A Phase II/III Randomized, Double-Blind, Placebo-Controlled, Cognitive Endpoint, Multi-Center Study of Potential Disease Modifying Therapies in Individuals at Risk for and With Dominantly Inherited Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimers Disease, Dementia, Alzheimers Disease, Familial
Sponsor: Washington University School of Medicine

 
 
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Clinical Study Protocol:  
 
DIAN-TU-001 
 
A Phase II/III Randomized, Double-Blind, Placebo-Controlled, 
Cognitive Endpoint, Multicenter Study of Potential Disease Modifying 
Therapies in Individuals at Risk for and with Dominantly Inherited 
Alzheimer’s Disease 
 
Regulatory Sponsor: 
Washington University in St. Louis 
Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) 
Department of Neurology, Campus Box 8111 
660 S. Euclid 
Saint Louis, MO 63110 
Study Drugs: 
Gantenerumab (RO4909832) and Solanezumab (LY2062430)  
Protocol Number: 
DIAN-TU-001 
Investigational Phase: 
II/III 
Protocol Version: 
Amendment 10 
Version Date: 
20 Dec 2019 
IND Number: 
115,652 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains commercial information and trade secrets that are 
privileged or confidential and may not be disclosed unless such disclosure is required by 
applicable laws and regulations.  In any event, persons to whom the information is disclosed 
must be informed that the information is privileged or confidential and may not be further 
disclosed by them.  These restrictions on disclosure will apply equally to all future information 
supplied to you which is indicated as privileged or confidential. 
NCT04623242

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INVESTIGATOR’S STATEMENT 
I understand that all information concerning the product supplied to me by Washington 
University in St. Louis, in connection with this study and not previously published, is confidential 
information.  This information includes the Investigator’s Brochure, protocol (and applicable 
amendments), Case Report Forms, assay methods, technical methodology, and basic scientific 
data. 
I will conduct the study according to the protocol and I understand that any changes to the 
protocol must be approved in writing by Washington University in St. Louis, and the 
Institutional Review Board/Independent Ethics Committee (IRB/IEC) before implementation, 
except where necessary to eliminate apparent immediate hazards to the subjects. 
I confirm that I will report all adverse events and product complaints following the regulations 
referenced in the protocol. 
I confirm that I will conduct this study in conformance with the principles of the Declaration of 
Helsinki, Good Clinical Practice (GCP) as described in the United States (US) Code of Federal 
Regulations, 21 CFR Parts 11, 50, 54, and 312 (as applicable) and the ICH E6 guideline, and U.S.  
law and regulations or in conformance with the principles of the Declaration of Helsinki, Good 
Clinical Practice (GCP), and local laws and regulations if my site is located outside the US.   
I confirm that I am informed of the need for records retention and that no data will be 
destroyed without the written consent of Washington University in St. Louis. 
By my signature below, I hereby attest that I have read, understood, and agree to abide by all 
conditions, instructions, and restrictions contained in this protocol dated 20 Dec 2019. 
Investigator’s 
Signature: 
 
 
 
Name (printed): 
 
 
Date 
 

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PROTOCOL SYNOPSIS 
Protocol Number 
DIAN-TU-001 
Protocol Title 
A Phase II/III randomized, double-blind, placebo-controlled, cognitive 
endpoint, multicenter study of potential disease modifying therapies in 
individuals at risk for and with dominantly inherited Alzheimer’s disease. 
Clinical Phase 
Phase II/III 
Investigators 
Investigators will be selected based on patient population and clinical 
research competency.  The currently existing DIAN-TU sites will continue to 
be active for new study drug enrollment and new sites will continue to be 
identified and qualified. 
Study Centers 
Approximately 40 sites globally 
Study Objective 
To assess the safety, tolerability, biomarker and cognitive efficacy of 
investigational products in subjects who are known to have an Alzheimer’s 
disease-causing mutation by determining if treatment with the study drug 
slows the rate of progression of cognitive impairment and improves 
disease-related biomarkers.   
Study Population 
Subjects who are either known to have a mutation causing Alzheimer’s 
disease OR who do not know their gene status but are “at-risk” for a 
dominantly inherited Alzheimer’s disease (DIAD) mutation AND who are 
either 1) cognitively normal and are between 15 years younger (-15) to 10 
years older (+10) than their expected age at symptom onset or 2) have mild 
symptoms of dementia (Clinical Dementia Rating [CDR] 0.5 or 1) and are 
within 10 years of the onset of symptoms of dementia.   
 
 
Study Design 
This study is an adaptive platform-based study, which allows flexibility to add 
a new compound to the same protocol, allowing subjects to be randomized to 
study drug arms open to enrollment, and to maintain a cohort of trial ready 
subjects with or at risk for DIAD mutations.  Subjects have been enrolled to 
the gantenerumab and solanezumab study drug arms, with each enrolled 
subject randomized to active drug or the corresponding placebo. Previously, 
DIAN-TU-001 also included an atabecestat arm. For further information 
relevant to the atabecestat arm, see earlier versions of the protocol.   
All subjects enrolled to the gantenerumab and solanezumab arms will 
continue to be treated with active drug or placebo, while biomarker (e.g., 
positron emission tomography (PET) imaging, volumetric brain magnetic 
resonance imaging (MRI), cerebral spinal fluid (CSF), and plasma measures), 
clinical, cognitive, and safety assessments (including safety MRI scans, vital 

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signs, electrocardiogram (ECG), clinical chemistry, and hematology) are 
monitored throughout the study period.   
 
 
 
 
 
The primary efficacy hypothesis is that the active drug group will have a 
slower rate of progression on the DIAN-Multivariate Cognitive Endpoint 
(DIAN-MCE) compared to the mutation positive placebos (pooled placebos for 
both gantenerumab and solanezumab) and the eligible DIAN Observational 
(DIAN-OBS) study subjects after treatment for a minimum of 4 years. The 
biomarker and cognitive endpoints may be used to conduct interim analyses 
in any of the study drug arms; a study drug arm may be stopped early or 
revised (e.g., dose adjustment or treatment duration) based upon the results 
of the interim analyses or information from other clinical trials for the same 
drug, as outlined in each drug-specific appendix. 
Mutation positive subjects will be randomized in a 3:1 ratio for active 
drug:placebo.  Groups enrolled simultaneously will be balanced by a 
minimization algorithm including clinical state and stage of disease measures 
(CDR-SB, years from onset) and other factors (gene type [APP, PSEN1, PSEN2] 
years of education, age, presence of an APOE ε4 allele, region, study site and 
gender).  Subjects who are mutation negative will be assigned to one of the 
placebo groups. 
At the request of participants, mutation negative subjects are included to 
maintain blinding as to genetic status for those who do not wish to know their 
genetic status.  Mutation negative subjects will not be included in the primary 
efficacy or futility analyses.  Data from mutation negative subjects will be 
used to develop models for longitudinal changes in biomarkers and cognition 
in healthy adult controls. 
Number of Subjects 
This study will recruit subjects from the Dominantly Inherited Alzheimer 
Network (DIAN) observational study, a multicenter international study 
supported by the National Institutes of Health (Grant Number 
U01-AG032438; RJ Bateman), Dominantly Inherited Alzheimer Network Trial 
Units (DIAN-TU) sites, DIAN-TU partner sites, DIAN Expanded Registry (DIAN-
EXR), and families identified by the sites. 
Recruitment of mutation positive subjects is limited to those with a baseline 
CDR 0 to 1 (inclusive) with no more than 50% CDR >0 enrolled.  Mutation 
positive groups (active vs. placebo) will be balanced proportionally as to 
number of asymptomatic (CDR 0) and symptomatic (CDR>0) subjects. 

