neuropsychological 
Status
The RBANS is a validated neuropsychological assessment has been shown to be a 
useful tool in both clinical and research settings.  The RBANS consists of ten subtests 
that are combined to provide five indices, one for each of the five domains tested 
(immediate memory, visuospatial/constructional, language, attention, and delayed 
memory) (Randolph et al. 1998).  Extensive normative values are provided in the testing 
manuals.


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The RBANS was initially developed as an assessment tool for dementia and has been 
validated in a number of studies of dementia and MCI (Kotani et al. 2006). The RBANS 
has also been related to functional limitations in patients with dementia and MCI (Freilich 
and Hyer 2007; Badenes Guia et al. 2008; Hobson et al, 2010).  More recently, the 
diagnostic accuracy of the RBANS has been shown to adequately detect cognitive 
impairment associated with AD (Duff et al. 2008).  Although several studies have used 
the RBANS as a tool to examine cognitive dysfunction, there remains little information 
regarding the diagnostic accuracy of the RBANS and its ability to detect milder deficits in 
cognition in the elderly.  The RBANS is administered to the patients. 
4.5.7.4
Alzheimer’s Disease Assessment Scale–Cognitive Subscale
The Alzheimer’s Disease Assessment ScaleCognitive Subscale (ADAS-Cog) is the 
most frequently used scale to assess cognition in clinical trials for mild to moderate AD
(Rozzini et al. 2007; Connor and Sabbagh 2008; Ihl et al. 2012).  The modified version 
will be used; which has 13 items (ADAS-Cog 13). This version includes the addition of 
delayed word recall and number cancellation, as well as use of only 1 trial for word 
recognition.  This is the version used in the Alzheimer’s Disease Neuroimaging Initiative 
protocol (2013).  The ADAS-Cog13 is administered to the patient. Equivalent alternate
forms of the word recall, word recognition, and number cancellation subtests will be used 
in successive test administrations. 
4.5.7.5
Amsterdam Instrumental Activity of Daily Living Questionnaire
The Amsterdam iADL questionnaire (Sikkes et al. 2013) is an informant-based
instrument for measuring iADL problems in patients with dementia.  This instrument 
consists of 70 items, scored on a 5-point scale, that uses item response theory for 
scoring.  Items presented to the informant are tailored to responses to earlier items; thus 
each administration of the Amsterdam iADL may consist of less than the total of 70 items.  
The Amsterdam iADL has been shown to possess good content validity, high internal 
consistency, good test-retest reliability, and good construct validity (Sikkes et al. 2013).
4.5.7.6
Alzheimer’s Disease Cooperative StudyActivities of Daily 
Living Inventory
The Alzheimer’s Disease Cooperative Study GroupActivities of Daily Living Inventory
(ADCS-ADL; Galasko et al. 1997) is the scale most widely used to assess functional 
outcome in patients with AD (Vellas et al. 2008).  The ADCS-ADL is administered to 
caregivers and covers both basic ADL (e.g., eating and toileting) and more complex ADL 
or instrumental ADL (e.g., using the telephone, managing finances, preparing a meal). 
4.5.7.7
Alzheimer’s Disease Event Inventory
The Alzheimer’s Disease Event Inventory is an informant-based instrument for collecting 
information on important events that occur in the lives of a patient and their caregivers 
during a clinical trial.  The Event Inventory was developed at Genentech.


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4.5.7.8
Resource Utilization in DementiaLite Questionnaire
The Resource Utilization in Dementia (RUD)-Lite is an instrument administered to
caregivers to assess health resource use by patients (Wimo and Winblad 2008). The 
RUD-Lite comprises 26 questions that evaluate informal time a caregiver spends caring 
for a patient and patient’s work status and use of social and health services including 
respite care, day care, nursing facility use, and hospitalization (Wimo and Winblad 
2008). 
4.5.7.9
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 suicidal on the basis of C-SSRS will be referred for appropriate 
psychiatric evaluation and management as per local clinical practice.
4.5.7.10
Diagnostic Classification
At specified visits, a diagnostic classification should be made using the forms provided 
by the electronic device vendor.
4.5.7.11
Caregiver Global Impression of Change Scales
The Caregiver Global Impression of Change Scales for Alzheimer’s disease (CaGI-Alz) 
include four items assessing caregivers’ perceptions of change in the patient disease 
severity. 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 clinical outcome 
assessments.
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.


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If a prospective participant has received an amyloid PET scan within 12 months before 
the start of screening as part of their prior medical care, and they have not received prior 
amyloid immunotherapy, this prior scan may be used to determine eligibility if all of the 
following requirements are met:

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 and undergo a PET scan 
on multiple occasions as described in the Schedule of Activities in Appendix 1 and 
Appendix 2.  Refer to the study overview (Section 3.1.1) for details regarding the 
circumstances when [18F]GTP1 PET scans must be performed.  Appendix 1 and 
Appendix 2 specify when a final [18F]GTP1 PET scan should be performed if a patient 
discontinues from the study, provided that local radiation limits have not been exceeded.
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 CRO 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.


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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 (performed by a central laboratory).  Urine pregnancy tests will be 
performed at specified subsequent visits (by the study site’s local laboratory).  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy 
test (performed by a central laboratory).
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, 
differential count (absolute counts of neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells)

Chemistry panel (serum or plasma):  sodium, potassium, chloride, magnesium, 
bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH, 
gamma glutamyl transpeptidase, lactate dehydrogenase, 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): glycosylated hemoglobin, B12, folic acid,
TSH, thyroxine
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 (see Table 4)

Blood samples for DNA extraction for WGS and analyses of single nucleotide 
polymorphisms (SNPs) (see Section 4.5.11)


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Exploratory biomarker research may include, but will not be limited to, the biomarkers 
listed in Table 4.
Table 4
Exploratory Biomarkers
Sample Type
Proposed Biomarkers
Plasma
Markers include, but are not limited to, soluble tau and 
neurofilament light chain
Cerebrospinal fluid
Markers include, but are not limited to, soluble tau and 
neurofilament light chain
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Exploratory biomarker research may include, but will not be limited to, analysis of fluid 
biomarkers and genetic markers associated with AD, neurodegeneration, and 
neuro-inflammation.  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.
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 
used 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 20 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 germline mutations, will be subject 
to the confidentiality standards described in Section 8.4.
Given the complexity and exploratory nature of the analyses, data derived from SNP or 
WGS specimens will generally not be provided to study investigators or patients unless 


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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 
Schedule of Activities (see Appendix 1 and Appendix 2), and may be obtained at 
unscheduled timepoints as indicated.
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.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and a large and/or 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 mean QTcF is 500 ms and/or 60 ms longer
than the baseline value, another ECG must be recorded, ideally within the next 
5 minutes, and ECG monitoring should continue until QTcF has stabilized on 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
Mandatory Samples for Genetic Analysis
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.  The blood 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 SNP sampling, 
this section of the protocol (Section 4.5.11) will not be applicable at that site.


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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).
Patient medical information associated with WGS and SNP specimens is confidential 
and may be disclosed to third parties only as permitted by the Informed Consent Form
(or separate authorization for use and disclosure of personal health information) signed 
by the patient, unless permitted or required by law.
Given the complexity and exploratory nature of the 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.
Genomics is increasingly informing researcher's understanding of disease pathobiology.
WGS and SNP analysis provide, respectively, comprehensive and partial/limited/
targeted/focused characterization of the genome and, along with clinical data collected in 
this study, may increase the opportunity for developing new therapeutic approaches.
Data will be analyzed in the context of this study but will also be explored in aggregate 
with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents.
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.
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 biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection, 
storage, and analysis of RBR specimens will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests, which may allow for 
individualized drug therapy for patients in the future.


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Specimens for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR specimens will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy, adverse events, or disease 
progression

To increase knowledge and understanding of disease biology

To study drug response, including drug effects and the processes of drug absorption 
and disposition

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays
4.5.12.2
Approval by the Institutional Review Board or Ethics 
Committee
Collection and submission of biological samples to the RBR is contingent upon the 
review and approval of the exploratory research and the RBR portion of the Informed 
Consent Form by each site's IRB/EC and, if applicable, an appropriate regulatory body.  
If a site has not been granted approval for RBR sampling, this section of the protocol 
(Section 4.5.12) 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, or
diseases:

Leftover whole blood samples

Leftover plasma samples

Leftover CSF samples

Leftover blood sample for DNA extraction
The above samples may be sent to one or more laboratories for analysis of germline or
somatic mutations via WGS, whole exome sequencing (WES), next-generation 
sequencing, 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.  Data will be analyzed in the 
context of this study but will also be explored in aggregate with data from other studies.  
The availability of a larger dataset will assist in identification of important pathways, 
guiding the development of new targeted agents.
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.


