Tau PET Longitudinal Substudy Associated With: A Double-Blind, Placebo-Controlled Parallel-Group Study in Preclinical PSEN1 E280A Mutation Carriers Randomized to Crenezumab or Placebo, and in Non-randomized, Placebo-treated Non-carriers From the Same Kindred, to Evaluate the Efficacy and Safety of Crenezumab in the Treatment of Autosomal-Dominant Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer Disease
Sponsor: Hoffmann-La Roche

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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. 
 
GTP1⎯F. Hoffmann−La Roche Ltd 
Protocol BN40199 Tau PET Longitudinal Substudy, Version 3 
PROTOCOL 
TITLE: 
TAU PET LONGITUDINAL SUBSTUDY 
ASSOCIATED WITH:  A DOUBLE-BLIND, 
PLACEBO-CONTROLLED PARALLEL-GROUP 
STUDY IN PRECLINICAL PSEN1 E280A MUTATION 
CARRIERS RANDOMIZED TO CRENEZUMAB OR 
PLACEBO, AND IN NON-RANDOMIZED, 
PLACEBO-TREATED NON-CARRIERS FROM THE 
SAME KINDRED, TO EVALUATE THE EFFICACY 
AND SAFETY OF CRENEZUMAB IN THE 
TREATMENT OF AUTOSOMAL-DOMINANT 
ALZHEIMER'S DISEASE 
PROTOCOL NUMBER: 
BN40199 (Tau PET Longitudinal Substudy) 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
NA 
IND NUMBER: 
NA 
NCT NUMBER: 
NCT03977584 
TEST PRODUCT: 
[18F]GTP1 (RO6880276) 
MEDICAL MONITOR: 
, M.D., M.A.S. 
SPONSOR: 
F. Hoffmann−La Roche Ltd
APPROVAL DATE: 
See electronic date stamp below. 
 
11-Jun-2020 23:21:01
Title
Approver's Name
Company Signatory
Date and Time (UTC)

GTP1F. HoffmannLa Roche Ltd
2/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
PROTOCOL HISTORY
Version
Date Final
Protocol Number
2
4 October 2017
GN28352-1
1
5 January 2017
GN28352-1

GTP1F. HoffmannLa Roche Ltd
3/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
PROTOCOL AMENDMENT, VERSION 3:
RATIONALE
Protocol BN40199 (originally GN283521, see below) has been amended to adjust the 
timing between [18F] Genentech Tau Probe 1 (GTP1)tau positron emission tomography 
(PET) scans. Changes to the protocol, along with a rationale for each change, are 
summarized below.

The study number has been changed.  The Tau PET substudy associated with 
main Study GN28352 was originally assigned study number GN283521.  However, 
extending the main study number for the substudy proved to be incompatible with 
internal Sponsor information technology platforms that report into ClinicalTrials.gov.  
Therefore, a new study number, BN40199, has been issued for the Tau PET 
substudy associated with the main Study GN28352.

The Sponsor of Protocol BN40199 has been changed from Genentech to 
F. Hoffmann-La Roche Ltd (hereafter referred to as Roche) as a global change.  
Genentech is a member of the Roche group.

Updated safety information from clinical studies with [18F]GTP1 has been included 
(Section 1.2).  These studies demonstrate that [18F]GTP1 exposure and imaging 
procedures are generally well tolerated. 

The timing of [18F]GTP1tau PET scans has been adjusted (Section 3.1 and 
Appendix 1) in order to standardize the interval between the first and second scans, 
and to clarify the timing of the final scan.  The second [18F]GTP1tau PET scan, 
which was previously performed between Weeks 248 and 260, is now scheduled 52 
[2] weeks from the first [18F]GTP1tau PET scan.  In addition, timing of the third 
[18F]GTP1tau PET scan has been specified in greater detail to clarify how this scan 
should be integrated with either the ET (early termination) or final visit. 

Re-consent language for participants who lose capacity to consent during the trial 
has been added to harmonize with the main study protocol (Section 4.3.1). 

Language has been revised to account for the fact that some sites may not allow 
follow-up on partner pregnancies (Section 5.3.1.2).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

The process for reviewing and handling protocol deviations has been updated per 
internal standard operating procedures (Section 9.2).

Language has been revised to clarify that study data may be shared with others who 
are not participating in this study and that redacted Clinical Study Reports and other 
summary reports will be made available upon request (Section 9.5).
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.

 
GTP1⎯F. Hoffmann−La Roche Ltd 
4/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM ............................................ 7 
PROTOCOL SYNOPSIS ...................................................................................... 8 
1. 
BACKGROUND .......................................................................................... 12 
1.1 
Background on Tau Positron Emission 
Tomography .......................................................................... 12 
1.2 
Human Safety and Tolerability of [18F]GTP1.......................... 12 
1.3 
Substudy Rationale and Benefit-Risk 
Assessment ........................................................................... 13 
2. 
OBJECTIVE ................................................................................................ 13 
3. 
SUBSTUDY DESIGN .................................................................................. 13 
3.1 
Description of the Substudy ................................................... 13 
3.2 
End of Substudy .................................................................... 15 
4. 
STUDY POPULATION ................................................................................ 15 
4.1 
Participants ............................................................................ 15 
4.1.1 
Inclusion Criteria .................................................................... 15 
4.1.2 
Exclusion Criterion ................................................................. 16 
4.2 
Study Treatment .................................................................... 16 
4.2.1 
Investigational Agent [18F]GTP1 ............................................ 16 
4.2.2 
Source of Production of [18F]GTP1 ........................................ 16 
4.3 
Study Assessments ............................................................... 16 
4.3.1 
Informed Consent Forms ....................................................... 16 
4.3.2 
Tau Positron Emission Tomography ...................................... 17 
4.3.2.1 
Positron Emission Tomography Imaging 
Procedures ............................................................................ 17 
4.3.2.2 
Tau PET Imaging Metrics ...................................................... 17 
4.4 
Participant, Treatment, and Substudy 
Discontinuation ...................................................................... 18 
4.4.1 
Blinding and Unblinding ......................................................... 18 
4.4.2 
Participant Discontinuation .................................................... 18 
4.4.3 
Substudy Discontinuation ...................................................... 18 
5. 
ASSESSMENT OF SAFETY ....................................................................... 18 