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For the gantenerumab and solanezumab arms, the recruitment goal was 52 
mutation carriers for each active drug group and 34 mutation carriers for the 
placebo groups combined for a total of 138 mutation carriers.  An estimated 
72 non-carriers (mutation negative subjects who are unaware of their genetic 
status, estimated to be about 1/3 of total subjects) would also be recruited.  
Recruitment was closed once 52 mutation carriers were enrolled in each 
active drug group and 34 were enrolled in the placebo groups.  
 
 
 
 
 
 
  
Main Inclusion 
Criteria 
Subjects must meet ALL inclusion criteria based on estimated years from 
symptom onset (EYO).  The main inclusion criteria are as follows:   
• 
–15 to +10 EYO (secondary prevention population): within −15 to +10 
years of the estimated age at symptom onset, or, if symptomatic, 
within 10 years of their age at symptom onset, CDR 0 to 1, inclusive, 
known carrier or at 50% risk (affected parent or sibling) 
• 
Younger than –15 EYO (primary prevention population): more than 
15 years younger (< –15) than estimated age at symptom onset, CDR 
0, known carrier or mutation in their family pedigree; if the at-risk 
parent is deemed a non-carrier at any point, subject will be 
withdrawn from study  
• 
Are able and willing to complete all study-related testing, evaluations, 
and procedures 
Main Exclusion 
Criteria 
Subjects will be excluded if they have a major or unstable illness or are unable 
to complete all study related testing.  Exclusions include implanted metal that 
cannot be removed for MR scanning, required anticoagulation therapy and 
pregnancy.   
Route and Dosage 
Form 
Route and dosage forms are included in each drug-specific appendix.  
 
 
Dosage 
Dosage is included in each drug-specific appendix. 
Duration of 
Treatment 
For the gantenerumab and solanezumab arms, subjects will continue to 
receive blinded study drug until every subject concurrently randomized to 
any blinded study drug arm has received a minimum of 4 years (208 weeks) of 
treatment or is withdrawn. 
Based on the recruitment time needed for the gantenerumab and 
solanezumab arms, the total treatment duration for both blinded study drug 

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arms is expected not to exceed 81 months (6.75 years), with an average 
duration of 5.3 years. 
 
 
 
 
 
 
 
If a study drug arm demonstrates a potential for clinical benefit at the end of 
the double-blind treatment period, subjects may be offered, if eligible, to 
continue or start treatment, via an open-label extension (OLE) period in which 
all subjects will receive active study drug.  The OLE period may last up to an 
additional 2 years (24 months) or until the treatment becomes commercially 
available in a subject’s country, whichever occurs first. 
Primary Outcome 
Measure 
The primary efficacy hypothesis of the study is that the active drug group will 
have a slower rate of progression on the DIAN-MCE compared to the 
mutation positive placebos (pooled placebos for both gantenerumab and 
solanezumab) and the eligible DIAN-OBS subjects after treatment for a 
minimum of 4 years. 
The DIAN-MCE consists of the following tests:  1) The Delayed Recall score of 
the International Shopping List Test, 2) The Delayed Recall score of the Logical 
Memory IIa subtest from the Wechsler Memory Scale-Revised, 3) The Digit 
Symbol Substitution Test total score from the Wechsler Adult Intelligence 
Scale-Revised, and 4) The Mini-Mental State Examination total score.  
Comparisons will be made between each active drug, mutation positive 
placebos, and the eligible DIAN-OBS subjects, but not between the active 
drugs. 
Additional Outcome 
Measures 
Additional outcome measures, which will be further categorized as secondary 
or exploratory in the drug-specific statistical analysis plans (SAPs), include the 
following: 
1. Assess safety and tolerability of each study drug in individuals who have 
mutations causing dominantly inherited Alzheimer’s disease. 
2. Biomarker Endpoints used at interim analysis: Assess target engagement 
of each study drug in individuals who have mutations causing dominantly 
inherited Alzheimer’s disease as measured by the change from baseline 
to interim analysis for the biomarker measure for each drug.  The 
biomarker endpoints are specified for each drug based on mechanism of 
action.  Comparisons between the active drug and mutation positive 
placebos will be made at each interim for a study drug arm; however, 
there will be no comparisons between active drugs. 

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3. Comparisons between each drug and placebo for change in values 
between baseline and endpoint for the clinical and cognitive measures 
listed below.
 
 
 
 
• 
Clinical measures to be obtained at baseline, and annual visits will be 
administered at the host DIAN-TU site include: 
o Clinical Dementia Rating™ (CDR), including Clinical Dementia 
Rating Sum of Boxes™ (CDR-SB) and clinician’s diagnostic 
assessment 
o Geriatric Depression Scale (GDS) 
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Examination (MMSE) 
• 
Cognitive measures to be obtained at baseline and annual visits will 
be administered at host DIAN-TU site include: 
o International Shopping List Test (12-Item Word List Learning): 
3 learning trials, Immediate Recall, 30-min Delayed Recall 
(Cogstate) 
o Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, 
Immediate Recall, 30-min Delayed/Reversed Recall (Cogstate)  
o 
  
   
 
   
 
 
 
 
 
o Trailmaking Test parts A & B 
o WMS-R Digit Span  
o WAIS-R Digit-Symbol Substitution Test 
o Raven’s Progressive Matrices (Set A) 
o Category Fluency (Animals & Vegetables) 
o WMS-R Logical Memory (Immediate & Delayed Recall) 
• 
A subset of clinical and cognitive measures will be administered by 
the site or home health nurse at 24-week intervals when not the 
annual visits.  This subset includes: 
o International Shopping List Test (12-ltem Word List Learning): 
3 learning trials, Immediate Recall,30-min Delayed Recall 
(Cogstate) 
o Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, 
Immediate Recall,30- min Delayed/Reversed Recall (Cogstate) 
 
 
 
 
 
 

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o Trailmaking Test parts A & B 
o WMS-R Digit Span 
o WAIS-R Digit-Symbol Substitution Test 
o WMS-R Logical Memory (Immediate & Delayed Recall) 
o 
 
 
 
  
4. Additional imaging measures that may be included as secondary or 
exploratory endpoints as specified in the drug-specific SAP, include the 
following:  
a. Change from baseline in amyloid load based on imaging with [11C]PiB-
PET 
b. FDG-PET metabolism in specific regions of interest (e.g., precuneus) in 
treated group compared with mutation carrier placebos and eligible 
DIAN-OBS subjects. 
c. Tau PET imaging  
d. Rate of brain atrophy as measured by cortical thickness of regions of 
interest, including whole brain volume and ventricular volume 
(volumetric MRI) 
e. Functional connectivity MRI (fc-MRI) 
f. 
 
 
g. 
 
h. 
 
 
 
 
5. Additional fluid biomarker measures that may be included as secondary 
or exploratory endpoints as specified in the drug-specific SAP, include the 
following: 
a. Change in total CSF amyloid-beta 1-42 (Aβ42)  
b. Change in CSF amyloid-beta peptide concentrations 
c. Change in CSF biomarkers: tau and ptau values 
d. Plasma amyloid-beta isoform analysis 
e. Neurofilament light chain (NfL as measured in plasma and CSF) 
 
6. 
 