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RBR specimens 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).
4.5.12.4
Confidentiality
Specimens and associated data will be labeled with a unique patient identification 
number.
Patient medical information associated with RBR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Given the complexity and exploratory nature of the analyses of RBR specimens, 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 specimens 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 specimens.  
Patients who decline to participate will not provide a separate signature.
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF.
In the event of an RBR participant's death or loss of competence, the participant's 
specimens and data will continue to be used as part of the RBR research.


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4.5.12.6
Withdrawal from the Research Biosample Repository
Patients who give consent to provide RBR specimens 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 
specimens have been tested prior to withdrawal of consent, results from those tests will
remain as part of the overall research data.  If a patient wishes to withdraw consent to 
the testing of his or her specimens, the investigator must inform the Medical Monitor in 
writing of the patient's wishes through use of the appropriate RBR Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the 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 GN39763 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 GN39763.
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 specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Sponsor monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RBR for the purposes 
of verifying the data provided to the Sponsor.  The site will permit monitoring, audits, 
IRB/EC review, and health authority inspections by providing direct access to source 
data and documents related to the RBR samples.
4.6
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 determines it is in the best interest of the patient

Pregnancy


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The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for a treatment discontinuation visit 12 weeks (7 days)
after the last dose of study drug (see Appendix 1 and Appendix 2 for additional details).
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.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF, as well as in the site source document.  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 
been fulfilled)


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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 is not approved by any health authority, and clinical development is ongoing.  
The safety plan for participants in this study is based on clinical experience with 
[18F]GTP1 in 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 
will be performed by an iDMC (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 5 for precautions).  Study sites 
will be prepared to manage any hypersensitivity or hypersensitivity-like events.
All participants will be monitored for infusion reactions, hypersensitivity, or 
hypersensitivity-like reactions during the infusion and immediately afterwards (see 
Section 5.1.3.2 for additional instructions on monitoring and management of infusion 
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 and Appendix 2). 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.

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.

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 central nervous system 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.
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. There was no evidence of treatment emergent ADA 
in the ongoing Phase I study (GN39058). Immunogenicity in humans will be evaluated 
using validated immunoassays and by assessing the incidence of ADAs after treatment 
relative to their prevalence at baseline.  The study site will be prepared to manage any 
hypersensitivity events.
Refer to Section 5.6 of the MTAU9937A Investigator’s Brochure for ADA data from 
clinical trials.


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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 reactions both during the infusion and 
immediately afterwards. Infusion 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, 
contributes 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 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, in the Investigator’s Brochures.  See the local 
labeling instructions or, depending on locality, the Investigator’s Brochures, in addition to 
consulting with the local PET imaging center for additional radiation exposure due to 
potential head CT (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. 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 


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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 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).
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, 
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.


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5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
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

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 or an amyloid radioligand 
(if considered to be an IMP)

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.11)


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
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug or [18F]GTP1 or an amyloid radioligand (if considered to be an IMP)

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).
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, 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 is suspected.

Clinically significant MRI abnormalities (see Section 5.1.1.2)

Severe (Grade 3) infusion-related reactions


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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 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).
After initiation of study drug or [18F]GTP1 or an amyloid radioligand, all adverse events 
will be reported until 12 weeks after the last dose of study drug or 4 days after the last 
dose of [18F]GTP1 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 6) will be used for assessing adverse 
event severity.  Table 5 will be used for assessing severity for adverse events that are 
not specifically listed in the WHO toxicity grading scale.


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Table 5
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).
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 or an amyloid 
radioligand (if [18F]GTP1 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 6):

Temporal relationship of event onset to the initiation of study drug or [18F]GTP1 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 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 
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Table 6
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug or [18F]GTP1 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 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 or an amyloid radioligand; and/or the adverse 
event abates or resolves upon discontinuation of the study drug or [18F]GTP1 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 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 or an 
amyloid radioligand (e.g., cancer diagnosed 2 days after first dose of study drug or 
[18F]GTP1 or an amyloid radioligand).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the 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 or an amyloid radioligand and are judged to be related to study drug infusion 
or [18F]GTP1 or an amyloid radioligand should be captured as a specific diagnosis 
(e.g., "infusion-related reaction," "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 a systemic reaction to the same dose of study drug, 
[18F]GTP1, 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 


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and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.3
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

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.


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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 
Note:  For oncology trials, certain abnormal values may not qualify as adverse 
events.
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5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)


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
Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events).
5.3.5.7
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
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 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 


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be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of AD, "Alzheimer’s Disease progression" should 
be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.9
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
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


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
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease
The patient has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours
5.3.5.12
Adverse Events Associated with an Overdose or Error in Drug 
Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug or [18F]GTP1 or an 
amyloid radioligand (if considered to be an IMP) should be recorded on the Adverse 
Event eCRF.  If the associated adverse event fulfills seriousness criteria, the event 
should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2).
No safety data related to overdosing of MTAU9937A are available.
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.  However, if any 
COA responses suggestive of a possible adverse event are identified during site review 
of the COA data (including 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.


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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 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.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information 
Medical Monitor contact information:
Primary Medical Monitor:
 M.D. (IQVIA North and Latin 
America)
Telephone Nos.:
United States:
International:
Secondary Medical Monitor:
 M.D., Ph.D.
(Genentech North America)
Telephone No.:


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IQVIA Emergency Medical Contact Telephone Nos.:
+1 973-659-6677 or 
(United States)
Alternate Medical Monitor contact information:
Medical Monitor supporting E.U. sites:
 M.D.
(IQVIA Slovakia)
Telephone Nos.:
Office: 
Mobile:
Medical Monitor supporting APAC sites:
, M.D. (IQVIA India)
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 or an amyloid radioligand
After informed consent has been obtained but prior to initiation of study drug or 
[18F]GTP1 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 or 
an Amyloid Radioligand 
After initiation of study drug or [18F]GTP1 or an amyloid radioligand, serious adverse 
events and adverse events of special interest will be reported until 12 weeks after the 
last dose of study drug or 4 days after the last dose of [18F]GTP1 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.
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.  


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Instructions for reporting serious adverse events that occur 12 weeks after the last 
dose of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 9 weeks after the last 
dose of study drug or 4 days after the last dose of [18F]GTP1 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 last dose of study drug or 4 days after the last dose of [18F]GTP1 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.  The pregnant partner will need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy.  After the authorization has been signed, the investigator 
will submit a 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 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 or an amyloid radioligand or the female partner of a male patient 
exposed to study drug or [18F]GTP1 or an amyloid radioligand should be classified as a 
serious adverse event, recorded on the Adverse Event eCRF, and reported to the 


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Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  Any abortion should be reported in the same fashion (as the Sponsor 
considers abortions to be medically significant).
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 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.
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 last dose of study drug or 4 days after the last dose of [18F]GTP1 or 
an amyloid radioligand, whichever is longer), if the event is believed to be related to prior 
study drug or [18F]GTP1 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.


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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

GTP1 Investigator's Brochure

Investigator’s Brochure or Summary of Product Characteristics or US Package 
Insert for amyloid ligand used, depending on whether the amyloid ligand is 
considered to be an IMP in the local jurisdiction
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of the above-listed anticipated events during the 
study.  An aggregate report of any clinically relevant imbalances that do not favor the 
test product will be submitted to health authorities.
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 primary efficacy CDR-SB 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, or GTP1. Patients will be grouped according to 
MTAU9937A treatment actually received.

A primary analysis will occur after the last patient has completed the Week 73 
assessment. 

A final analysis will occur after the last patient has finished the OLE and completed 
the Week 169 assessment.


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6.1
DETERMINATION OF SAMPLE SIZE
This study was designed to enroll approximately 360 patients randomized to one of three 
active, IV dose arms or to an IV placebo dose arm in a 2:3:2:3 ratio.  This sample size 
provides reasonable precision for estimating a clinically significant treatment effect on 
CDR-SB scores when MTAU9937A is compared with placebo. Assuming an observed
0.6-point difference in mean CDR-SB decline between the 4500 mg MTAU9937A arm
and placebo at Week 73, a standard deviation across patients of 2, and a 25% dropout
rate, a 90% confidence interval on the population treatment effect point estimate for the 
CDR-SB is approximately 0.081.12.
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 study (through Week 73), 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.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is change in CDR-SB score from baseline to Week 73.
The difference in mean change from baseline to Week 73 between MTAU9937A- and 
placebo-treated patients will be estimated using an analysis of covariance model 
adjusting for ApoE4 status and baseline clinical status (i.e., prodromal AD vs. mild AD 
dementia). Confidence intervals as well as least squares estimates will be used to aid in 
interpretation of study results. Detailed statistical methods will be outlined in the 
Statistical Analysis Plan (SAP).
6.4.2
Secondary Efficacy Endpoints
The secondary endpoints include the RBANS total score, ADAS-Cog (13-item), 
Amsterdam iADL, and ADCS-ADL. Secondary efficacy endpoints will be analyzed in the 
same manner as the primary endpoint.