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5/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
5.1
Safety Parameters and Definitions ........................................ 19
5.2
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 19
5.2.1
Adverse Events Reporting Period.......................................... 19
5.3
Procedures for Recording Adverse Events............................ 19
5.3.1
Recording Adverse Events on the eCRF............................... 19
5.3.1.1
Pregnancies in Female Participants ...................................... 20
5.3.1.2
Pregnancies in Female Partners of Male 
Participants............................................................................ 20
5.4
Expedited Reporting Requirements for Serious 
Adverse Events (and Protocol-Defined Events of 
Special Interest)..................................................................... 20
5.5
Type and Duration of Follow-Up of Participants 
after Adverse Events ............................................................. 20
5.6
Post-Study Adverse Events................................................... 21
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 21
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 21
6.1
Determination of Sample Size ............................................... 21
6.2
Summaries of Conduct of SUBStudy..................................... 22
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 22
6.4
Safety Analyses..................................................................... 22
7.
DATA COLLECTION AND MANAGEMENT ............................................... 22
7.1
Data Quality Assurance......................................................... 22
7.2
Source Data Documentation.................................................. 22
7.3
Use of Computerized Systems .............................................. 22
7.4
Retention of Records............................................................. 22
8.
ETHICAL CONSIDERATIONS.................................................................... 22
8.1
Compliance with Laws and Regulations ................................ 22
8.2
Informed Consent.................................................................. 23
8.3
Institutional Review Board or Ethics Committee.................... 24
8.4
Confidentiality........................................................................ 24

GTP1F. HoffmannLa Roche Ltd
6/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
9.
SUBSTUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 25
9.1
Substudy Documentation....................................................... 25
9.2
Protocol Deviations................................................................ 25
9.3
Site Inspections ..................................................................... 25
9.4
Administrative Structure......................................................... 25
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 25
9.6
Protocol Amendments ........................................................... 26
10. REFERENCES ........................................................................................... 28
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 30

GTP1F. HoffmannLa Roche Ltd
7/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
TAU PET LONGITUDINAL SUBSTUDY 
ASSOCIATED WITH:  A DOUBLE-BLIND, 
PLACEBO-CONTROLLED PARALLEL-GROUP 
STUDY IN PRECLINICAL PSEN1 E280A MUTATION 
CARRIERS RANDOMIZED TO CRENEZUMAB OR 
PLACEBO, AND IN NON-RANDOMIZED, 
PLACEBO-TREATED NON-CARRIERS FROM THE 
SAME KINDRED, TO EVALUATE THE EFFICACY 
AND SAFETY OF CRENEZUMAB IN THE 
TREATMENT OF AUTOSOMAL-DOMINANT 
ALZHEIMER'S DISEASE
PROTOCOL NUMBER:
BN40199 (Tau PET Longitudinal Substudy)
VERSION NUMBER:
3
EUDRACT NUMBER:
NA
IND NUMBER:
NA
NCT NUMBER:
NCT03977584
TEST PRODUCT:
[18F]GTP1 (RO6880276)
MEDICAL MONITOR:
, M.D., M.A.S.
SPONSOR:
F. HoffmannLa Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name  (print)
Principal Investigator's Signature
Date
Please return the signed original of this form as instructed by your local study monitor.  Please 
retain a copy for your study files.

GTP1F. HoffmannLa Roche Ltd
8/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
PROTOCOL SYNOPSIS
TITLE:
TAU PET LONGITUDINAL SUBSTUDY ASSOCIATED WITH:  A 
DOUBLE-BLIND, PLACEBO-CONTROLLED PARALLEL-GROUP 
STUDY IN PRECLINICAL PSEN1 E280A MUTATION CARRIERS 
RANDOMIZED TO CRENEZUMAB OR PLACEBO, AND IN NON-
RANDOMIZED, PLACEBO-TREATED NON-CARRIERS FROM THE 
SAME KINDRED, TO EVALUATE THE EFFICACY AND SAFETY 
OF CRENEZUMAB IN THE TREATMENT OF 
AUTOSOMAL-DOMINANT ALZHEIMER'S DISEASE
PROTOCOL NUMBER:
BN40199 (Tau PET Longitudinal Substudy)
VERSION NUMBER:
3
EUDRACT NUMBER:
NA
IND NUMBER:
NA
NCT NUMBER:
NCT03977584
TEST PRODUCT:
[18F]GTP1 (RO6880276)
INDICATION:
Alzheimer’s Disease
SPONSOR:
F. HoffmannLa Roche Ltd
Objective
The objective of this substudy is to assess changes in tau burden over time in participants 
enrolled in Study GN28352 who are treated with crenezumab or placebo.
Study Design
Description of Study
Participants enrolled in the main Study GN28352 will have the option to participate in this 
substudy.  Participants must sign a separate Informed Consent Form and fulfill entry criteria.  
Enrollment in this substudy does not preclude enrollment in other substudies of the main study 
unless radiation exposure limits are expected to be exceeded.
Only participants from the Medellin and Yarumal sites will be eligible for enrollment into this 
substudy.  There are approximately 150 participants expected to enroll in this substudy, which
may include up to the entire enrolled participant pool at the Medellin and Yarumal sites.  
Approximately 50 participants per treatment arm in the main study are expected to enroll in the 
substudy.  Participants enrolled in the substudy will be allocated to the main study treatment 
(crenezumab or placebo) as described in the main study protocol. 
Participants enrolled in this substudy will receive up to three intravenous (IV) injections of [18F] 
Genentech Tau Probe 1 (GTP1) and will undergo a tau positron emission tomography (PET) 
scan after each IV injection of [18F]GTP1.  Because this substudy is being introduced after the 
main study has started, the schedule for [18F]GTP1 injections and PET scans has been made 
flexible to maximize the number of participants who may be enrolled in the substudy.  
Participants should only be enrolled into this substudy if it is reasonably expected that at least 
two [18F]GTP1-tau PET scans can be obtained, per the schedule provided below.
As with the [18F]fluorodeoxyglucose (FDG) and [18F]florbetapir PET scans described in the main 
study, [18F]GTP1tau PET scans should only be performed if the investigator has determined 
that the total annual radiation exposure from all PET and CT scans (and including any other 
scans involving radiation that may have been acquired outside of this study) does not exceed 