 

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7. Assess longitudinal change in biomarker and cognitive measures in 
individuals who do not have mutations causing dominantly inherited 
Alzheimer’s disease (mutation-negative placebo group) 
Additional drug-specific endpoints may be listed in each drug-specific 
appendix. Refer to the final SAP for drug-specific differentiation of endpoint 
classification based on the respective drug’s target and mechanism of action. 
Statistical 
Considerations 
 
Descriptive statistics:  Descriptive statistics will be provided for both safety 
and efficacy variables at each time point collected by treatment groups and 
across combined placebo groups.  Continuous variables (e.g., biomarker 
values) will be summarized using the number of observations, mean, standard 
deviation, minimum, lower quartile, median, upper quartile, and the 
maximum.  Categorical variables (e.g., presence or absence of an APOE ε4 
allele) will be summarized using the number and percentage in each category.   
Safety analyses:  Safety analyses will include all subjects who consent to 
participate and are randomized to receive any active study drugs or placebo.  
Adverse events will be characterized using standard terminology (adverse 
events, serious adverse events, treatment-emergent serious adverse events).  
The seriousness and causality of adverse events will be summarized.   
Interim analyses for biomarker endpoints:  Interim biomarker analyses will be 
conducted for each study drug arm to assess whether the active study drug is 
engaging its biological target.  The timing of the interim analyses may vary for 
each study drug arm.  At each interim, an analysis will be conducted for the 
biomarker endpoints, comparing the active drug to its own placebo group 
(direct placebos) or to the mutation positive placebos.  Pre-specified 
definitions for early termination for futility will be drug-specific and based on 
collection of appropriate biomarker assessments following sufficient drug 
exposure.  Details about the interim analyses are described in each drug-
specific appendix. 
Interim analyses for cognitive endpoints: Interim cognitive analyses may be 
conducted to assess whether active study drug has achieved significant 
slowing in cognitive decline.  At each interim, an analysis will be conducted 
for the DIAN-MCE, comparing the active drug to its own placebo group (direct 
placebo) or the mutation positive pooled placebo group.  If the test of the 

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interim analysis is significant, the study drug may be terminated earlier for 
efficacy.  Details about any planned interim analyses are described in each 
drug-specific appendix. 
All interim analyses will be conducted on the modified intent-to-treat (mITT) 
population, which is defined as all subjects who will be randomized, treated, 
and assessed for their primary cognitive outcomes at least once after the 
baseline assessment. 
Efficacy analyses for the cognitive endpoint:  All efficacy analyses will be 
conducted on the modified intent-to-treat (mITT) population.  The primary 
efficacy hypothesis will be tested by comparing the cognitive decline relative 
to estimated years from symptom onset (EYO) between the active drug, the 
mutation positive placebos, and the eligible DIAN-OBS subjects using the 
cognitive multivariate disease progression model (MDPM) developed by the 
DIAN-TU.  The MDPM includes two subject-level random effects to account 
for the between-subject variability and a model of the mean rate of decline as 
a function of EYO.  Treatment efficacy will be measured as a proportional 
slowing in decline of the primary cognitive endpoint in active drug compared 
with the mutation positive placebos and the eligible DIAN-OBS subjects. 
Sample Size 
Considerations 
For the gantenerumab and solanezumab arms, the recruitment goal was for 
52 mutation positive subjects per active drug group and 34 mutation carriers 
for the mutation positive placebo group to allow for 5% annual attrition 
during the minimum 4-year double-blind treatment period.  Assuming 5% 
annual attrition rate, at the end of the 4-year study, there will be 
approximately 42 subjects on each active treatment and 27 mutation positive 
placebos.  Power analysis for the biomarker endpoints suggests that this 
sample size will provide over 99% power to detect calculated effect sizes for 
changes in PiB and CSF total Aβ 1-42 (Aβ42).  Power analysis for the DIAN-MCE 
suggests that 42 mutation positive subjects in the active drug groups, 27 
mutation positive placebos, and eligible DIAN-OBS subjects will provide over 
90% power to detect a 40% effect size (slowing of decline in cognition for 
active drug in comparison to placebo) when the last subject randomized to 
the study drug arm reaches the end of the minimum 4-year double-blind 
treatment period. 

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TABLE OF CONTENTS 
INVESTIGATOR’S STATEMENT ................................................................................................ 2 
PROTOCOL SYNOPSIS ............................................................................................................ 3 
TABLE OF CONTENTS ........................................................................................................... 11 
LIST OF APPENDICES ............................................................................................................ 15 
LIST OF FIGURES .................................................................................................................. 16 
ABBREVIATIONS/GLOSSARY OF TERMS ................................................................................ 17 
1 
INTRODUCTION ........................................................................................................ 24 
 
Background ........................................................................................................... 24 
 
Drug-specific Background ..................................................................................... 26 
 
Rationale for Biomarkers ...................................................................................... 27 
 
Rationale for the DIAN-Multivariate Cognitive Endpoint ..................................... 32 
 
Rationale for Cognitive Run-in Assessments ........................................................ 32 
 
Rationale for Open-label Extension ...................................................................... 33 
2 
STUDY OBJECTIVE ..................................................................................................... 34 
3 
STUDY DESIGN ......................................................................................................... 34 
 
Overall Design ....................................................................................................... 34 
 
Rationale for Study Design .................................................................................... 36 
 
Number of Subjects and Sites ............................................................................... 38 
 
Subject Enrollment and Randomization ............................................................... 39 
 
Primary Study Endpoints....................................................................................... 40 
 
Additional Study Endpoints .................................................................................. 40 
 
Safety Endpoints ................................................................................................... 45 
 
Study Schedule ...................................................................................................... 46 
 
Total Study Duration and Duration of Treatment ................................................ 46 
 
Open-label Extension ............................................................................................ 47 
4 
STUDY POPULATION AND SITES ................................................................................ 48 
 
Inclusion Criteria ................................................................................................... 48 
 
Exclusion Criteria................................................................................................... 51 
 
Subject Recruitment and Screening...................................................................... 54 

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Discontinuation/Early Withdrawal of Subjects ..................................................... 54 
4.4.1 
Criteria for Discontinuation ................................................................ 54 
4.4.2 
Replacement of Subjects .................................................................... 56 
 
Transfer of Subjects Between Sites ...................................................................... 57 
 
Expectations and Withdrawal of Sites .................................................................. 57 
5 
STUDY DRUGS .......................................................................................................... 57 
 
Blinding ................................................................................................................. 57 
 
Breaking the Blind ................................................................................................. 58 
 
Concomitant Medications ..................................................................................... 58 
 
Treatment Compliance ......................................................................................... 59 
6 
STUDY PROCEDURES ................................................................................................ 60 
 
Procedures ............................................................................................................ 60 
6.1.1 
Subject Informed Consent .................................................................. 60 
6.1.2 
Family History/Age at Onset Assessment/Demographics/Study 
Partner Information ............................................................................ 61 
6.1.3 
Medical/Treatment History, Concomitant Medications, Adverse 
Event Assessment ............................................................................... 61 
6.1.4 
Clinical Assessment ............................................................................. 61 
6.1.5 
Physical and Neurological Examination .............................................. 62 
6.1.6 
Vital Signs ............................................................................................ 62 
6.1.7 
Electrocardiogram ............................................................................... 62 
6.1.8 
C-SSRS ................................................................................................. 63 
6.1.9 
Genetic Testing ................................................................................... 63 
6.1.10 
Clinical Laboratory Tests ..................................................................... 64 
6.1.11 
Drug-specific Testing ........................................................................... 64 
6.1.12 
Stored Samples (Plasma and/or Serum and DNA) – Treatment 
Period Only .......................................................................................... 65 
6.1.13 
Study Drug Administration ................................................................. 65 
6.1.14 
Cognitive Testing ................................................................................. 65 
6.1.15 
Baseline and Annual Magnetic Resonance Imaging (MRI) ................. 70 
6.1.16 
Safety Magnetic Resonance Imaging (MRI) ........................................ 71 