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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.
Dose-limiting adverse events and adverse events of special interest 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.
6.6
PHARMACOKINETIC ANALYSES
Individual and mean serum MTAU9937A concentration–time data will be tabulated and 
plotted by cohort/dose level, 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).  Individual and mean 
MTAU9937A CSF concentration–time data will be tabulated by cohort/dose level. 
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 
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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 the Exploratory Biomarker Objective of
Section 1.3.  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 data will be analyzed in the context of this study and explored in aggregate with 
data from other studies to increase researcher's understanding of disease pathobiology 
and guide the development of new therapeutic approaches.
6.9
INTERIM ANALYSES
6.9.1
Optional Interim Analysis
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct an interim efficacy analysis.  The rationale for conducting an 
interim analysis will be on the basis of factors and information external to this study such 
as new, emergent data from other clinical trials.  Below are the specifications in place to 
ensure the study continues to meet the highest standards of integrity when an optional 
interim analysis is executed.
If an interim analysis is conducted, the Sponsor will remain blinded.  The interim analysis 
will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the iDMC 
charter. 
The decision to conduct an optional interim analysis, along with the rationale and timing,
will be documented in the protocol. Statistical details for the interim analysis will be 
contained within the Statistical Analysis Plan (SAP). A substantial protocol amendment 
(in the European Union) or the SAP (other jurisdictions) will be submitted to relevant 
health authorities, as appropriate, prior to the conduct of the interim analysis.  The iDMC 
charter will also be updated to document potential recommendations the iDMC can 
make to the Sponsor as a result of this analysis and the iDMC charter will be submitted 
to relevant health authorities.  All documents submitted to health authorities would be 
simultaneously submitted to the study master file to further document this information 
appropriately.  The Clinical Study Report will also document that such an interim 
analysis occurred.


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If the interim analysis plan allows for early assessment of efficacy, the type I error rate 
will be controlled to ensure statistical validity is maintained.  Specifically, the Lan-DeMets 
-spending function that approximates the O’Brien-Fleming boundary will be applied to 
determine the critical value for stopping for positive efficacy at the interim analysis 
(DeMets and Lan 1994).  Additional criteria for recommending that the study be stopped 
for positive efficacy may be added to the iDMC charter.  If the study continues beyond 
the interim analysis, the critical value at the final analysis would be adjusted accordingly 
to maintain the overall type I error rate, per standard Lan-DeMets methodology.  The 
select efficacy endpoints provided to the iDMC as part of ongoing safety review do not 
enable and are not considered sufficient for a formal interim analysis to assess early 
efficacy or futility.
If the interim analysis plan allows for early assessment for futility, the threshold for 
declaring futility will include an assessment of the predictive probability that the primary
endpoint will achieve statistical significance.  An interim analysis that might lead to 
stopping the study for futility will not occur before at least 50% of the information has 
been accumulated for the primary endpoint.
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 3
(see Section 4.5.7), 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.


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7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC CLINICIAN-REPORTED OUTCOME DATA
Clinicians will use an electronic device to capture ClinRO 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, the data, audit trail, and trial and system documentation 
will be archived.  The investigator will receive patient data for the site in a 
password-protected, machine-readable format.  Sites should extract the data soon as 
possible after receiving it. 
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.


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Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
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.


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8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the 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 
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 a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who
decline to participate will not provide a separate signature.
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.


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Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
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.


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Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of 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.
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 
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, 


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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. 
Globally, 97 sites have enrolled 457 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 iDMC will be employed to monitor and evaluate patient safety throughout the study.
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses, 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
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 


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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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Arriagada PV, Growdon JH, Hedley-Whyte ET, et al. Neurofibrillary tangles but not 
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Badenes Guia D, Casas Hernanz L, Cejudo Bolivar JC, et al. Evaluation of the capacity 
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MTAU9937A—Genentech, Inc.
107/Protocol GN39763, Version 4
Appendix 1
Schedule of Activities
Assessment
Screening
Days 56 to 1ii
Baseline a
Double-Blind Treatment Period
Unplanned 
Visit b
Tx 
Completionc
Tx 
D/C c
Week
1 a
3 d
5 d
9
13
17
21
25
29
33
37
41
45
49
53
57
61
65
69
73
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Informed consent
x e
Medical history, AD 
history, personal status, 
and demographics f
x
Diagnostic verification
x
Diagnostic classification
x
x
x
x
x
x
x g
MMSE h
x
x
x
x
x
x
x
x
x g
Event inventory h
x
x
x
x
x
x
x
x g
CDR h
x
x
x
x
x
x
x i
RBANS h
x
x
x
x
x
x i
ADAS-Cog 13 h
x
x
x
x
x i
Amsterdam iADL h
x
x
x
x
x i
ADCS-ADL h
x
x
x
x
x i
RUD-lite h
x
x
x
x
x
x
x
x g
C-SSRS
x
x
x
x
x
x
x
x
x
x
CaGI-Alz jj
x
x
x
Vital signs j
x
x k
x
x
x
x
x
x
x
x
x
x
x
x
x
x k
x
x
x
x
x
x k
x
x
x k
Weight
x
x
x
x
x
x
x
Height
x
Complete physical 
examination l
x
x
x
x
x
x


Appendix 1
Schedule of Activities (cont.)
MTAU9937A—Genentech, Inc.
108/Protocol GN39763, Version 4
Assessment
Screening
Days 56 to 1ii
Baseline a
Double-Blind Treatment Period
Unplanned 
Visit b
Tx 
Completionc
Tx 
D/C c
Week
1 a
3 d
5 d
9
13
17
21
25
29
33
37
41
45
49
53
57
61
65
69
73
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Limited physical 
examination m
x
x
x
x
x
x
Neurological examination
x
x
x
x
x
x
x
x
x
x
x
x
MRI kk
x
x
x
x
x i
Amyloid PET
x n
[18F]GTP1 PET o
x
x
x
x p
ECG
x q
x r
x r
x
x s
Hematology t
x q
x
x
x
x
x
x
Chemistry, lipids, 
coagulation u
x q
x
x
x
x
x
x
HbA1c, B12, folic acid, 
TSH thyroxine
x q
Viral serology v
x q
Pregnancy test w
x
x x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis y
x q
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
x
x
Serum PK sample z
x aa x bb x bb x bb x bb x bb
x bb
x bb
x bb
x
x i
x i
Serum ADA sample z
x
x
x
x
x
x i
x i
Blood sample for APOE
x
Blood sample for SNPs cc
x
Blood sample for WGS dd
x
Blood sample for 
biomarkers ee
x
x bb
x
x
x
x
x bb
x
x
x
x
x
x i


Appendix 1
Schedule of Activities (cont.)
MTAU9937A—Genentech, Inc.
109/Protocol GN39763, Version 4
Assessment
Screening
Days 56 to 1ii
Baseline a
Double-Blind Treatment Period
Unplanned 
Visit b
Tx 
Completionc
Tx 
D/C c
Week
1 a
3 d
5 d
9
13
17
21
25
29
33
37
41
45
49
53
57
61
65
69
73
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
LP for CSF sample for 
PK and biomarkers ff
x
x
x
x
x i
Concomitant medications gg
x hh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x hh
x hh
Adverse events hh
x hh
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x hh
x hh
[18F]GTP1fluorine-18 Genentech tau probe 1; AD=Alzheimer’s disease; ADA=anti-drug antibody; ADAS-Cog=Alzheimer’s Disease 
Assessment ScaleCognitive Subscale; ADCS-ADL=Alzheimer’s Disease Cooperative Study Group–Activities of Daily Living Inventory; 
CaGI-Alz Caregiver Global Impression of Change Scales for Alzheimer's disease; C-SSRS=Columbia-Suicide Severity Rating Scale; 
CDR=Clinical Dementia Rating; COA=clinical outcome assessment; CSF=cerebrospinal fluid; D/C=discontinuation; DVF Diagnostic 
Verification Form; eCRF=electronic Case Report Form; HbA1cglycosylated hemoglobin; HBsAghepatitis B surface antigen; HCVhepatitis 
C virus; iADL=Instrumental Activity of Daily Living; LP=lumbar puncture; MMSE=Min-Mental State Examination; MRI=magnetic resonance 
imaging; OLE=open-label extension; PET=positron emission tomography; PK=pharmacokinetic; RBANS=Repeatable Battery for the 
Assessment of Neuropsychological Status; RUD=Resource Utilization in Dementia; SNP=single nucleotide polymorphism; 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/Dose 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. 
On study drug administration days, pre-infusion laboratory samples should be drawn 0–4 hours before the start of infusion, and post-infusion 
laboratory samples should be drawn 030 minutes after the end of infusion, unless otherwise specified. 