GTP1F. HoffmannLa Roche Ltd
9/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
local safety guidelines.  Radiation exposure for [18F]GTP1 doses can be found in the [18F]GTP1 
Investigator’s Brochure.  Radiation exposure for [18F]florbetapir doses can be found in the 
Amyvid U.S. Package Insert (0.019 mSv/MBq whole-body Effective Dose).  Radiation exposure 
for [18F]FDG can be found in Quinn et al. (2016) (7.4 mSv whole-body Effective Dose for a 
10 mCi [18F]FDG dose).
There will be up to three [18F]GTP1-tau PET scans for each participant in this substudy (see 
the schedule of activities).  The first two [18F]GTP1-tau PET scans will be 52 [2] weeks 
apart.  To maximize the ability to detect changes in tau burden, the third scan should be at 
the early termination (ET) or final visit, whichever is later, under the timing constraints 
described below.
The first [18F]GTP1tau PET scan may occur on any visit that occurs in the main protocol 
(GN28352), from the Week 130 visit to the Week 224 visit.  The timing of this first scan visit may 
be different for each participant.  For each participant, this first scan should occur as early as 
possible within the Week 130 to Week 224 visit period.  The flexibility in the timing of this first 
scan is intended to allow the maximum number of participants to receive this scan, since 
participants may join this substudy at different timepoints relative to their enrollment in the 
main study.
The second scan may occur at any visit that occurs in the main protocol (GN28352) that is
approximately 52 [2] weeks after the first scan.  The timing of this second scan visit may be 
different for each participant.  
The third [18F]GTP1 tau PET scan is intended to maximize the interval in which tau 
pathology might develop between the first and last scan, with the goal of maximizing the 
ability to detect potential treatment effects of crenezumab.  Thus, the third [18F]GTP1 tau 
PET scan would take place at the ET or final visit if at least 6 months elapsed since the 
previous [18F]GTP1tau PET scan.  The timing of this third scan will take into consideration 
the total annual radiation exposure and will not exceed local safety guidelines for each 
participant.  
Number of Participants
There are approximately 150 participants expected to enroll in this substudy, which may include 
up to all participants enrolled at the Medellin and Yarumal sites.  Per the randomization 
schedule in the main Study Protocol GN28352, approximately 50 participants in each of the 
main study’s three treatment arms are expected to be enrolled into the substudy.
Target Population
Inclusion Criteria
Participants must meet all the criteria listed in the main Study Protocol GN28352 and the 
following criteria for substudy entry:

Enrolled in main Study GN28352

Signed separate consent for participation in the Tau PET Longitudinal Substudy BN40199
(co-signed by the participant's next of kin or study partner, if required by the local 
regulations, guidelines, and Ethics Committee [EC])

Ability to comply with the substudy protocol, in the investigator's judgment
Exclusion Criteria
Participants will be excluded from this substudy if they meet the following criterion:

Contraindication to PET scan procedures, possibly including, but not limited to, the following:
Current, past, or planned participation in studies involving radioactive agents, including 
the main Study GN28352 and this Tau PET substudy, such that the total 
research-related radiation dose to the participant in any given year would exceed the 
limits set forth in the U.S.  Code of Federal Regulations (CFR) Title 21 Section 361.1 
(http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=361.1)
For further information on crenezumab, please refer to the main Study Protocol GN28352, the 
pharmacy manual, and the crenezumab Investigator's Brochure.

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10/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
End of Study
The end of this substudy is defined as the date when all participants enrolled in the substudy 
have completed their final tau PET scan or discontinued from the main study.
Investigational Medicinal Products
The selective tau PET radioligand, [18F]GTP1, will be used in this substudy.  It is intended that 
participants will receive [18F]GTP1 on up to three occasions.
Statistical Methods
Analysis
The absolute change from the first [18F]GTP1 scan in several measures of tau burden (including 
but not limited to SUVR and tau distribution metrics) will be analyzed using a mixed-effects 
model for repeated measures similar to that described for the primary efficacy endpoint in the 
main study.  Additional descriptive summaries that describe the relationship between tau PET 
and other endpoints will be generated.
The specific tau distribution metrics used will be further defined after key data, external to this 
study (for example study GN30009), become available.  Such details (as well as details of 
hypothesis testing) will be specified in the Statistical Analysis Plan, prior to unblinding of study 
treatment (crenezumab or placebo) in the main protocol. 
Other exploratory analyses may also be conducted that may not be pre-specified prior to 
database unblinding.
Determination of Sample Size  
The sample size was determined based on the maximum number of participants from the main 
Study GN28352 who can still undergo two tau PET scans with at least one year in between.

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11/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AD
Alzheimer's disease
CRO
contract research organization
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
ET
early termination
FDG
fluorodeoxyglucose
GTP1
Genentech Tau Probe 1
ICH
International Council for Harmonisation
IMP
investigational medicinal product
IND 
Investigational New Drug
IRB
Institutional Review Board
IV
intravenous
PET
positron emission tomography
SUVR
standardized uptake value ratio

GTP1F. HoffmannLa Roche Ltd
12/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
1.
BACKGROUND
1.1
BACKGROUND ON TAU POSITRON EMISSION TOMOGRAPHY 
Tau protein has been identified as one of the key pathological features of Alzheimer's 
disease (AD) (Grundke-Iqbal et al. 1986; Kosik et al. 1986; Wood et al. 1986).  Tau is 
the primary protein composing neurofibrillary tangles, and post-mortem studies have 
shown that neurofibrillary tangle density correlates with neurodegeneration and cognitive 
impairment (Duyckaerts et al. 1987, 1990; Delaere et al. 1989; Arriagada et al. 1992; 
McLean et al. 1999).  Given the role of tau protein in the pathology of AD, expanding 
neuroimaging biomarkers to include a tau radioligand offers the potential to improve 
understanding of the pathological process in AD. Thus, a positron emission tomography 
(PET) imaging agent that binds to aggregated tau has the potential to serve as a 
biomarker for monitoring disease progression and for monitoring efficacy of therapeutics 
that influence AD progression.
Until recently, post-mortem examination of brain tissues was the only means available 
for directly evaluating the changes occurring in the brain in AD.  In the last decade, the 
development of highly specific techniques for imaging the brain in AD and other 
dementias has expanded our ability to measure the disease process over time in a living 
individual.  Briefly, these techniques involve intravenous (IV) administration of 
radioactively-labeled compounds that bind to selective target sites in the brain.  PET is 
able to detect the spatial distribution of the radioactive compound in the brain and can be 
used as an objective, sensitive, and accurate method to quantify the concentration of the 
target in different brain regions.  Using these PET techniques, β-amyloid aggregates 
have been successfully imaged in several studies in AD patients using high affinity 11-C 
and 18-Flabeled PET radioligands (PIB and florbetapir, AV-1) (Klunk et al. 2004, 2005; 
Clark et al. 2011; Hyman et al. 2012).  Now there are multiple studies comparing amyloid 
PET scans to histopathologic assessment that support the relationship between PET 
amyloid imaging results and cortical neuritic plaque density (Leinonen et al. 2008;
Sojkova et al. 2011; Ni et al. 2013; Quiroz et al. 2016).
[18F] Genentech Tau Probe 1 (GTP1) (also known as [18F]RO6880276) has been 
developed as a positron emitting radiopharmaceutical for in vivo imaging of tau protein 
aggregates.  [18F]GTP1 has been previously evaluated in three completed studies in 
humans and is currently being evaluated in a longitudinal, observational study in humans 
(Study GN30009).  Refer to the [18F]GTP1 Investigator's Brochure for more details on 
these studies. 
1.2
HUMAN SAFETY AND TOLERABILITY OF [18F]GTP1
Available safety data from the initial clinical studies with [18F]GTP1 show that exposure 
to [18F]GTP1 and imaging procedures are generally well tolerated. There have been no 
deaths, no adverse events of special interest, and no hypersensitivity reactions.  
Currently there are no adverse drug reactions identified for [18F]GTP1. Refer to the 