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6.1.17 
Lumbar Puncture (LP) – Cerebrospinal Fluid (CSF) ............................. 72 
6.1.18 
Positron Emission Tomography .......................................................... 73 
 
Overview of Visit Flow .......................................................................................... 79 
 
Study Visits ............................................................................................................ 81 
 
 
6.3.2 
Screening (Visit 1) ............................................................................... 82 
6.3.3 
Baseline (Visit 2/First Dose) ................................................................ 84 
6.3.4 
Double-blind Treatment Period .......................................................... 86 
6.3.5 
End-of-Treatment / Safety Follow-up Visit ......................................... 87 
6.3.6 
Open-label Extension .......................................................................... 88 
6.3.7 
Early Termination/Post-treatment Follow-up .................................... 90 
 
Termination of the Study ...................................................................................... 91 
7 
SAFETY AND ADVERSE EVENTS ................................................................................. 92 
 
Definitions ............................................................................................................. 92 
7.1.1 
Adverse Events .................................................................................... 92 
7.1.2 
Serious Adverse Event ........................................................................ 93 
 
Adverse Event (AE) Severity .................................................................................. 93 
 
Relationship to Study Drug ................................................................................... 94 
 
Adverse Event Collection Period ........................................................................... 95 
 
Adverse Event Reporting ...................................................................................... 95 
 
Serious Adverse Event Reporting.......................................................................... 95 
 
Pregnancy Reporting ............................................................................................. 96 
 
Adverse Events of Special Interest ........................................................................ 96 
 
Data Safety Monitoring Board (DSMB) ................................................................. 97 
8 
STATISTICAL PLAN .................................................................................................... 97 
 
Descriptive Statistics ............................................................................................. 97 
 
Safety Analysis ...................................................................................................... 97 
 
Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification .... 97 
 
Cognitive Endpoint Statistical Analysis, Power and Sample Size Justification ..... 98 
8.4.1 
Cognitive Analysis Populations and Primary Efficacy Analysis ........... 98 

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8.4.2 
Cognitive Endpoint Power Analysis and Sample Size Determination . 99 
9 
DATA HANDLING AND RECORD KEEPING .................................................................. 99 
10 
STUDY MONITORING, AUDITING AND INSPECTING ................................................... 99 
 
Protocol Deviations ............................................................................................. 100 
 
Study Reporting Requirements ........................................................................... 100 
 
Investigator Documentation ............................................................................... 100 
11 
ETHICAL CONSIDERATIONS ...................................................................................... 101 
12 
STUDY FINANCES ..................................................................................................... 102 
13 
PUBLICATION PLAN ................................................................................................. 102 
14 
REFERENCES ............................................................................................................ 103 
 

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LIST OF APPENDICES 
 
APPENDIX 2: SCHEDULE OF VISITS: SCREENING AND BASELINE ................................................ 121 
APPENDIX 3: GANTENERUMAB ................................................................................................... 123 
APPENDIX 4: SOLANEZUMAB ...................................................................................................... 201 
 

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LIST OF FIGURES 
Figure 1 Cross-sectional Analyses of Clinical, Cognitive, Structural, Metabolic, and 
Biochemical Changes in Autosomal Dominant Alzheimer’s Disease Mutation 
Carriers versus Non-carriers, According to Estimated Years from Expected 
Symptom Onset ............................................................................................................ 30 
 
Figure 3 Overview of Subject Visit Flow ..................................................................................... 81 
 

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ABBREVIATIONS/GLOSSARY OF TERMS 
Abbreviation/ 
Term 
Definition 
[11C]PiB-PET 
Positron emission tomography with [11C]-Pittsburgh Compound B (PiB) 
[18F]AV-1451 
Flortaucipir, a [18F] tau PET imaging tracer, aka T807 
[18F]MK-6240 
A [18F] tau PET imaging tracer 
Aβ 
Amyloid beta peptide 
Aβ40   
Amyloid beta peptide fragment with amino acids 1-40 
Aβ42   
Amyloid beta peptide fragment with amino acids 1-42 
AChEI 
Acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADA 
Anti-drug antibody; drug-specific testing may include measurement of 
antibodies directed against the investigational drug  
ADCS 
Alzheimer’s Disease Cooperative Study 
ADNI 
Alzheimer’s Disease Neuroimaging Initiative 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase (liver function test) 
ANCOVA 
Analysis of covariance 
API 
Alzheimer’s Prevention Initiative 
APOE 
Apolipoprotein E genotype, the APOE ε4 allele is associated with increased risk 
of developing AD pathology 
APP 
Amyloid precursor protein 
ARC 
Ambulatory Research in Cognition is the smartphone-based cognitive testing 
ARIA 
Amyloid-related imaging abnormalities (includes those that occur both after 
treatment and during the natural history of untreated Alzheimer’s disease) 
ARIA-E 
Amyloid-related imaging abnormality characterized by vasogenic edema, 
including both parenchymal and in leptomeningeal spaces 
ARIA-H 
Amyloid-related imaging abnormality characterized by hemorrhage, including 
microhemorrhage, macrohemorrhage (e.g., lobar hemorrhage) and superficial 
hemosiderin deposits 

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Abbreviation/ 
Term 
Definition 
ASL 
Arterial spin labeling 
AST 
Aspartate aminotransferase  
AUC0-τ 
Area under the concentration – time curve for a drug between time 0 and the 
end of the dosing interval (τ) 
CDR 
Clinical Dementia Rating™ 
CDR-SB 
Clinical Dementia Rating Sum of Boxes™ 
Central laboratory 
manual 
Manual that describes details for processing and shipping of laboratory samples 
CFR 
Code of Federal Regulations  
CLIA 
Clinical Laboratory Improvement Amendments (FDA regulation of clinical 
laboratories) 
Cmax 
Maximum (peak) plasma drug concentration 
Ctrough 
Minimum (trough) plasma drug concentration, measured at the end of a dosing 
interval  
Cogstate 
A global technology company that supports the use of cognitive measures in 
clinical trials 
Concurrently 
randomized 
placebos 
The group of mutation-positive subjects that were randomized to placebo while 
another treatment arm was actively randomizing, but were not direct placebos 
for the other arm(s) 
CNS 
Central nervous system 
CPR 
Cognitive progression ratio 
 
 
CSF 
Cerebrospinal fluid 
CSR 
Clinical Study Report 
C-SSRS 
Columbia suicide severity rating scale 
C-SUVR 
Composite standardized uptake volume ratio 
CV 
Curriculum vitae 
DAT 
Dementia of the Alzheimer’s type; symptomatic dementia clinically diagnosed 
as likely due to Alzheimer’s disease pathology 
DCA 
Dominantly Inherited Alzheimer Network Central Archive 
DIAD 
Dominantly inherited Alzheimer’s disease 