Appendix 1
Schedule of Activities (cont.)
MTAU9937A—Genentech, Inc.
110/Protocol GN39763, Version 4
a The baseline visit must occur after enrollment (randomization) and may be split over multiple visit days; the first and last visit days of the 
baseline visit must be separated by no more than 14 days from each other (e.g., the baseline visit may start on a Monday and end on the 
Monday 2 weeks forward).  All COA assessments at the baseline visit should be performed as close to the last visit day of the baseline visit 
as possible.  COA assessments, [18F]GTP1 PET scans, and LP from the baseline visit 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 first baseline assessment (e.g., if the first 
baseline visit day is a Monday, then the first dosing of study drug must occur no later than the Tuesday two 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.
b Visit not specified by the protocol.  Assessments (possibly including PK sample collection) should be performed as clinically indicated. 
c 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 81 (7 days).  Patients who complete the OLE treatment period will return to the clinic 
for a treatment completion visit (safety follow-up) at Week 181 (7 days).  Patients who discontinue study drug prematurely either in the 
double-blind treatment period or in the OLE treatment period will return to the clinic for a treatment discontinuation visit 12 weeks (7 days) 
after the last dose of study drug. 
d At these visits, all activities/assessments must be performed within 3 days of the scheduled visit.
e Informed consent must be documented before any study-specific screening procedure is performed and may be obtained up to 56 days 
before initiation of study treatment.
f
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; and all medications (e.g., prescription drugs, over-the-counter drugs, herbal/homeopathic remedies, nutritional 
supplements) used by the patient within 3 months prior to the screening visit.  Demographics include age, sex, self-reported race/ethnicity, 
and years of education.  Demographics of caregiver will also be collected.
g Only perform assessment if discontinuation visit is 8 weeks after last assessment for this instrument or procedure.
h Please see the GN39763 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 and diagnostic classification form will be rater-administered before the patient or 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/diagnostic classification form and the C-SSRS) must be 
completed prior to blood draws or imaging performed on the same day.  For details on permitted concomitant medication use prior to COA 
assessments, see Section 4.1.2.


Appendix 1
Schedule of Activities (cont.)
MTAU9937A—Genentech, Inc.
111/Protocol GN39763, Version 4
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 last administration of study drug.
j
Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  
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.  On study drug treatment visits, vital signs should be 
collected 04 hours prior to infusion and 6090 minutes after completion of infusion.
k Vital signs should be assessed on the same day(s) that the [18F]GTP1 PET scan and/or LP are performed.  Vital signs should be assessed 
just prior to injection of [18F]GTP1 or initiation of the LP procedure, but no earlier than 1 hour prior to injection of [18F]GTP1 or initiation of the 
LP procedure.  Vital signs should also be assessed just after injection of [18F]GTP1 or conclusion of the LP procedure, but no later than 
1 hour after injection of [18F]GTP1 or conclusion of the LP procedure.
l
Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 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 amyloid PET is used to confirm amyloid positive eligibility, an LP will not be performed as part of screening.  If amyloid PET result 
suggests a patient is amyloid negative, an LP may be performed as part of screening to re-assess amyloid positivity eligibility on the basis of 
CSF. 
o If a [18F]GTP1 PET scan is performed at the baseline visit, [18F]GTP1 PET scans must be performed at all indicated postbaseline visits.  
[18F]GTP1 PET scans must be performed if [18F]GTP1 is available at the PET imaging center through the [18F]GTP1 distribution network, 
unless local restrictions preclude [18F]GTP1 PET imaging.  If a [18F]GTP1 PET scan is not performed at the baseline visit, [18F]GTP1 PET 
scans become optional at any of the indicated postbaseline visits.  Postbaseline [18F]GTP1 PET scans may be performed prior to or after
study treatment administration at the corresponding visit. Postbaseline [18F]GTP1 PET scans should be performed within 14 days of 
the scheduled visit. Further extensions to the Week 73 visit [18F]GTP1 PET scan window may be granted on a case-by-case basis by the 
Medical Monitor. The Week 49 and 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, the site should contact the Sponsor to discuss alternative timing.


Appendix 1
Schedule of Activities (cont.)
MTAU9937A—Genentech, Inc.
112/Protocol GN39763, Version 4
p A [18F]GTP1 tau PET scan should only be performed if the following has been met:  at least 24 weeks have elapsed since any previous 
[18F]GTP1 tau PET scan and local annual radiation limits have not been exceeded.
q Results obtained up to 90 days prior to obtaining informed consent may be used to determine eligibility; such tests do not need to be 
repeated during screening.
r
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.  On the Week 5 visit and all following visits, ECG should be performed 030 minutes after the end of infusion. 
s Only perform assessment if clinically indicated.
t
Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (absolute counts of neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).
u Chemistry panel (serum or plasma) includes sodium, potassium, chloride, magnesium, bicarbonate, glucose, BUN or urea, creatinine, 
total protein, albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH, gamma glutamyl 
transpeptidase, lactate dehydrogenase, creatine kinase.  Glomerular filtration rate should also be calculated from creatinine using the 
Cockcroft-Gault formula.  Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, 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).
v Viral serology panel includes:  HIV, HBsAg, total hepatitis B core antibody, HCV antibody. 
w For women of childbearing potential only:  A serum pregnancy test must be performed at screening.  Urine pregnancy tests will be performed 
at specified subsequent visits, prior to dosing of study drug, [18F]GTP1 or an amyloid radioligand.  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 MTAU9937A (or placebo) or [18F]GTP1 or an 
amyloid radioligand.
x Only perform if a [18F]GTP1 PET scan is being performed.
y 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.
z At all indicated visits, serum ADA sample should be taken 04 hours before the start of infusion.  In addition, concurrent ADA and PK samples 
should also be collected in patients with signs and symptoms of an infusion-related reaction at the time of the infusion-related event, for 
analyses of antibodies to MTAU9937A and/or other components of the drug product.  Concurrent ADA and PK samples should also be 
collected in all patients at the treatment completion or treatment discontinuation visit (see footnote i, above for more details).


Appendix 1
Schedule of Activities (cont.)
MTAU9937A—Genentech, Inc.
113/Protocol GN39763, Version 4
aa Serum PK samples should be taken 04 hours before the start of infusion and 1 hour (15 minutes), 2 hours (20 minutes), and 4 hours 
(30 minutes) after the end of infusion. 
bb Serum PK and blood biomarker samples should be taken 04 hours before the start of infusion and 030 minutes after the end of infusion. 
cc Not applicable for a site that has not been granted approval for blood collection for SNP. 
dd Not applicable for a site that has not been granted approval for WGS.
ee Blood biomarker samples should be taken 04 hours before the start of infusion unless otherwise noted.
ff When an LP is performed, it should be performed only once during either screening or the baseline visit, and may be used for assessment of 
amyloid positivity (if performed at screening) and/or for assessing tau or other biomarkers.  If a [18F]GTP1 PET scan is not performed at the 
baseline visit, an LP at the baseline visit is mandatory for collection of CSF (unless performed during screening) to enable the assessment of 
tau biomarkers.  Follow-up LPs must also be performed at postbaseline visits if a [18F]GTP1 PET scan is not performed at the baseline visit.  
If [18F]GTP1 PET is performed at baseline and LP is performed at the screening or baseline visit, then follow-up LPs are optional.  
gg 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.
hh 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 last dose of study 
drug.  After this period, all deaths, regardless of cause, should be reported.  In addition, 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 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 or amyloid radioligand or trial-related procedures until a final 
outcome can be reported.
ii Extensions to this 8-week screening period may be granted by contacting the Medical Monitor on a case-by-case basis.
jj At the Week 25 visit, only CaGI-Alz assessments referring to changes relative to start of study should be administered. At subsequent 
administrations, both CaGI-Alz assessments referring to changes relative to start of study and relative to the prior assessment should be 
administered.
kk The MRI must 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).