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13/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
[18F]GTP1 Investigator's Brochure for more details of these studies and for a full non-
clinical evaluation of the tracer and the clinical experience to date.
1.3
SUBSTUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
This is a substudy associated with the main Study GN28352, which is a Phase II study 
to evaluate the safety and efficacy of crenezumab in preclinical PSEN1 E280A mutation 
carriers and non-carriers from the same kindred. This substudy will evaluate the effect 
of crenezumab on tau burden as measured by [18F]GTP1tau PET in this study 
population.  The results of this substudy are expected to help understand the effects of 
crenezumab on the longitudinal progression of tau burden as well as the relationship 
between changes in [18F]GTP1tau PET and changes in other endpoints in the main 
study.
Participants in this substudy must be enrolled in the main Study GN28352. In order to 
blind substudy participants to their mutation carrier status, similar to the main study, 
carriers and non-carriers of the PSEN1 E280A mutation will be enrolled in this substudy.
There is no expected therapeutic benefit of [18F]GTP1 to trial participants.  However, 
participation in this substudy will enhance the understanding of disease progression in 
the preclinical stage of familial AD and will enhance the understanding of the effect of 
crenezumab on familial AD progression.  Participation in this substudy may also 
enhance the understanding of the progression of sporadic AD, as current and future 
investigations delineate the overlap in the pathophysiology of familial and sporadic 
disease. The emerging safety profile of [18F]GTP1 indicates that there is no measurable 
added risk of participation in this substudy, aside from potential risks from radiation 
exposure.  Please see Section 3.1 and 4.1.2 for instruction on limiting radiation exposure 
to that permitted by local safety guidelines to minimize this risk.
2.
OBJECTIVE 
The objective of this substudy is to assess changes in tau burden over time in 
participants enrolled in Study GN28352 who are treated with crenezumab or placebo.
3.
SUBSTUDY DESIGN
3.1
DESCRIPTION OF THE SUBSTUDY
Participants enrolled in the main Study GN28352 will have the option to participate in 
this substudy.  Participants must sign a separate Informed Consent Form and fulfill entry
criteria as detailed in Section 4.1.  Enrollment in this substudy does not preclude 
enrollment in other substudies of the main study unless radiation exposure limits are 
expected to be exceeded.
Only participants from the Medellin and Yarumal sites will be eligible for enrollment into 
this substudy.  There are approximately 150 participants expected to enroll in this 
substudy, which may include up to the entire enrolled participant pool at the Medellin 

GTP1F. HoffmannLa Roche Ltd
14/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
and Yarumal sites.  Approximately 50 participants per treatment arm in the main study
are expected to enroll in the substudy.  Participants enrolled in the substudy will be 
allocated to the main study treatment (crenezumab or placebo) as described in the main 
study protocol.
Participants enrolled in this substudy will receive up to three IV injections of [18F]GTP1
and will undergo a tau PET scan after each IV injection of [18F]GTP1.  Because this 
substudy is being introduced after the main study has started, the schedule for 
[18F]GTP1 injections and PET scans has been made flexible to maximize the number of 
participants who may be enrolled in the substudy. Participants should only be enrolled
into this substudy if it is reasonably expected that at least two [18F]GTP1-tau PET scans 
can be obtained, per the schedule provided below.
As with the [18F]fluorodeoxyglucose (FDG) and [18F]florbetapir PET scans described in 
the main study, [18F]GTP1tau PET scans should only be performed if the investigator 
has determined that the total annual radiation exposure from all PET and CT scans (and 
including any other scans involving radiation that may have been acquired outside of this 
study) does not exceed local safety guidelines.  Radiation exposure for [18F]GTP1 doses 
can be found in the [18F]GTP1 Investigator’s Brochure. Radiation exposure for 
[18F]florbetapir doses can be found in the Amyvid U.S. Package Insert (0.019 mSv/MBq
whole-body Effective Dose). Radiation exposure for [18F]FDG can be found in Quinn et 
al. (2016) (7.4 mSv whole-body Effective Dose for a 10 mCi [18F]FDG dose).
There will be up to three [18F]GTP1-tau PET scans for each participant in this 
substudy (see the schedule of activities in Appendix 1).  The first two [18F]GTP1-tau 
PET scans will be 52 [2] weeks apart.  To maximize the ability to detect changes in 
tau burden, the third scan should be at the early termination (ET) or final visit, 
whichever is later, under the timing constraints described below.
The first [18F]GTP1tau PET scan may occur on any visit that occurs in the main protocol 
(GN28352), from the Week 130 visit to the Week 224 visit.  The timing of this first scan 
visit may be different for each participant.  For each participant, this first scan should 
occur as early as possible within the Week 130 to Week 224 visit period.  The flexibility 
in the timing of this first scan is intended to allow the maximum number of participants to 
receive this scan, since participants may join this substudy at different timepoints relative 
to their enrollment in the main study.
The second scan may occur at any visit that occurs in the main protocol (GN28352) 
that is approximately 52 [2] weeks after the first scan.  The timing of this second scan 
visit may be different for each participant.  
The third [18F]GTP1tau PET scan is intended to maximize the interval in which tau 
pathology might develop between the first and last scan, with the goal of maximizing 
the ability to detect potential treatment effects of crenezumab.  Thus, the third 