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Abbreviation/ 
Term 
Definition 
DIAN-OBS 
DIAN Observational study - Dominantly Inherited Alzheimer Network, a 
multicenter international observational study supported by the National 
Institutes of Health 
DIAN-EXR 
Dominantly Inherited Alzheimer Network Expanded Registry; an international 
repository coordinated by the DIAN-TU whose purpose is to connect 
researchers with individuals and families affected by the disease 
DIAN-MCE 
DIAN-Multivariate Cognitive Endpoint 
DIAN-NPC 
Dominantly Inherited Alzheimer Network-Neuropathology Core  
DIAN-TU 
Dominantly Inherited Alzheimer Network Trials Unit 
DIAN Trials Unit 
Cognition Core 
Procedures Manual  
Manual providing specific information on procedures for cognitive testing 
DIAT 
Diaminothiazine 
Direct placebos 
The group of mutation-positive subjects that were randomized to the blinded 
placebo for a specific treatment 
DSMB 
Data Safety Monitoring Board 
DSM-IV 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
DTI 
Diffusion Tensor Imaging 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
Eligible DIAN-OBS 
subjects 
The group of mutation-positive subjects that enrolled in the DIAN-OBS study 
and met the eligibility criteria to be borrowed for the DIAN-TU-001, as defined 
in the Statistical Analysis Plan (SAP) 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOS 
End of study 
ET 
Early Term 
EYO 
Estimated years from symptom onset 
FAS 
Functional Assessment Scale (previously Functional Assessment Questionnaire 
[FAQ]) 
fc-MRI 
Functional connectivity MRI 

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Abbreviation/ 
Term 
Definition 
FDA 
Food and Drug Administration 
FDG-PET 
PET imaging with 2-[18F] fluoro-2-deoxy-D-glucose 
FLAIR 
Fluid-attention inversion recovery 
Florbetapir 
AV-45, an FDA-approved [18F] PET amyloid imaging agent  
GCP 
Good clinical practice 
GDS 
Geriatric Depression Scale 
Global Manual of 
Operations 
Manual describing details of DIAN-TU trial operations; see also DIAN Trials Unit 
Cognition Core Procedures Manual, central laboratory manual, MRI Technical 
Manual, PET Technical Procedures Manual and Pharmacy Manual. 
GRE 
Gradient-recalled echo (MRI sequence) 
HCLF 
high-concentration liquid formulation 
Home health nurse 
A licensed nurse that is an extension of the trial site and is delegated by a site 
principal investigator (PI).  Home health nurse staffing is provided by a nursing 
vendor that is contracted through the DIAN-TU. Home health nurses complete 
visits in subjects home and/or other trial-identified locations.  Home health 
nurses may also complete training to become trial-certified cognitive raters. 
Hy’s Law case 
Situation where there is a 3-fold elevation above upper limit of normal of ALT 
or AST, accompanied by a two-fold increase of total bilirubin above upper limit 
of normal, in the absence of other explanations for these changes.  This 
suggests possible drug-induced liver injury.   
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent ethics committee 
IgG1 
Monoclonal antibody of the immunoglobulin subclass G1 
INR 
International Normalized Ratio 
IRB 
Institutional review board  
IV 
Intravenous  
IVRS 
Interactive voice response system (used only if technological constraints 
preclude use of interactive web response system) 
IWRS 
Interactive web response system 

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Abbreviation/ 
Term 
Definition 
LFT 
Liver function test 
LOCF 
Last observation carried forward 
LP 
Lumbar puncture 
Lyo-F 
lyophilized formulation 
mAbs 
Monoclonal antibodies 
MAC-Q 
Memory Complaint Questionnaire 
MAD 
Multiple ascending dose 
Mayo-ADIR 
Mayo Clinic Aging and Dementia Imaging Research 
Mc+ and mc- 
Mutation carriers (mc+) and non-carriers or those known not to have an DIAD-
causing mutation (mc-) 
MDPM 
Multivariate Disease Progression Model 
MedDRA 
Medical Dictionary for Regulatory Activities 
Medical Director 
The sponsor’s Medical Director will lead discussion and make final decisions on 
reporting of adverse events and other medical issues (e.g., inclusion/exclusion 
criteria).  Some discussions (e.g., regarding ARIA) will include the Project Arm 
Leaders.   
Medical Monitor 
The
 Medical Monitor will be available 24/7 and serve as first contact for 
sites.   
mITT 
Modified intent-to-treat 
MMSE 
Mini-Mental State Exam  
MRI Technical 
Manual 
Manual providing specific information on procedures for MRI 
MRI 
Magnetic resonance imaging 
Mutation positive 
placebos 
Combination of direct placebos and concurrently randomized placebos 
NfL 
Neurofilament light chain 
NONMEM 
A non-linear mixed effects modeling software tool used in population 
pharmacokinetic-pharmacodynamic analysis 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
NYHA 
New York Heart Association  
OLE 
Open-label extension 

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Abbreviation/ 
Term 
Definition 
PD 
Pharmacodynamic 
PAL 
Project Arm Leader.  Each study drug arm will have a PAL.  This individual will 
have experience with the same or similar study drugs and will advise the site 
investigators and Medical Director as needed and will help ensure consistency 
between sites for each study drug. 
PET 
Positron emission tomography 
PET Technical 
Procedures Manual 
Manual providing specific guidance on procedures for PET imaging 
PI 
Principal investigator; if needed, a site PI may delegate duties to a qualified 
sub-investigator 
Pharmacy Manual 
Manual describing specific procedures for pharmacy operations, drug handling 
and administration 
PK 
Pharmacokinetic 
Proband 
An individual identified by the study team who is known to have a disease-
causing mutation; relatives of the proband may be potentially eligible for the 
study. 
PSEN1 
Presenilin 1 
PSEN2 
Presenilin 2 
Ptau 
Phosphorylated tau protein 
ptau181 
Tau protein phosphorylated at threonine 181 
PT, PTT 
Prothrombin time (PT) and partial thromboplastin time (PTT) are measures of 
blood clotting 
QC 
Quality control 
QT and QTc 
Period from the beginning of the QRS complex to the end of the T wave on the 
ECG 
Q4W 
Every four weeks 
QW 
Each week 
RBBB 
Right bundle branch block 
SAD 
Single ascending dose  
SAE 
Serious adverse event   
SAP 
Statistical Analysis Plan 
sAPP 
Soluble amyloid precursor protein 

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Abbreviation/ 
Term 
Definition 
SC 
Subcutaneous 
SD 
Standard deviation 
study partner 
A person identified by the subject who agrees to accompany the subject on 
annual study visits and is able to provide accurate information as to the 
subject's cognitive and functional abilities to enable completion of scales which 
require informant, and who signs the necessary consent form if applicable 
subject 
An individual who is or becomes a participant in clinical research, either as a 
recipient of the investigational product(s) or as a control.   
SUSAR 
Suspected unexpected serious adverse reaction 
SUVR 
Standardized uptake value ratio (a measurement for PET imaging) 
T2* 
MRI sequence used to detect hemorrhage  
Tau 
Tau protein 
TEAE 
Treatment-emergent adverse event 
TIA 
Transient ischemic attack 
Tmax 
Time it takes a drug to reach peak plasma concentration after administration 
Trial-certified 
cognitive rater 
Any rater that has been certified by the DIAN-TU Cognition Core or designee, as 
described in the Cognition Core Procedures Manual, and may include DIAN-TU 
staff, trial-certified home health nurses, or study site staff 
TSH 
Thyroid stimulating hormone 
UA 
Urinalysis 
ULN 
Upper limit of normal 
vMRI 
Volumetric magnetic resonance imaging 
WAIS-R 
Wechsler Adult Intelligence Scale-Revised  
WMS-R 
Wechsler Memory Scale-Revised 
Woman of child 
bearing potential 
A non-menopausal female who has not had a hysterectomy, bilateral 
oophorectomy or medically documented ovarian failure.  Menopause is defined 
as amenorrhea for one year in the absence of any other medical or 
physiological cause for the amenorrhea0F1.   
                                                     
1 Women who have undergone tubal ligation should have pregnancy testing done at all visits as indicated for a 
woman of child bearing potential.   