MTAU9937A—Genentech, Inc.
114/Protocol GN39763, Version 4
Appendix 2
Schedule of Activities (Open-Label Extension)
Open-label Treatment Period
Unplanned 
Visit a
Tx 
Completionb
Tx 
D/C b
Week 77 81 85 89 93 97 101 105 109 113 117 121 125 129 133 137 141 145 149 153 157 161 165 169
Diagnostic classification
x
x
x
x
x
x
x
x
x c
MMSE d
x
x
x
x
x
x
x
x
x c
CDR d
x
x
x e
RBANS d
x
x
x e
ADAS-Cog 13 d
x
x
x e
Amsterdam iADL d
x
x
x e
ADCS-ADL d
x
x
x e
C-SSRS
x
x
x
x
x
x
x
x
x
x
x
CaGI-Alz z
x
x
x
Vital signs f
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x g
x
x
x g
Weight
x
x
x
x
x
x
x
Complete physical 
examination h
x
x
x
x
x
x
Limited physical 
examination i
x
x
x
x
x
Neurological examination
x
x
x
x
x
x
x
x
x
x
x
MRI j
x
x
x e
[18F]GTP1 PET k
x
x l
ECG
x m
Hematology n
x
x
x
x
Chemistry and lipids o
x
x
x
x


Appendix 2
Schedule of Activities (Open-Label Extension) (cont.)
MTAU9937A—Genentech, Inc.
115/Protocol GN39763, Version 4
Open-label Treatment Period
Unplanned 
Visit a
Tx 
Completionb
Tx 
D/C b
Week 77 81 85 89 93 97 101 105 109 113 117 121 125 129 133 137 141 145 149 153 157 161 165 169
Coagulation p
x
x
Pregnancy test q
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 r
x
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
x s
x t
x t
x t
x t
x t
x t
x e
x e
Serum ADA sample u
x 
x
x
x
x
x
x
x e
x e
Blood sample for 
biomarkers v
x 
x
x
x
x e
LP for CSF sample for PK 
and biomarkers w
x
x
Concomitant medications 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 x
x x
Adverse events y
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 y
x y
[18F]GTP1fluorine-18 Genentech tau probe 1; ADA=anti-drug antibody; ADAS-Cog=Alzheimer’s Disease Assessment ScaleCognitive 
Subscale; ADCS-ADL=Alzheimer’s Disease Cooperative Study Group–Activities of Daily Living Inventory; CaGI-Alz Caregiver Global 
Impression of Change Scales for Alzheimer's disease; C-SSRS=Columbia-Suicide Severity Rating Scale; CDR=Clinical Dementia Rating; 
COA=clinical outcome assessment; CSF=cerebrospinal fluid; D/C=discontinuation; eCRF=electronic Case Report Form; iADL=Instrumental
Activity of Daily Living; LP=lumbar puncture; MMSE=Mini-Mental State Examination; MRI=magnetic resonance imaging; OLE=open-label 
extension; PET=positron emission tomography; PK=pharmacokinetic; RBANS=Repeatable Battery for the Assessment of Neuropsychological 
Status; Tx=treatment.
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. 
On study drug administration days, pre-infusion laboratory samples should be drawn 0–4 hours before the start of infusion, and post-infusion 
laboratory samples should be drawn 030 minutes after the end of infusion, unless otherwise specified.


Appendix 2
Schedule of Activities (Open-Label Extension) (cont.)
MTAU9937A—Genentech, Inc.
116/Protocol GN39763, Version 4
a Visit not specified by the protocol.  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 181
(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 last dose of study drug. 
c Only perform assessment if discontinuation visit is 8 weeks after last assessment for this instrument.
d Please see the GN39763 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 diagnostic classification form) will be rater administered before the patient or rater or caregiver receives 
any information on disease status, prior to LP 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 diagnostic classification form and the C-SSRS) must be completed prior to 
blood draws or imaging performed on the same day.  For details on permitted concomitant medication use prior to COA assessments, see 
Section 4.1.2.
e 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 
last administration of study drug.
f
Includes respiratory rate, pulse rate, and systolic and diastolic blood pressure while the patient is in a seated position, and temperature.  
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.  On study drug treatment visits, vital signs should be collected 
04 hours prior to infusion and 6090 minutes after completion of infusion.
g Vital signs should be assessed on the same day(s) that the [18F]GTP1 PET scan and/or LP are performed. Vital signs should be assessed just
prior to injection of [18F]GTP1 or initiation of the LP procedure, but no earlier than 1 hour prior to injection of [18F]GTP1 or initiation of the LP 
procedure.  Vital signs should also be assessed just after injection of [18F]GTP1 or conclusion of the LP procedure, but no later than 1 hour
after injection of [18F]GTP1 or conclusion of the LP procedure.
h Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, 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.
i
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
Schedule of Activities (Open-Label Extension) (cont.)
MTAU9937A—Genentech, Inc.
117/Protocol GN39763, Version 4
j
The MRI must 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).
k If a [18F]GTP1 PET scan is performed at the baseline visit, [18F]GTP1 PET scans must be performed at all indicated postbaseline visits.  
[18F]GTP1 PET scans must be performed if [18F]GTP1 is available at the PET imaging center through the [18F]GTP1 distribution network, 
unless local restrictions preclude [18F]GTP1 PET imaging.  If a [18F]GTP1 PET scan is not performed at the baseline visit, [18F]GTP1 PET scans 
become optional at any of the indicated postbaseline visits.  Postbaseline [18F]GTP1 PET scans may be performed prior to or after study 
treatment administration at the corresponding visit. The Week 169 and 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 should appropriate extenuating circumstances arise. If, at any time, local restrictions for radiation exposure 
disallow performing a [18F]GTP1 PET scan, the site should contact the Sponsor to discuss alternative timing. 
l
A [18F]GTP1 tau PET scan should only be performed if the following has been met:  informed consent has been obtained, at least 24 weeks
have elapsed since any previous [18F]GTP1 tau PET scan, and local annual radiation limits have not exceeded.
m Only perform assessment if clinically indicated.
n Hematology includes WBC count, RBC count, hemoglobin, hematocrit, platelet count, differential count (absolute counts of neutrophils, 
eosinophils, basophils, monocytes, lymphocytes, other cells).
o Chemistry panel (serum or plasma) includes sodium, potassium, chloride, magnesium, bicarbonate, glucose, BUN or urea, creatinine, 
total protein, albumin, phosphorus, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, uric acid, LDH, gamma glutamyl 
transpeptidase, lactate dehydrogenase, creatine kinase.  Glomerular filtration rate should also be calculated from creatinine using the
Cockcroft-Gault formula.  Lipid panel includes cholesterol, LDL cholesterol, HDL cholesterol, triglycerides.
p 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 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).  The Week 169 coagulation 
laboratory tests are only applicable to patients participating in the optional CSF collection (lumbar puncture).
q For women of childbearing potential, 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 
MTAU9937A (or placebo) or [18F]GTP1 or an amyloid radioligand.


Appendix 2
Schedule of Activities (Open-Label Extension) (cont.)
MTAU9937A—Genentech, Inc.
118/Protocol GN39763, Version 4
r
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.
s Serum PK samples should be taken 04 hours before the start of infusion and 1 hour (15 minutes), 2 hours 20 minutes), and 4 hours 
(30 minutes) after the end of infusion. 
t
Serum PK samples should be taken 04 hours before the start of infusion and 030 minutes after the end of infusion. 
u At all indicated visits, serum ADA sample should be taken 04 hours before the start of infusion.  In addition, concurrent ADA and PK samples 
should also be collected in patients with signs and symptoms of an infusion-related reaction at the time of the infusion-related event, for 
analyses of antibodies to MTAU9937A and/or other components of the drug product. Concurrent ADA and PK samples should also be 
collected in all patients at the treatment completion or treatment discontinuation visit (see footnote e, above, for more details).
v Blood biomarker samples should be taken 04 hours before the start of infusion.
w LPs are optional during the OLE period.
x 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 until the final study visit.
y All adverse events will be reported until 12 weeks after the last dose of study drug.  After this period, all deaths, regardless of cause, should be 
reported.  In addition, 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 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 or amyloid radioligand or trial-related procedures until a final outcome can be reported.
z Both CaGI-Alz assessments referring to changes relative to start of study and relative to the prior assessment (e.g., the prior 6 months) should 
be administered.


MTAU9937A—Genentech, Inc.
119/Protocol GN39763, Version 4
Appendix 3
National Institute on Aging/Alzheimer’s Association Criteria for
Mild Alzheimer’s Disease
NIA-AA category
Description
Probable Dementia: 
core Clinical Criteria
Meets criteria for 
dementia described 
earlier in the text, and 
in addition, has the 
following 
characteristics:
A. Insidious onset. Symptoms have a gradual onset over months to 
years, not sudden over hours or days;
B. Clear-cut history of worsening of cognition by report or observation; 
and
C.The initial and most prominent cognitive deficits are evident on history 
and examination in one of the following categories.
a. Amnestic presentation: It is the most common syndromic 
presentation of AD dementia. The deficits should include 
impairment in learning and recall of recently learned information. 
There should also be evidence of cognitive dysfunction in at least 
one other cognitive domain, as defined earlier in the text.
b. Non-amnestic presentations:
Language presentation: The most prominent deficits are in 
word-finding, but deficits in other cognitive domains should be 
present.
Visuospatial presentation: The most prominent deficits are in 
spatial cognition, including object agnosia, impaired face 
recognition, simultanagnosia, and alexia. Deficits in other cognitive 
domains should be present.
Executive dysfunction: The most prominent deficits are impaired 
reasoning, judgment, and problem solving. Deficits in other 
cognitive domains should be present.
D.The diagnosis of probable AD dementia should not be applied when 
there is evidence of (a) substantial concomitant cerebrovascular 
disease, defined by a history of a stroke temporally related to the onset 
or worsening of cognitive impairment; or the presence of multiple or 
extensive infarcts or severe white matter hyperintensity burden; or (b) 
core features of Dementia with Lewy bodies other than dementia itself; 
or (c) prominent features of behavioral variant frontotemporal 
dementia; or (d) prominent features of semantic variant primary 
progressive aphasia or nonfluent/agrammatic variant primary 
progressive aphasia; or (e) evidence for another concurrent, active 
neurological disease, or a non-neurological medical comorbidity or use 
of medication that could have a substantial effect on cognition.