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[18F]GTP1tau PET scan would take place at the ET or final visit if at least 6 months 
elapsed since the previous [18F]GTP1tau PET scan.  The timing of this third scan will 
take into consideration the total annual radiation exposure and will not exceed local 
safety guidelines for each participant.  
If a participant discontinues the study prior to the end of the GN28352 study, a 
[18F]GTP1tau PET scan should occur at the time of ET unless any of the following 
conditions are met:

The participant discontinued for safety reasons that would contraindicate 
PET scans

The interval between the most recent [18F]GTP1tau PET scan and the ET scan 
would be less than 6 months

The annual radiation exposure including the ET scan would exceed locally 
permitted limits  
3.2
END OF SUBSTUDY
The end of this substudy is defined as the date when all participants enrolled in the 
substudy have completed their final tau PET scan or discontinued from the main study.
4.
STUDY POPULATION
4.1
PARTICIPANTS
There are approximately 150 participants expected to enroll in this substudy, but it may 
include up to all participants enrolled at the Medellin and Yarumal sites.  Per the 
randomization schedule in the main study protocol (GN28352), approximately 
50 participants in each of the main study’s three treatment arms are expected to be 
enrolled into the substudy. Participants will be eligible for this substudy if they are 
eligible for the main study and satisfy the following additional inclusion and exclusion 
criteria.
4.1.1
Inclusion Criteria
Participants must meet all the criteria listed in the main study protocol (GN28352) and 
the following criteria for substudy entry:

Enrolled in main Study GN28352

Signed separate consent for participation in the Tau PET Longitudinal 
Substudy BN40199 (co-signed by the participant's next of kin or study partner, if 
required by the local regulations, guidelines, and Ethics Committee [EC])

Ability to comply with the substudy protocol, in the investigator's judgment

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4.1.2
Exclusion Criterion
Participants will be excluded from this substudy if they meet the following criterion:

Contraindication to PET scan procedures, possibly including, but not limited to, the 
following:
Current, past, or planned participation in studies involving radioactive agents, 
including the main Study GN28352 and this Tau PET substudy, such that the 
total research-related radiation dose to the participant in any given year would 
exceed the limits set forth in the U.S.  Code of Federal Regulations (CFR) Title 
21 Section 361.1 
(http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=361.1)
For further information on [18F]GTP1 please refer to the [18F]GTP1 Investigator's 
Brochure.
4.2
STUDY TREATMENT
4.2.1
Investigational Agent [18F]GTP1
[18F]GTP1 is a clear solution formulated for IV injection.  [18F]GTP1 is formulated in 0.9% 
sodium chloride injection containing ethanol and ascorbic acid.  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.  [18F]GTP1 
will be stored at ambient temperature in its original container.
[18F]GTP1 is supplied as a sterile non-pyrogenic unit dose solution in a sterile syringe.  
The syringe is contained within an outer lead or tungsten shield (“pig”) to protect from 
gamma radiation.  For more detail, please refer to the GTP1 Investigator Brochure and 
the [18F]GTP1Tau PET Technical Operations Manual.
[18F]GTP1 will be considered an investigational product because [18F]GTP1 is not 
approved for marketing in Colombia.
4.2.2
Source of Production of [18F]GTP1
[18F]GTP1 will be provided by Ciclotron SAS (Medellin, Colombia) in accordance with the 
locally approved prescribing information and in accordance with approved national 
and/or local standards.
4.3
STUDY ASSESSMENTS 
See Appendix 1 for the schedule of activities performed during the study.
4.3.1
Informed Consent Forms 
All participants or their authorized representatives must review, sign, and date the most 
current Institutional Review Board/Ethics Committee (IRB/EC) approved written 
Informed Consent Form for participation in the Tau PET Longitudinal Substudy BN40199
before any substudy-specific evaluations are performed.  Informed Consent Forms for 

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enrolled participants and for those who are not subsequently enrolled will be maintained 
at the study site.
If, during the course of the trial, a participant develops dementia and loses his/her 
capacity to consent, the most recently signed consent form prior to loss of capacity will 
remain active.  Any revisions to the consent form will require re-consent by the
participant’s authorized representative (consisting of either a legally authorized 
representative or a temporary representative if a legally authorized representative is 
unavailable) as well as assent from the participant as per site standard operating 
procedure TR-Pr-058.
For further details on the main study, please see the protocol and Informed Consent 
Forms for Study GN28352.
4.3.2
Tau Positron Emission Tomography
Up to three [18F]GTP1tau PET scans are included in this substudy.  For details of scan 
timing, please refer to Section 3.1.  
If occurring in the same visit, [18F]GTP1tau PET scans will be performed after 
neurocognitive testing but prior to dosing of crenezumab or placebo. [18F]GTP1tau 
PET scans should be performed a minimum of 12 hours apart from other PET scans and 
a maximum of 14 days apart from any accompanying fibrillar amyloid-PET or FDG-PET 
scan.
The selective tau PET radioligand, [18F]GTP1, will be used in this substudy. It is 
intended that each participant will receive [18F]GTP1 on up to three occasions.  
Detailed methodology, including scanning procedures, is included in the [18F]GTP1Tau 
PET Technical Operations Manual.
4.3.2.1
Positron Emission Tomography Imaging Procedures
The Sponsor in conjunction with the imaging contract research organization (CRO) will 
prepare and distribute a detailed [18F]GTP1Tau PET Technical Operations Manual for 
image acquisition and reconstruction procedures and parameters for the PET imaging 
center prior to the start of the study.  All imaging data will be transferred to the imaging 
CRO for quality control, qualitative image assessment, and quantitative image analysis 
as documented in the [18F]GTP1Tau PET Technical Operations Manual.
4.3.2.2
Tau PET Imaging Metrics
Imaging metrics for [18F]GTP1 Tau PET imaging will assess tau pathology burden and 
longitudinal change; potential examples include:

Standardized uptake value ratio (SUVR) for multiple cortical brain regions of interest 
(e.g., middle or inferior temporal gyrus) using cerebellar gray matter as a reference 
region 

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
Tau distribution measured by SUVR and/or extent of tau positive voxels