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1 INTRODUCTION 
 Background 
This study will recruit subjects from the Dominantly Inherited Alzheimer Network (DIAN) 
observational study, a multicenter international study supported by the National Institutes of 
Health (Grant Number U01-AG032438; RJ Bateman), Dominantly Inherited Alzheimer Network 
Trial Units (DIAN-TU) sites, DIAN-TU partner sites, DIAN Expanded Registry (DIAN-EXR), and 
families identified by the sites.  As part of the DIAN-TU-001 protocol, subjects undergo 
longitudinal assessments that include clinical assessment, cognitive testing, magnetic resonance 
imaging (MRI) and amyloid imaging, and analysis of cerebrospinal fluid 
There are DIAN Observational study sites located in multiple countries including the USA, 
Argentina, Australia, Germany, Japan, and the United Kingdom.  Subjects in DIAN are recruited 
from families that have at least one member who has been identified as having a mutation 
linked to dominantly inherited Alzheimer’s disease (DIAD).  The mutations in presenilin 1 
(PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) that are associated with 
dominantly inherited Alzheimer’s disease have very high penetrance (near 100%).  This study will 
target individuals who are either known to have a disease-causing mutation or who are at risk 
for such a mutation (the child or sibling of a proband with a known mutation) and unaware of 
their genetic status.  Because the age at onset of cognitive changes is relatively consistent within 
each family and with each mutation (Ryman, Acosta-Baena et al. 2014), an age at onset is 
determined for each affected parent or mutation as part of the DIAN Observational (DIAN-OBS) 
study protocol.  This study will enroll subjects who are either asymptomatic and are within a 
specific window of time of expected age at onset for their family and/or mutation or who have 
symptoms of mild Alzheimer’s disease. 
The ability to identify individuals destined to develop Alzheimer’s disease (AD) within the next 
10-15 years with a high degree of confidence provides a unique opportunity to assess the 
efficacy of therapies at asymptomatic and very early stages of dementia.  Families with known 
disease-causing mutations are extremely rare and are geographically dispersed throughout the 
world.  These constraints necessitate a specialized study design.  Many of the subjects in this 
study will not yet have any cognitive symptoms of AD; they will be “asymptomatic” carriers of 
mutations that cause dominantly inherited Alzheimer’s disease and would be expected to 
perform normally on standard cognitive and functional testing.  Imaging and fluid biomarkers 
will be used to demonstrate that the treatment compounds have engaged their therapeutic 
targets.  A set of cognitive measures designed to assess the very earliest and most subtle 
cognitive changes will be collected.  Additionally, because many at-risk individuals decide not to 
know whether they have the disease-associated mutation or not, some of the at-risk individuals 
enrolled in this study will not have the disease-causing mutations; they will be “mutation 
negative”.  It is important to enroll non-carrier subjects to avoid coercion (e.g., potential subjects 
may be pressured into genetic testing to learn their genetic status in order to be eligible for the 
trial).  These mutation negative individuals will be assigned to the placebo group and will not be 

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included in the primary efficacy or futility analyses.  Subjects and site study staff will remain 
blinded as to these individuals’ active or placebo group assignment and mutation status.  Thus, 
the study will be double blinded for placebo and for mutation status, except for mutation 
positive subjects who are aware of their genetic status.  There may be exceptional circumstances 
when required by local regulation or health authorities where enrollment may be restricted to 
mutation carriers only but such mandates will be thoroughly documented and agreed upon by 
the governing regulatory agency and sponsor. 
This study is an adaptive platform-based study (Woodcock, LaVange 2017). Several different 
therapies (each referred to as a study drug arm) will be tested in order to increase the likelihood 
that an effective treatment will be discovered.  The compounds are selected for this trial based 
on mechanism of action and available data on efficacy and safety profile.  The study design 
includes a pooled placebo group (referred to as the mutation positive placebos) shared by all 
study drug arms.  Mutation positive subjects will be assigned to a study drug arm and 
subsequently randomized within that arm in an overall 3:1 ratio to active drug:placebo.  
Mutation negative subjects will all receive placebo treatment.  Importantly, subjects and study 
staff will not be blinded as to which study drug arm each subject has been assigned; they will be 
blinded as to whether subjects have been randomized to active drug or placebo.  Biomarker 
endpoints will be specified for each study drug arm.  Biomarker data will be analyzed for pre-
specified endpoints consistent with the drug’s mechanism of action and known effects on the 
tested biomarkers.  The primary cognitive endpoint will be the same for all study drug arms. 
Interim analyses of the imaging or fluid biomarker endpoint will assess safety and whether each 
study drug engages its biological targets.  This biomarker approach is particularly important in 
this study as most study subjects will be cognitively normal at baseline and most will remain 
cognitively normal during the first 2 years of the study.  The DIAN-Multivariate Cognitive 
Endpoint (DIAN-MCE) is designed to assess subtle cognitive changes that may be detectable 
before the onset of dementia.  The cognitive multivariate disease progression model (MDPM) 
will allow for detection of these subtle cognitive changes. 
After the last subject in a study drug arm completes the 4-year treatment period, subjects in that 
study drug arm may be eligible to receive active study drug in an open-label extension period 
(section 3.10). 
 
 
 
 
 
 
 
 
 

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 Drug-specific Background 
Complete drug-specific information for each study drug used in this trial is included as a drug-
specific appendix to this protocol.  All therapies are currently in clinical trials in individuals with 
or at risk for sporadic AD.  Refer to the respective Investigator’s Brochures (provided separately) 
for additional information. 
Gantenerumab (RO4909832); see Appendix 3.  Gantenerumab is a recombinant human anti-
amyloid beta peptide (Aβ) monoclonal antibody of the immunoglobulin subclass G1 (IgG1) that 
binds specifically to aggregated forms of Aβ peptide.  In a Phase 1 multiple ascending dose 
(MAD) study, subjects treated with gantenerumab for up to 6 months had a dose dependent 
reduction in brain amyloid, as measured by a reduction in [11C]-Pittsburgh Compound B 
([11C]PiB) binding, using a volume-weighted average from 6 cortical areas (Ostrowitzki, Deptula 
et al. 2012). 
Solanezumab (LY2062430); see Appendix 4.  Solanezumab is humanized anti-Aβ peptide 
immunoglobulin G-1 (IgG1); solanezumab recognizes an epitope in the middle of the Aβ peptide 
and binds to soluble Aβ.  In a Phase 2 trial, treatment with solanezumab resulted in a dose-
dependent increase in levels of Aβ40 and Aβ42 in both CSF and plasma (Siemers, Friedrich et al. 
2010). 
Drugs that target amyloid beta peptide may be associated with amyloid-related imaging 
abnormalities (ARIA), including both vasogenic edema (ARIA-E) and hemorrhages (ARIA-H), 
which are typically microhemorrhages, but larger hemorrhages and frank infarction have also 
been reported (Sperling, Salloway et al. 2012).  Subjects will undergo MRI scans to monitor for 
ARIA.  The schedule is drug arm specific and the frequency reflects the likely risk, based on 
available safety studies and the mechanism of action of the treatment.  Should new ARIA 
changes be detected, the site PI or designated sub-investigator, DIAN-TU Medical Director 
and/or designee, and Project Arm Leader will review ARIA findings and clinical information and 
will decide on what, if any, actions should be taken.  See the gantenerumab- and solanezumab-
specific appendices (Appendices 3 and 4) for details of drug-specific dose adjustment strategies. 