Appendix 3
National Institute on Aging/Alzheimer’s Association Criteria for
Mild Alzheimer’s Disease (cont.)
MTAU9937A—Genentech, Inc.
120/Protocol GN39763, Version 4
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.   


MTAU9937A—Genentech, Inc.
121/Protocol GN39763, Version 4
Appendix 4
National Institute on Aging/Alzheimer’s Association Criteria for 
Prodromal Alzheimer’s Disease (Mild Cognitive Impairment due 
to Alzheimer’s Disease)
NIA-AA category
Clinical and Cognitive Criteria
Clinical Criteria
Cognitive concern reflecting a change in cognition reported by patient or
informant or clinician (i.e., historical or observed evidence of decline
over time)
Objective evidence of Impairment in one or more cognitive domains,
typically including memory (i.e., formal or bedside testing to establish
level of cognitive function in multiple domains)
Preservation of independence in functional abilities
Not demented
Etiology of MCI 
consistent with AD 
pathophysiological 
process
Rule out vascular, traumatic, medical causes of cognitive decline, where
possible.
Provide evidence of longitudinal decline in cognition, when feasible
Report history consistent with AD genetic factors, where relevant
pAD dementia with 
evidence of the AD 
pathophysiological 
process
pAD is part of a continuum of clinical and biological phenomena. pAD is 
fundamentally a clinical diagnosis. To make a diagnosis of pAD with 
biomarker support, the core clinical diagnosis of pAD must first be 
satisfied.
Relevant biomarkers include amyloid-β(CSF or PET); tau (CSF or PET) 
AD=Alzheimer’s disease; CSF=cerebrospinal fluid; MCI=mild cognitive impairment;
NIA-AA=National Institute on Aging/Alzheimer’s Association; pAD=prodromal AD; PET=positron 
emission tomography.
Reference:  Albert MS, DeKosky ST, Dickson B, et al. The diagnosis of mild cognitive 
impairment due to Alzheimer’s disease: recommendations from the National Institute on 
Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimers Dement 2011;7:27079.


MTAU9937A—Genentech, Inc.
122/Protocol GN39763, Version 4
Appendix 5
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.  


MTAU9937A—Genentech, Inc.
123/Protocol GN39763, Version 4
Appendix 6
World Health Organization Toxicity Grading Scale


Appendix 6
World Health Organization Toxicity Grading Scale (cont.)
MTAU9937A—Genentech, Inc.
124/Protocol GN39763, Version 4


Appendix 6
World Health Organization Toxicity Grading Scale (cont.)
MTAU9937A—Genentech, Inc.
125/Protocol GN39763, Version 4


Appendix 6
World Health Organization Toxicity Grading Scale (cont.)
MTAU9937A—Genentech, Inc.
126/Protocol GN39763, Version 4

SAP_001.pdf: 
Official Title: 
A Phase II, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Parallel-Group, Efficacy, and Safety Study of MTAU9937A 
in Patients With Prodromal to Mild Alzheimer's Disease 
NCT Number: 
NCT03289143 
Document Date: 
SAP Version 3: 16-August-2020 


 
 
CONFIDENTIAL 
 
This is a Genentech, Inc document that contains confidential information.  Nothing herein is to be 
disclosed without written consent from Genentech, Inc. 
 
MTAU9937A — Genentech, Inc. 
Statistical Analysis Plan GN39763 
 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A PHASE II, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY, 
AND SAFETY STUDY OF MTAU9937A IN PATIENTS WITH 
PRODROMAL TO MILD ALZHEIMER’S DISEASE  
PROTOCOL NUMBER: 
GN39763 
STUDY DRUG: 
Semorinemab (MTAU9937A, RO7105705) and  
[18F]GTP1 (RO6880276)  
VERSION NUMBER: 
3 
IND NUMBERS: 
129270, 125702  
EUDRACT NUMBER: 
2017-001800-31  
SPONSOR: 
Genentech, Inc. 
PLAN PREPARED BY: 
 
DATE FINAL: 
26 November 2019 final draft 
DATE(S) AMENDED 
4 June 2020 (Version 2) and 16 August 2020 
(Version 3) 


 
MTAU9937A—Genentech, Inc. 
2/Statistical Analysis Plan GN39763 
STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
Version 1 (3DEC2019) 
Based on Version 4 of the Protocol GN39763 (11JUN2019) 
 
Version 2 (27MAY2020) 
Updated to expand the sensitivity analyses section to address intercurrent events and the 
impact of the COVID-19 pandemic. 
Other small edits for clarity/style. 
 
Version 3 (16AUG2020) 
Updated to clarify use of alternative modeling strategies for sensitivity analyses under situations 
where MMRM model assumptions for the primary analysis are violated.




 
MTAU9937A—Genentech, Inc. 
4/Statistical Analysis Plan GN39763 
1. 
BACKGROUND 
This Phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
will evaluate the efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of 
Semorinemab (MTAU9937A) in patients with prodromal-to-mild Alzheimer’s Disease (AD).  
MTAU9937A is a pan-tau IgG4 monoclonal antibody that has the 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. In addition to this Phase II 
clinical study (GN39763), the safety and efficacy of MTAU9937A in AD is also being evaluated 
in the ongoing LAURIET Phase II study in moderate AD (GN40040). 
Fluorine-18 Genentech tau probe 1 ([18F]GTP1 or RO6880276) 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 two additional Phase I studies: a test re-test study (e0048) 
with 5 patients with AD and 5 elderly HVs, and a radiation dosimetry study (e0049) with 6 HVs. 
In addition, [18F]GTP1 is currently being evaluated in a Phase I longitudinal natural history study 
(Study GN30009; clinicaltrials.gov identifier NCT02640092).  
[18F]GTP1 is also being evaluated in a longitudinal PET-imaging substudy of two Phase III trials 
of the anti-A antibody gantenerumab (Studies WN29922 and WN39658; clinicaltrials.gov 
identifiers NCT03444870 and NCT03443973, respectively) as well as a PET-imaging substudy 
of a Phase II trial of the anti-A antibody crenezumab (study GN28352; clinicaltrials.gov 
identifier NCT01998841). It also has been evaluated in a longitudinal PET-imaging substudy of 
two discontinued Phase II trials of the anti-A antibody crenezumab (Studies BN29552 and 
BN29553; clinicaltrials.gov identifiers NCT02670083 and NCT03114657, respectively). 
 
2. 
STUDY DESIGN 
The study consists of a screening period, a double-blind treatment period, an optional OLE 
period, and a safety follow-up period (see protocol for details). 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 in the double-blind treatment period. MTAU9937A will be administered Q4W in the 
OLE period. Study treatment is defined as study drug plus the PET radioligand used during PET 
imaging procedures ([18F]GTP1 for tau PET imaging and the amyloid radioligand for amyloid 
PET imaging). 
This study has enrolled 457 patients at 97 sites in North America, Europe, and the Asia-Pacific 
region. Patients were randomly assigned to one of three active, IV dose arms (1500 mg, 
4500 mg, or 8100 mg MTAU9937A) or to an IV placebo dose arm in a 2:3:2:3 (1500 
mg:4500 mg:8100 mg:placebo) ratio. All patients participating in the OLE will receive 


 
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MTAU9937A 4500 mg IV. To maintain balance in dementia status and APOE status between 
treatment arms, randomization will be stratified by dementia status (pAD vs. mAD) and APOE 
status (ApoE4+ vs. ApoE4).  
2.1 
OUTCOME MEASURES 
2.1.1 Primary Efficacy Endpoint 
Change in CDR-SB score from baseline to Week 73 (refer to Section 4.4 for detailed derivation) 
2.1.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are as follows: 
 
Change in ADAS-Cog13 score from baseline to Week 73 
 
Change in ADCS-ADL score from baseline to Week 73 
 
Change in RBANS total score from baseline to Week 73 
 
Change in Amsterdam iADL score from baseline to Week 73 
 
2.1.3 Safety Endpoints 
The safety endpoints are as follows: 
 
Nature, frequency, severity, and timing of adverse events and serious adverse events. 
Severity of adverse events will be determined through the use of the 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 C-SSRS  
 
Nature, frequency, severity, and timing of neuroimaging abnormalities  
 
2.1.4 Exploratory Biomarker Endpoints 
The key exploratory biomarker endpoints are as follows: 
 
Change in [18F]GTP1 tau PET imaging from baseline through Week 73 
 
Change in levels of CSF tau species from baseline through Week 73 
 
2.2 
DETERMINATION OF SAMPLE SIZE 
This study enrolled 457 patients randomized to one of three active IV dose arms or to an IV 
placebo dose arm in a 2:3:2:3 ratio. This sample size provides reasonable precision for 
estimating a clinically significant treatment effect on CDR-SB scores when MTAU9937A is 
compared with placebo. Assuming an observed 0.6-point difference in mean CDR-SB decline 
between the 4500 mg MTAU9937A arm and placebo at Week 73 (a 40% relative reduction in 
decline versus placebo), a standard deviation across patients of 2, and a 25% dropout rate, a 
90% confidence interval on the population treatment effect point estimate for the CDR-SB is 
approximately 0.14−1.06.  