Other potential measurements reflecting tau distribution, including use of other 
potential reference regions, will be identified based on data generated outside of the 
current substudy protocol
4.4
PARTICIPANT, TREATMENT, AND SUBSTUDY
DISCONTINUATION
4.4.1
Blinding and Unblinding 
In this Tau PET Longitudinal Substudy (BN40199), all enrolled participants will receive 
the unblinded [18F]GTP1 radioligand but will stay blinded with regard to their study 
treatment assigned in the main study (crenezumab or placebo).
4.4.2
Participant Discontinuation
Participants have the right to voluntarily withdraw from this substudy at any time for any 
reason.  In addition, the investigator has the right to withdraw a participant from the 
substudy at any time.  Reasons for withdrawal from the substudy may include, but are 
not limited to, the following:

Participant withdrawal of consent to participate in the substudy at any time without 
withdrawing from the main Study GN28352

Participant withdrawal of consent to participate in the main Study GN28352

Investigator or Sponsor determines it is in the best interest of the participant
Every effort should be made to obtain information on participants who withdraw from the 
substudy.  The primary reason for withdrawal from the substudy should be documented
on the appropriate electronic Case Report Form (eCRF).  However, participants will not 
be followed for any reason after consent has been withdrawn.  
4.4.3
Substudy Discontinuation
The Sponsor has the right to terminate this substudy at any time.  Reasons for 
terminating the substudy 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 participants

Participant enrollment is unsatisfactory
5.
ASSESSMENT OF SAFETY
Crenezumab 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 crenezumab in completed and ongoing studies and is detailed in the main Study 
Protocol GN28352.  Several measures will be taken to ensure the safety of participants 
who participate in this substudy.  Please refer to Section 5 of the main protocol for 
details of the safety plan.

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Please refer to the main protocol and the Crenezumab Investigator's Brochure for a 
complete summary of safety information related to crenezumab.
[18F]GTP1 is not approved by any health authority, and clinical development is ongoing.  
The safety plan for participants in this substudy is based on clinical experience with 
[18F]GTP1 in completed and ongoing studies and is detailed in the [18F]GTP1 
Investigator's Brochure, in Section 5 of the main study protocol, and in Section 1.2 in this 
protocol.  More details are provided in the [18F]GTP1 Investigator’s Brochure. 
5.1
SAFETY PARAMETERS AND DEFINITIONS
Refer to Section 5.1 and sub-sections of Section 5.1 of the main study protocol 
(GN28352) for an overview of safety assessments and relevant definitions.
In addition to crenezumab and florbetapir being considered investigational products (as 
stated in Section 5.1.1 of the main study protocol), [18F]GTP1 is also considered an 
investigational product for participants enrolled in this substudy.  
5.2
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
Refer to Section 5.2 and sub-sections of Section 5.2 of the main study protocol 
(GN28352) for the methods and timing for capturing and assessing safety parameters. 
5.2.1
Adverse Events Reporting Period
For participants in this substudy, the adverse event reporting period is the same as that 
described in Section 5.2.1 of the main study protocol.  This section has been included 
here solely to be explicit that [18F]GTP1 is considered to be an investigational product.
All adverse events and serious adverse events, regardless of attribution, will be collected 
until 16 weeks following the last administration of any investigational product 
(crenezumab/placebo, florbetapir, or [18F]GTP1) or discontinuation/termination of either 
the main study or this substudy, whichever is later.  After this 16-week follow-up period, 
investigators should report only serious adverse events that are felt to be related to prior 
administration of investigational product (see Section 5.6 of the main study protocol). 
5.3
PROCEDURES FOR RECORDING ADVERSE EVENTS
Refer to Section 5.3 and sub-sections of Section 5.3 of the main study protocol 
(GN28352) for procedures for recording adverse events. 
5.3.1
Recording Adverse Events on the eCRF
For participants in this substudy, reporting of pregnancies in participants, or in female 
partners of male participants, will be the same as that described in the main study 
protocol. The two subsections included below have been added to be explicit about the 
adverse event reporting periods, and to be explicit that [18F]GTP1 is considered to be an 
investigational product.

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5.3.1.1
Pregnancies in Female Participants
If a female participant becomes pregnant while receiving investigational therapy or within 
16 weeks after the last dose of investigational product (crenezumab/placebo, florbetapir,
or [18F]GTP1), a Pregnancy Report eCRF should be completed within 24 hours of 
learning of the pregnancy.  A pregnancy report will automatically be generated and sent 
to Roche Drug Safety by the electronic data capture (EDC) system.  Pregnancy should 
not be recorded on the Adverse Event eCRF.  In the event the EDC system is 
unavailable, a paper Pregnancy Report form and Pregnancy Fax Coversheet should be 
completed and faxed to Roche's Drug Safety Department, or its designee, at the fax 
numbers listed in Section 5.4.2 of the main study protocol (GN28352).
5.3.1.2
Pregnancies in Female Partners of Male Participants
Male participants will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant after the first dose of either 
crenezumab/placebo, florbetapir, or [18F]GTP1 has been administered or within 8 weeks
after the last dose of crenezumab/placebo, florbetapir, or [18F]GTP1 has been 
administered.  A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted 
via the EDC system. Attempts should be made to collect and report details of the course 
and outcome of any pregnancy in the partner of a male patient exposed to 
investigational product.  When permitted by the site, the pregnant partner would need to 
sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow 
for follow-up on her pregnancy.  If the authorization has been signed, the investigator 
should update the Pregnancy Report eCRF with additional information on the course 
and outcome of the pregnancy.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician.  In the event that the EDC system is unavailable, 
follow reporting instructions provided in Section 5.3.1.i of the main study protocol
(GN28352).
5.4
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS 
ADVERSE EVENTS (AND PROTOCOL-DEFINED EVENTS OF 
SPECIAL INTEREST)
Refer to Section 5.4 and sub-sections of Section 5.4 of the main study protocol 
(GN28352) for expedited reporting requirements for serious adverse events and 
protocol-defined events of special interest. 
5.5
TYPE AND DURATION OF FOLLOW-UP OF PARTICIPANTS 
AFTER ADVERSE EVENTS
Refer to Section 5.5 of the main study protocol (GN28352) for type and duration of 
follow-up of participants after adverse events. 

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5.6
POST-STUDY ADVERSE EVENTS
Refer to Section 5.6 of the main study protocol (GN28352) for reporting of post-study 
adverse events. 
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 GTP1 IB.
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The absolute change from the first [18F]GTP1 scan in several measures of tau burden 
(including but not limited to SUVR and tau distribution metrics) will be analyzed using a 
mixed-effects model for repeated measures similar to that described for the primary 
efficacy endpoint in the main study.  Additional descriptive summaries that describe the 
relationship between tau PET and other endpoints will be generated.
The specific tau distribution metrics used (see Section 4.3.2.2) will be further defined 
after key data, external to this study (for example study GN30009), become available.  
Such details (as well as details of hypothesis testing) will be specified in the Statistical 
Analysis Plan, prior to unblinding of study treatment (crenezumab or placebo) in the 
main protocol. 
Other exploratory analyses may also be conducted that may not be pre-specified prior to 
database unblinding.
6.1
DETERMINATION OF SAMPLE SIZE
The sample size was determined based on the maximum number of participants from 
the main Study GN28352 who can still undergo two tau PET scans with at least one year 
in between.