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 Rationale for Biomarkers 
More than half of the mutation positive subjects in this study will have normal cognition per 
randomization and enrollment criteria and will therefore be “asymptomatic” and without clinical 
manifestations of dementia of the Alzheimer’s type (DAT).  The pathological processes that 
define AD, amyloid plaques and neurofibrillary tangles, start to develop 10-20 years before 
clinical symptoms (Price and Morris 1999; Price, McKeel et al. 2009).  Findings from the DIAN 
observational study (Bateman, Xiong et al. 2012) indicate pathological and biomarker changes 
occur at least 15 years before the first estimated symptom onset in the DIAN cohort.  Fluid and 
imaging biomarkers such as uptake of the amyloid-binding dye positron emission tomography 
with [11C]-Pittsburgh Compound B (PiB) ([11C]PiB-PET) or cerebrospinal fluid (CSF) levels of 
amyloid beta peptide fragment 1-42 (Aβ42), total tau and phosphorylated tau181 (ptau181) may 
be able to measure amyloid deposition (CSF Aβ42 and positron emission tomography (PET) with 
[11C]PiB) and neuronal and synaptic integrity (CSF total tau and ptau181) in individuals at risk for 
DAT (Mintun, Larossa et al. 2006; Fagan, Roe et al. 2007; Fagan, Head et al. 2009; Morris, Roe et 
al. 2009). 
Neurofilament light chain (NfL) is another important marker of neurodegeneration in AD. 
Neurofilament light chain is a neuronal cytoplasmic protein; levels of NfL increase in CSF and 
blood proportionally to the degree of axonal damage in neurological disorders.  Evidence that 
both CSF and blood plasma NfL may serve as diagnostic, prognostic and monitoring biomarkers 
in neurological diseases is progressively increasing, and NfL is one of the most promising 
biomarkers to be used in clinical and research settings (Gaetani et al. 2019).  Neurofilament light 
chain has previously demonstrated changes in response to therapies in multiple sclerosis and 
HIV (Varhaug et al. 2019). Although NfL is non-specific for AD, it may allow for a measurement of 
disease modification in response to the active therapies. Further, NfL has demonstrated pre-
symptomatic changes in DIAD 7 to 16 years before symptom onset (Preische et al. 2019). 
Cortical volume loss (as measured by volumetric MRI [vMRI]) and cerebral metabolism 
(measured by uptake of 2-[18F] fluoro-2-deoxy-D-glucose [FDG-PET]) assess anatomic and 
metabolic sequelae of neurodegeneration.  Substantial literature supports the idea that these 
biomarkers correlate with pathological disease and may be predictive of clinical outcome.  Levels 
of the CSF biomarkers and [11C]PiB binding correlate with risk of developing dementia in 
asymptomatic individuals and with the risk of developing more severe impairment in those with 
very mild dementia or mild cognitive impairment (Hansson, Zetterberg et al. 2006; Fagan, Roe et 
al. 2007; Li, Sokal et al. 2007; Morris, Roe et al. 2009; Snider, Fagan et al. 2009).  In 
asymptomatic older individuals, increased levels of brain amyloid as detected by increased 
[11C]PiB-PET binding or reduced CSF Aβ42 are not benign as they are associated with increased 
rates of brain atrophy (Wang, Fagan et al. 2011; Chetelat, Villemagne et al. 2012).  
Nondemented individuals with amyloid deposition as detected by the recently approved PET 
imaging agent florbetapir 18F have poorer performance on episodic memory testing and are 
more likely to experience cognitive decline (Doraiswamy, Sperling et al. 2012; Sperling, Johnson 

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et al. 2012), suggesting that florbetapir 18F may also be useful in detecting amyloid pathology in 
asymptomatic individuals.   
In contrast to Aβ accumulation, autopsy studies suggest that the density and distribution of 
phosphorylated tau and of neurofibrillary tangles increases during the course of dementia, with 
higher levels observed in individual with mild cognitive impairment and at more severe levels of 
dementia (Braak and Braak 1995).  Tau accumulation may correlate with neurodegeneration 
across the entire spectrum of the illness (Duyckaerts, Brion et al. 1987; Nelson, Alafuzoff et al.  
2012).  Aβ accumulation may serve as a biomarker for the earliest stages of disease, while 
longitudinal and quantitative assessments of the level and extent of tau deposits may better 
reflect the progression of neurodegeneration over time.  Studies of CSF Aβ42 and tau levels in 
participants with dominantly inherited Alzheimer’s disease in the Dominantly Inherited 
Alzheimer’s Network support this idea (Bateman, Xiong et al. 2012; Benzinger, Blazey et al. 2013; 
Fagan, Xiong et al. 2014). 
The DIAN-TU-001 trial provides a critical opportunity to investigate the potential for tau imaging 
to enhance basic understanding of the evolution of tau pathology during the AD disease process, 
to understand the relationship between tau imaging and tau measurements in CSF and may 
support a role for tau imaging as a new surrogate biomarker. 
Tau scanning in the gantenerumab and solanezumab arms of this trial will take advantage of 
the recent developments of a PET tracer ([18F]AV-1451, also known as 18F-T807 and flortaucipir) 
that has high affinity for the human phosphorylated tau deposits in AD brain (Pontecorvo M et 
al. 2015; Schwarz A et al. 2016; Marquié, Marta, et al. 2015; Wang, Liang, et al. 2016; Brier, 
Matthew R., et al. 2016; Gordon, Brian A., et al. 2016).  This will be the first opportunity to 
evaluate this imaging agent in the dominantly inherited Alzheimer’s disease population and to 
determine whether treatment with an anti-beta amyloid therapy slows tau deposition over 
time, as measured by sequential PET scans with [18F]AV-1451 in mutation positive subjects 
enrolled in the DIAN-TU-001 trial.  To achieve this goal, [18F]AV-1451 PET measurements will be 
conducted up to three times for each subject, at baseline, year 1, year 2, and/or year 4 of the 
double-blind period, and potentially at baseline, at year 1 and year 2 of the open-label 
extension period.  Since not all sites in this international study will have access to [18F]AV-1451 
necessary to perform the tau PET scans, this measure was included as an addendum rather 
than as part of the main study protocol for the double-blind period.  It is included in the drug-
specific appendices for the OLE period when approved by the sponsor and where the tracer is 
available.  
 
 
 
 
 
 

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Studies in individuals who carry a mutation linked to early onset AD suggest that these 
biomarker changes are detectable 15 or more years before the anticipated time of disease onset 
(See Figure 1 and Bateman, Xiong et al. 2012; Portelius, Fortea et al. 2012; Ringman, Coppola et 
al. 2012).  Data from the DIAN observational study suggests that changes in biomarkers begin 
about 20 years before expected age at onset in this cohort, as shown for [11C]PiB-PET measures 
of amyloid burden in the precuneus (Figure 1) and changes in CSF total tau, Aβ42, FDG-PET, and 
cerebral atrophy (Bateman, Xiong et al. 2012). 
These studies in the DIAN cohort, although cross-sectional, suggest that measuring levels of 
these biomarkers could provide insight into whether disease-modifying therapies are altering 
their therapeutic targets (e.g., brain amyloid deposition) in these individuals.  This idea is 
corroborated by the limited available dataset in those who have undergone longitudinal 
assessments.  CSF and imaging biomarkers are likely to provide a measure of target engagement 
in the preclinical stage. 