 
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The primary analysis detailed in Section 4.4 proposes the first hypothesis test for CDR-SB be a 
comparison between a single pooled 4500 mg and 8100 mg dose arm versus placebo  
(pre-dropout n = 228 and 137, respectively). Assuming a true 0.6-point difference in mean  
CDR-SB decline between the pooled MTAU9937A arm and placebo at Week 73 (a 40% relative 
reduction in decline versus placebo), a standard deviation across patients of 2, and a 25% 
dropout rate, this hypothesis test is expected to have 68% power at the alpha = 0.05 level. 
2.3 
ANALYSIS TIMING 
The analysis will be conducted once all patients have either completed the Week 73 
assessment or discontinued the study. At the time of analysis, treatment assignments will be 
unblinded to Sponsor personnel. At this time, all patients enrolled in the study will have either 
discontinued or transitioned into the open-label extension period of the study. All non-Sponsor 
personnel who are involved in the conduct of the study (e.g. patients, site monitors, and 
investigators) will remain blinded to treatment assignments until all patients complete the 
blinded safety follow-up period or transition into the OLE. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION ISSUES 
Patients will be randomly assigned to one of three active, IV dose arms (1500, 
4500, or 8100 mg MTAU9937A) or to an IV placebo dose arm in a 2:3:2:3 (1500mg:4500 mg: 
8100 mg:placebo) ratio. Randomization of patients will be managed by a central interactive 
voice or Web-based response system (IxRS) vendor using stratified permuted block 
randomization. The randomization will be stratified by dementia status (pAD vs. mAD) and 
APOE status (ApoE4+ vs. ApoE4). The iDCC vendor periodically checks the IxRS to ensure 
that randomization is being performed correctly and that the correct kits are being assigned. 
3.2 
INDEPENDENT REVIEW FACILITY 
Clinicians/raters (but not caregivers or patients) will use an electronic device to capture clinical 
outcome assessment (COA) data from all patients and/or caregivers enrolled in this study. This 
includes the primary and all secondary endpoints. COA data from the electronic device will be 
transmitted to a centralized database maintained by the electronic device vendor.  
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 done in 
accordance with instructions provided in the GN39763 COA Manual and the 
training/documentation provided by the rating-scale vendor.  
In addition, given that the primary outcome measure in this study involves subjective judgment, 
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 


 
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adequately monitor such ratings can substantially increase the risks of failed trials (Becker and 
Greig 2008; Kobak 2010).  
Please see the GN39763 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.  
3.3 
DATA MONITORING 
The incidence and nature of adverse events, serious adverse events, and adverse events of 
special interest; responses on the C-SSRS; and abnormalities in vital signs, standard safety 
blood tests, ECG, and MRI will be assessed on a regular basis, approximately every  
3-4 months, by an unblinded iDMC. The unblinded iDMC may also receive select summary 
statistics of COA endpoints.  
At each safety review meeting, the iDMC will meet in a closed session to recommend whether 
the study should continue without modification, continue with minor modification, continue with 
substantial modification, suspend enrollment or treatment, or be terminated. There are currently 
no planned interim analyses to stop the trial early for either futility or clear signs of efficacy. 
Details of the iDMC are provided in the iDMC Charter.  
The Sponsor also monitors all safety data continuously on a blinded basis.  
4. 
STATISTICAL METHODS 
The primary statistical analyses will be performed using SAS software (Version 9.2 or higher). 
R software (Version 3.3.2 or higher) may be used for creating figures, for QC purposes, and for 
sensitivity and subgroup analyses. 
4.1 
ANALYSIS POPULATIONS 
Two analysis populations are defined for this study: the modified intend-to-treat (mITT) 
population and the safety-evaluable population. 
4.1.1 Modified Intent-to-Treat Population 
Efficacy analyses for each endpoint will be performed on the modified intent-to-treat population 
(mITT). For the primary and each secondary endpoint, the mITT population will include all 
randomized patients that have both a baseline measurement and at least one post-baseline 
measurement for the primary endpoint. The treatment groups will be based on the treatment 
assigned at randomization.  
4.1.2 Safety-Evaluable Population 
The safety-evaluable population will include all patients who were randomly allocated and 
received at least one dose of study drug (MTAU9937A or placebo) during the double-blind 
treatment period with treatment groups defined according to actual treatment received.  


 
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4.2 
ANALYSIS OF STUDY CONDUCT 
The number of patients who enroll, discontinue (early discontinuation of treatment or early 
termination from the study), complete the study (through Week 73), 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.  
4.3 
 ANALYSIS 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.  
4.4 
 EFFICACY ANALYSIS 
All efficacy analyses will be based on the modified intent-to-treat populations defined in Section 
4.1.2. The primary and secondary endpoints will be analyzed as change scores, calculated as 
follows:  
Outcome measure change score  (post-baseline value  baseline value) 
 
In the above determination of change score for CDR-SB and RBANS, the baseline value will be 
defined as the average of all non-missing values before the first dose of study drug, which 
should be an average of the screening and baseline values. For all other cognitive and 
biomarker endpoints, baseline value will be defined as latest observed value before the first 
dose of study drug. 
For the primary and secondary endpoints, mean changes from baseline will be compared 
across treatment arms using mixed-models for repeated measures (MMRM). 
Each model will have an intercept term, a term for baseline value of the endpoint, a term for 
APOE4 strata (carrier vs. non-carrier), a term for dementia status strata (pAD vs. mAD), an 
interaction term of the two stratification factors, categorical visit terms, a term for treatment 
group, a term for baseline age, and terms for treatment-by-visit interactions. This will be 
implemented using SAS proc mixed syntax similar to the excerpt below:  
proc mixed data=data; 
class PATNUM VISIT TRT APOE4 DEMSTATUS; 
model var = BASE BAGE APOE4 DEMSTATUS APOE4*DEMSTATUS VISIT TRT TRT*VISIT 
/solution noint ddfm=kr; 
repeated VISIT / subject=PATNUM type=UN; 
lsmeans VISIT*TRT / pdiff cl alpha=0.05; 
estimate ‘MTAU9937A vs Placebo Wk 73’ TRT -1 1/cl;  
An unstructured variance-covariance matrix for within-subject errors will be assumed. If the 
unstructured covariance structure matrix results in a lack of convergence, the heterogeneous 
Toeplitz covariance structure followed by the heterogeneous first-order autoregressive 


 
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covariance structure will be used. In these cases, the sandwich estimator will be used to get the 
variance of the treatment effect estimator. 
If model assumptions are violated (e.g. large deviations from normality of residuals), alternative 
modeling strategies including data transformations, permutation-based approaches, and/or 
robust mixed effects modeling methodology (Koller, Journal of Statistical Software 2016) will be 
used as appropriate for additional sensitivity analyses.  
Comparisons of Interest 
Comparisons of efficacy will be performed between each MTAU9937A treatment arm and the 
placebo group by first pooling data from the middle and high doses for the first statistical test of 
the primary endpoint and then subsequently testing each treatment arm individually. Thus, there 
will be four comparisons across the doses: 
MTAU9937A dose groups for hierarchical testing: 
 
Group 1: MTAU9937A 4500 mg + MTAU9937A 8100 mg vs placebo 
 
Group 2: MTAU9937A 4500 mg vs placebo 
 
Group 3: MTAU9937A 8100 mg vs placebo 
 
Group 4: MTAU9937A 1500 mg vs placebo 
One model pooling middle and high doses will be used to test the Group 1 hypothesis. A second 
model including all 3 active arms separately will be used for Groups 2-4. 
Type I Error Management 
Type I error for the primary endpoint will be controlled using a fixed sequence testing procedure 
at the two-sided 5% significance level. The testing procedure will proceed with comparisons 
following the order across the four dose groups detailed above. After the first hypothesis test, 
each subsequent hypothesis will only be formally tested if the preceding one is significant at the 
5% level. 
For each dose group that has a significant result for the hypothesis test for the primary endpoint, 
a separate fixed sequence testing procedure will be ungated for that dose group’s secondary 
endpoints that will similarly proceed at the 5% level. The overall testing procedure is detailed 
visually in the table below.  
 