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6.2
SUMMARIES OF CONDUCT OF SUBSTUDY
Enrollment, participant disposition, and incidence of protocol deviations will be 
summarized for the intent-to-treat population according to the randomly assigned 
treatment arms. The number of participants who enroll, discontinue, or complete the 
substudy will be summarized.  Reasons for premature substudy withdrawal will be listed 
and summarized.  Enrollment and major protocol deviations will be listed and evaluated 
for their potential effects on the interpretation of substudy results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age and sex) of the participants
who participate in this substudy will be summarized using means, standard deviations, 
medians, and ranges for continuous variables and proportions for categorical variables, 
as appropriate.  
6.4
SAFETY ANALYSES
The safety analyses for [18F]GTP1 will include all participants who participate in the 
substudy and receive at least one dose of [18F]GTP1.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
Refer to Sections 6.5 and 6.6 of the main study protocol (GN28352) for requirements for 
study monitoring and use of eCRFs in the substudy. 
7.2
SOURCE DATA DOCUMENTATION
Refer to Section 6.7 of the main study protocol (GN28352) for requirements for source 
data documentation in the substudy. 
7.3
USE OF COMPUTERIZED SYSTEMS
Refer to Section 6.8 of the main study protocol (GN28352) for requirements of 
computerized systems used in the substudy. 
7.4
RETENTION OF RECORDS
Refer to Section 6.11 of the main study protocol (GN28352) for requirements for 
retention of records in the substudy. 
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This substudy will be conducted in full conformance with the International Council for 
Harmonisation (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 

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substudy 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. Food and Drug Administration 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 Tau PET Longitudinal Substudy (BN40199) sample Informed Consent 
Form will be provided to participating sites.  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 Informed 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 participant the 
objectives, methods, and potential risks associated with each optional procedure.  
Participants 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 participant's agreement to participate in optional procedures.  Participants
who decline to participate will not provide a separate signature.
The Informed Consent Forms must be signed and dated by the participant or the 
participant’s authorized representative before his or her participation in the substudy.  
The case history or clinical records for each participant shall document the informed 
consent process and that written informed consent was obtained prior to participation in 
the substudy.
The Informed Consent Forms should be revised whenever there are changes to 
substudy procedures or when new information becomes available that may affect the 
willingness of the participant to participate.  The final revised IRB/EC-approved Informed 
Consent Forms must be provided to the Sponsor for health authority submission 
purposes.
Participants must be re-consented to the most current version of the Informed Consent 
Forms (or to a significant new information/findings addendum in accordance with 
applicable laws and IRB/EC policy) during their participation in the substudy.  For any 
updated or revised Informed Consent Forms, the case history or clinical records for each 
participant shall document the informed consent process and that written informed 
consent by the participant or the participant’s authorized representative was obtained 

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using the updated/revised Informed Consent Forms for continued participation in the 
substudy (Section 4.3.1).
A copy of each signed Informed Consent Form must be provided to the participant or the 
participant's authorized representative.  All signed and dated Informed Consent Forms 
must remain in each participant's study file or in the site file and must be available for 
verification by study monitors at any time.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the participant, 
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 substudy is initiated.  
In addition, any participant recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the substudy 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 participant enrolled in 
the substudy and the main study through assignment of a unique participant
identification number.  This means that participant names are not included in data sets 
that are transmitted to any Sponsor location.
Participant medical information obtained by this substudy 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 
participant, unless permitted or required by law.
Medical information may be given to a participant's personal physician or other 
appropriate medical personnel responsible for the participant's welfare, for treatment 
purposes.

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Data generated by this substudy 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.
9.
SUBSTUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
SUBSTUDY 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 participant 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 participant safety 
and data integrity to the Sponsor and to the IRB/EC in accordance with established 
IRB/EC policies and procedures.  The Sponsor will review all protocol deviations and 
assess whether any represent a serious breach of Good Clinical Practice guidelines and 
require reporting to health authorities. As per the Sponsor's standard operating 
procedures, prospective requests to deviate from the protocol, including requests to 
waive protocol eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants' medical records, and eCRFs.  The investigator will 
permit national and local health authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
The overall procedures for quality assurance of clinical study data are described in the 
Roche standard operating procedures.  This study will be sponsored by 
F. Hoffmann-La Roche Ltd.  Roche will provide clinical operations oversight, site 
monitoring and management, data management support, and medical monitoring
Central facilities will be used for study assessments (i.e., PET assessments). 
9.5
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals. The Sponsor will comply with all 

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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.  For 
more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data at 
the following Web site:
http://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 participants involving an investigational medicinal product (IMP) for which 
a marketing authorization application has been filed or approved in any country, the 
Sponsor aims to submit a journal manuscript reporting primary clinical trial results within 
6 months after the availability of the respective Clinical Study Report.  In addition, for all 
clinical trials in participants 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 