 
 
 
 
 




 
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4.4.3 Sensitivity Analyses 
Mixed-models for repeated measures (MMRM) methods have been selected for the primary and 
secondary analyses due to their ability to accommodate the potential effects of missing data. An 
advantage of such models is that they rely on the assumption that the missing data mechanism 
is missing-at-random (MAR), rather than the more restrictive assumption that it is missing-
completely-at-random (MCAR).  
To evaluate the robustness of MMRM analyses to potential effects of missing data and validity 
of the MAR assumption, sensitivity analyses will be performed in the mITT population for the  
co-primary and secondary endpoints. At each time point (Week 25, Week 49, and Week 73), an 
ordinary least squares model for the change scores at that timepoint will be fit to estimate the 
treatment effect. These models will have terms for the baseline value of the endpoint, APOE4 
strata, dementia status strata, the interaction between APOE4 strata and dementia status strata, 
baseline age, and treatment effect. These models will be fit using the following imputations for 
missing data:  
 
No imputation (a completer analysis) 
 
Using linear extrapolation imputation based on the values at baseline and the last week 
with a non-missing value  
 
Using last-observation-carried-forward  
 
Tipping point analysis  
Intercurrent events may also influence the primary endpoint even if they do not directly result in 
missing data. Additional sensitivity analyses will be conducted using the above methods, but 
treating data collected after a given intercurrent event as missing. Proposed intercurrent events 
include missed study drug administration and initiation or modification of AD symptomatic 
concomitant medications. A separate section detailing intercurrent events and protocol 
deviations due to COVID-19 is included below. We propose to apply the same set of sensitivity 
analyses listed above when considering this additional set of intercurrent events. 
 
Additional analyses looking at treatment effect estimates in subpopulations of patients receiving 
at least a minimum number of doses will also be conducted to assess if any observed treatment 
effect could have been potentially diluted by patients who did not fully adhere to the study drug 
administration schedule. 
COVID-19 Sensitivity Analyses 
Trial conduct in the double-blind period of most TAURIEL subjects up until their respective 
Week 49 visits was unimpacted by COVID-19, with roughly 1/3 of subjects completing the entire 
double-blind period with zero impact. For subjects that were still active in the double-blind period 
during the COVID pandemic, the following additional measures were taken to mitigate the effect 
of COVID-19 on drug exposure and data collection: 
 
Some subjects received blinded study drug administration remotely at their homes. 
Adverse events were also collected at these visits. 
 
A subset of COAs, including CDR-SB and ADCS-ADL (primary and secondary 
endpoints), were administered over the phone if subjects were unable to travel to clinic. 


 
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At-home study drug administration has been flagged so as to allow for a comparative safety 
assessment between in-clinic and at-home dosing. Similarly, phone COAs have been flagged to 
enable sensitivity analyses including/excluding phone COAs as their quality may be seen as 
less reliable. Although phone COAs have been explicityly allowed since version one of the 
protocol, all phone COA assessments were only collected as a result of the COVID-19 
pandemic. 
Protocol deviations due specifically to the COVID-19 pandemic have been flagged. Each 
subject’s first COVID-19 protocol deviation will be treated as an intercurrent event indicating the 
earliest timepoint at which a given subject’s trial conduct was meaningfully affected by the 
pandemic. All data points after this first protocol deviation are then flagged as “post-COVID” on 
a per-subject level and treated as missing for sensitivity analyses. Similarly, sensitivity analyses 
using a single date applied broadly to all subjects using a sliding window will be used as an 
alternative means to exclude “post-COVID” data. As mentioned previously, missed study drug 
administration is treated as a post-randomization event and can be identified as COVID-related 
or not from the protocol deviation log.  
4.4.4 Subgroup Analyses 
Exploratory subgroup analyses of the primary efficacy endpoint will be performed to evaluate 
the consistency of the primary analysis results across pre-specified subgroups defined by 
demographic and baseline characteristics. The following subgroups will be analyzed with 
respect to the primary efficacy endpoint: 
 
Age (൑ 65 years, > 65 years) 
 
Sex (male, female) 
 
Dementia status (prodromal, mild) 
 
APOE4 status (positive, negative) 
 
Geographic region (North America, EU, rest-of-world) 
Biomarker subgroup analyses are specified in Section 4.4.5. 
For above subgroup analyses, a MMRM model as specified for the primary analysis in 
Section 4.4 will be used for each subgroup analyses based on the available data subset for the 
patient subgroup of interest with the exception of the dementia status and APOE4 status 
subgroup analyses (bullets 3 and 4) which will not contain the respective indicator variables 
since they are being used to define the subgroup. 
4.4.5 Biomarker Analyses 
Biomarker subgroup analyses 
Additional biomarker analyses will be performed to further evaluate the treatment benefit in 
biomarker-defined patient subpopulations based on baseline levels of tau pathology as 
measured by [18F]GTP1 which was collected from roughly 85% of patients at baseline. 
Based on the primary and secondary efficacy endpoints, the treatment benefit will be assessed 
for the following pre-specified biomarker-defined patient subpopulations: 
 
[18F]GTP1 at baseline: [18F]GTP1-high patients will be defined as having a temporal 
meta-ROI SUVR ≥ 1.3. [18F]GTP1-low patients will be defined as temporal meta-ROI 


 
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SUVR < 1.3 (Jack et al., Brain 2017). From the baseline data, roughly 75% of patients 
who received a [18F]GTP1 scan were defined as [18F]GTP1-high at the baseline visit. 
Additional sensitivity analyses will be conducted to assess the robustness of the proposed 
SUVR threshold and region of interest for defining [18F]GTP1-high vs low.  
An MMRM model similar to that specified for the primary and secondary analyses will be used 
for each subgroup analysis based on the data subset for the biomarker subgroup of interest. 
Point estimates for the treatment benefit within each biomarker patient group as defined above 
will be presented along with 95% confidence intervals and p-values. 
Pharmacodynamic biomarker analyses 
[18F]GTP1 has been identified as a key exploratory imaging PD biomarker. [18F]GTP1 whole 
cortical gray SUVR change from baseline will similarly be analyzed and reported using the 
MMRM model described in Section 4.4. In addition to whole cortical gray SUVR, other 
exploratory [18F]GTP1 ROIs and metrics of tau spread will be explored. 
Several candidate fluid PD biomarkers have been identified (e.g. multiple CSF assays for 
different tau species and plasma tau measures) and will be measured to assess the effect of 
MTAU9937A. Descriptive summaries of the PD biomarker values at each visit, as well as 
changes from baseline will be summarized by treatment arm. 
4.5 
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 MedDRA 
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.  
Dose-limiting adverse events and adverse events of special interest 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.  
4.6 
MISSING DATA 
A careful examination of reasons for study discontinuation will be conducted to assess the 
nature of incomplete data. In addition, frequencies and percentages of missing data at Week 73 
will be compared between the two treatment arms. Missing data will not be imputed for the 


 
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primary analysis, but will instead be handled via the missing-at-random (MAR) assumption from 
the MMRM model as described in Section 4.4. Analyses to explore the sensitivity of results to 
missing data assumptions will be conducted as described in section 4.4.3. The issue of missing 
data for secondary and exploratory endpoints will be handled similarly with a MMRM model. 
Patients who discontinue the study will be included in the analysis up to the date of study 
discontinuation.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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5. 
REFERENCES 
Becker RE, Greig NH. Alzheimer’s disease drug development: old problems require new 
priorities. CNS Neurol Disord Drug Targets 2008;7:499-511 
Jack CR Jr, Wiste HJ, Weigand SD, et al. Defining imaging biomarker cut points for brain aging 
and Alzheimer's disease. Alzheimers Dement. 2017;13(3):205–216. 
https://dx.doi.org/10.1016/j.jalz.2016.08.005 
Koller, Manuel. robustlmm: An R Package for Robust Estimation of Linear Mixed-Effects 
Models. Journal of Statistical Software [Online], 75.6 (2016): 1 - 24. Web. 16 Aug. 2020 
Koback KA. Inaccuracy in clinical trials: effects and methods to control inaccuracy. Curr 
Alzheimer Res 2010;7:637-41. 
Sanabria Bohórquez, S., Marik, J., Ogasawara, A. et al. Eur J Nucl Med Mol Imaging (2019) 46: 
2077. https://doi.org/10.1007/s00259-019-04399-0