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

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10.
REFERENCES
AMYVID(Florbetapir F 18 Injection) U.S. Prescribing Information. Eli Lilly and 
Company. Available from https://pi.lilly.com/us/amyvid-uspi.pdf.
Arriagada PV, Growdon JH, Hedley-Whyte ET, et al. Neurofibrillary tangles but not 
senile plaques parallel duration and severity of Alzheimer's disease. Neurology 
1992;42(3 Pt 1):6319. 
Clark CM, Schneider JA, Bedell BJ, et al. Use of florbetapir-PET for imaging -amyloid 
pathology. J Am Med Assoc 2011;305:27583.
Delaere P, Duyckaerts C, Brion JP, et al. Tau, paired helical filaments and amyloid in 
the neocortex: a morphometric study of 15 cases with graded intellectual status 
in aging and senile dementia of Alzheimer type. Acta Neuropathologica 
1989;77:64553. 
Duyckaerts C, Brion JP, Hauw JJ, et al. Quantitative assessment of the density of 
neurofibrillary tangles and senile plaques in senile dementia of the Alzheimer 
type. Comparison of immunocytochemistry with a specific antibody and 
Bodian's protargol method. Acta Neuropathologica 1987;73:16770.
Duyckaerts C, Delaère P, Hauw JJ, et al. Rating of the lesions in senile dementia of 
the Alzheimer type: concordance between laboratories. A European 
multicenter study under the auspices of EURAGE. J Neurol Sci 
1990;97:295323.
Grundke-Iqbal I, Iqbal K, Tung YC, et al. Abnormal phosphorylation of the 
microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. 
Proc Natl Acad Sci USA 1986;83:49137. 
Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer's 
Association guidelines for the neuropathologic assessment of Alzheimer's disease. 
Alzheimers Dement 2012;8:113.
Klunk WE, Engler H, Nordberg A, et al. Imaging brain amyloid in Alzheimer's disease 
with Pittsburgh compound-B. Ann Neurol 2004;55:30619.
Klunk WE, Lopresti BJ, Ikonomovic MD, et al. Binding of the positron emission 
tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in 
Alzheimer's disease brain but not in transgenic mouse brain. J Neurosci 
2005;25:10598606.
Kosik KS, Joachim CT, Selkoe DJ. Microtubule-associated protein tau (tau) is a 
major antigenic component of paired helical filaments in Alzheimer disease. 
Proc Natl Acad Sci USA 1986;83:40448. 
Leinonen V, Alafuzoff I, Aalto S, et al. Assessment of beta-amyloid in a frontal 
cortical brain biopsy specimen and by positron emission tomography with 
carbon 11-labeled Pittsburgh compound B. Arch Neurol 2008;65:13049. 

GTP1F. HoffmannLa Roche Ltd
29/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
McLean CA, Cherny RA, Fraser FW, et al. Soluble pool of Abeta amyloid 
determinant of severity of neurodegeneration in Alzheimer's disease. Annals 
Neurol 1999;46:8606. 
Ni R, Gilberg PG, Bergfors A, et al. Amyloid tracers detect multiple binding sites in 
Alzheimer's disease brain tissue. Brain 2013;136(Pt 7):221727.
Quinn B, Dauer Z, Pandit-Taskar N, et al. Radiation dosimetry of 18F-FDG PET/CT: 
Incorporating exam-specific parameters in dose estimates.  BMC Medical Imaging 
2016; 16:4152.
Quiroz YT, Sperling R, Baena A, et al.  Tau and amyloid PET imaging in a Colombian 
kindred with autosomal-dominant Alzheimer’s disease.   Poster, AAIC, Toronto, 
2016.
Sojkova J, Driscoll I, Iacono D, et al. In vivo fibrillar beta-amyloid detected using 
[11C]PiB positron emission tomography and neuropathologic assessment in older 
adults. Arch Neurol 2011;68(2):23240.
Wood JC, Mirra SS, Polock MJ, et al. Neurofibrillary tangles of Alzheimer disease 
share antigenic determinants with the axonal microtubule-associated protein 
tau (tau). Proc Natl Acad Sci USA 1986;83:40403.

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30/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
Appendix 1
Schedule of Activities
First
[18F]GTP1 Scan a
Second
[18F]GTP1 Scan b
Third
[18F]GTP1 
Scanc/ET d
Informed consent for substudy protocol
x
Review of inclusion and exclusion criteria
x
Adverse Events
x
x
x
Concomitant Medications
x
x
x
Urine pregnancy test e
x
x
x
Vital signs f
x
x
x
[18F]GTP1tau PET scan g
x
x
x
ET early termination; FDG fluorodeoxyglucose; GTP1 Genentech Tau Probe 1; PET positron 
emission tomography.
a The first [18F]GTP1tau PET scan, and other activities in the table above, may occur on any 
visit that occurs in the main protocol (GN28352), from the Week 130 visit to the Week 224 visit.  
This first scan visit may be different for each participant, and only one [18F]GTP1 scan should 
be obtained per participant for this first scan. For each participant, this first scan should occur 
as early as possible within the Week 130 to Week 224 visit period.  The [18F]GTP1tau PET 
scan may be obtained in a 14-day window for visits in the Week 130 to Week 224 visit period.  
See Section 3.1 for details.
b The second [18F]GTP1tau PET scan, and other activities in the table above, may occur on 
any visit that occurs in the main protocol (GN28352), 52 [2] weeks after the first scan.  
This second scan visit may be different for each participant, and only one [18F]GTP1 scan 
should be obtained per participant for this second scan.  
c
The third [18F]GTP1tau PET scan should be obtained for each participant at the GN28352 
ET or final visit if at least 6 months has elapsed since the previous [18F]GTP1tau PET scan.  
See Section 3.1 for details.
d In the event a participant terminates Study GN28352 early, a [18F]GTP1tau PET scan should 
only be collected if informed consent has been obtained and at least 6 months has elapsed 
since any previous [18F]GTP1tau PET scan and if local annual radiation limits are not 
exceeded.  Refer to Study GN28352 schedule for other ET procedures.
e Urine pregnancy test must be administered and have a negative result before any 
[18F]GTP1tau PET scan, unless a negative urine pregnancy test was already obtained on the 
same calendar day as per the schedule of activities in the main study.  If the participant has 
discontinued the study drug but is continuing with study assessments, the urine pregnancy test 
must be administered for visits during which [18F]GTP1 is administered.  Pregnancy testing will 
apply to all women unless documented (by medical records or physician's note) to be surgically 
sterile or postmenopausal as defined in Section 3.4.4.3 of the main study protocol (GN28352).  
It is recommended, but not required, to use effective contraception during sexual intercourse 
occurring within 24 hours following a male or female participant receiving a [18F]GTP1tau PET 
scan.  

Appendix 1
Schedule of Activities (cont.)
GTP1F. HoffmannLa Roche Ltd
31/Protocol BN40199 Tau PET Longitudinal Substudy, Version 3
f
Vital signs will include measurements of heart rate, and systolic and diastolic blood pressure
while the participant has been supine for ≥ 3 minutes.  Vital signs should be measured prior to 
the administration of [18F]GTP1.
g If occurring in the same visit, [18F]GTP1tau PET scans will be performed after neurocognitive 
testing but prior to dosing of crenezumab or placebo.  The [18F]GTP1tau PET scan should be 
performed a minimum of 12 hours apart from any other amyloid or FDG PET scan that might be 
performed and a maximum of 14 days apart from any accompanying fibrillar amyloid-PET or 
FDG-PET scan.