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Figure 1 
Cross-sectional Analyses of Clinical, Cognitive, Structural, Metabolic, and 
Biochemical Changes in Autosomal Dominant Alzheimer’s Disease Mutation 
Carriers versus Non-carriers, According to Estimated Years from Expected 
Symptom Onset 
 
The clinical and cognitive measures of the CDR-SB (scores range from 0 [cognitive normality] to 18 [maximal cognitive impairment]) (Panel 
A), the Mini–Mental State Examination (scores range from 0 [severe impairment] to 30 [no impairment]) (Panel B), and the Logical Memory 
subtest of the Wechsler Memory Scale–Revised (scores range from 0 [no recall] to 25 [complete recall]) (Panel C) showed impaired ratings 
beginning approximately 5 to 10 years before expected symptom onset (EYO is expected year at onset).  MRI measures of hippocampal 
volume (Panel D) showed increased brain atrophy approximately 15 years before expected symptom onset.  Decreases in cerebral glucose 
metabolism, as measured by positron-emission tomography (PET) with the use of fluorodeoxyglucose (Panel E), occurred approximately 10 
years before expected symptom onset, and deposition of amyloid-beta (Aβ) in the precuneus, as measured by PET with the use of Pittsburgh 
compound B (Panel F), began approximately 15 to 20 years before expected symptom onset.  In the cerebrospinal fluid (CSF), levels of tau 
protein (Panel G) increased beginning 10 to 15 years before expected symptom onset, and levels of Aβ42 (Panel H) decreased at least 15 
years before expected symptom onset.  Plasma Aβ42 levels were elevated throughout the range of estimated years from expected symptom 
onset (Panel I).  Dashed lines represent 95% confidence intervals of the fitted curves.  SUVR denotes standardized uptake value ratio.  
Reproduced from Bateman et al., 2012. 
The imaging and CSF biomarkers measure different aspects of the AD pathogenic cascade and 
are correlated with underlying brain pathology.  There is no data on the effect of therapeutic 
interventions on these biomarkers in symptomatic or asymptomatic individuals with DIAD but 
there is some evidence to support the idea that therapeutic interventions can produce 
detectable changes in these biomarkers in symptomatic individuals with late onset sporadic 
dementia of the Alzheimer’s type (McKhann, Knopman et al. 2011).  For example, as noted 

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above in section 1.2, there was a significant reduction in binding of [11C]PiB in individuals with 
mild to moderate DAT who were treated with the amyloid immunotherapy agent gantenerumab 
(Ostrowitzki, Deptula et al. 2012).  A number of other compounds have also shown effects on 
these biomarkers (Chang et al., 2011; DeMattos et al., 2014; Jacobsen et al., 2014).  There was a 
slight reduction in CSF Aβ42 in individuals treated for 78 weeks with scyllo-inositol (ELND005), a 
compound thought to reduce the formation of amyloid fibrils; the reduction in total tau in the 
treated group did not achieve significance in this very small study (Salloway, Sperling et al. 
2011).  A 4-week dietary intervention (low saturated fat and low glycemic index) caused 
significant changes in CSF Aβ42; interestingly, the direction of the change varied depending on 
the individual’s cognitive status.  CSF Aβ42 levels were reduced in individuals without cognitive 
impairment and increased in those who had mild cognitive changes; there were no changes in 
total tau or ptau181 (Bayer-Carter, Green et al. 2011).  A small pilot study showed that patients 
treated with intranasal insulin for 4 months had less reduction in glucose metabolism in frontal 
cortex as measured by FDG-PET (Craft, Baker et al. 2012).  These studies, although small, support 
the idea that successful target engagement by the tested compounds would result in a 
detectable effect on imaging and fluid biomarkers, allowing the use of the biomarkers as 
potential predictors of treatment efficacy in individuals at risk for dominantly inherited 
Alzheimer’s disease (Strobel, 2015).  The specific biomarker endpoint chosen for each tested 
study drug will depend on the mechanism of action of the target compound and on available 
preliminary data on the effects of the therapy on relevant biomarkers (see each drug-specific 
appendix and respective Investigator’s Brochures for additional details).   
CSF levels of tau and ptau will be used as additional endpoints.  These biomarkers may reflect 
neuronal or axonal injury, as evidenced by the correlation of CSF levels of total tau with the 
amount of tissue damage and poor clinical outcome in acute brain disorders (Hesse, Rosengren et 
al. 2000; Ost, Nylen et al. 2006).  Levels of ptau measured in CSF samples obtained during life 
have been shown to correlate with the amount of neocortical tangle pathology at autopsy 
(Buerger, Ewers et al. 2006) suggesting it may serve as a marker of tangle pathology.  Some 
studies have shown that elevated tau and ptau alone predict progression from mild cognitive 
impairment (MCI) to DAT (Blom, Giedraitis et al. 2009), while other studies demonstrate that the 
ratio of tau(s) to Aβ42 are highly predictive of cognitive decline in cognitively normal cohorts 
(Fagan, Roe et al. 2007; Li, Sokal et al. 2007; Craig-Schapiro, Perrin et al. 2010) as well as 
individuals with MCI or very mild dementia (Hansson, Zetterberg et al. 2006; Snider, Fagan et al. 
2009; Craig-Schapiro, Perrin et al. 2010; Landau, Harvey et al. 2010; Tarawneh, D'Angelo et al. 
2011; Buchhave, Minthon et al. 2012).  Levels of CSF tau and ptau are also elevated in DIAD 
mutation carriers during both the presymptomatic and symptomatic stages (Moonis, Swearer et 
al. 2005; Ringman, Younkin et al. 2008; Bateman, Xiong et al. 2012; Ringman, Coppola et al. 
2012). 

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 Rationale for the DIAN-Multivariate Cognitive Endpoint 
Cognitive endpoints used in most clinical trials in symptomatic sporadic Alzheimer’s dementia 
may not be useful in this study as more than half of the study subjects will be cognitively normal 
and are likely to show only subtle changes in cognitive function over the course of the study.  
Available literature from cohort studies in cognitively normal individuals who progressed to 
symptomatic AD suggests that a measure sensitive to preclinical (asymptomatic) and early stage 
symptomatic AD should include assessment of at least three cognitive domains.  Prior studies 
have shown that measures of mental status and episodic memory, including both list learning 
and narrative recall measures, are sensitive to decline up to 10 years prior to clinical diagnosis of 
symptoms (Grober, Hall et al. 2008; Johnson, Storandt et al. 2008; Derby, Burns et al. 2013; Vos, 
Xiong et al. 2013).  In the DIAN Observational (DIAN-OBS) cohort, the group from which many 
subjects in this trial will be drawn, there are baseline differences in episodic memory and 
executive functions (including working memory and attentional control) between asymptomatic 
mutation carriers and mutation negative family members (Storandt, Balota et al. 2014). 
Several potential composite measures were examined as candidates for the DIAN-MCE using 
data from the DIAN-OBS cohort data (Data Freeze 9).  The pattern of deficits was similar to that 
observed in sporadic AD, with decline on global metrics of cognitive function and tests of 
episodic memory and executive function in the early asymptomatic stage, followed by 
widespread cognitive decline across all cognitive domains when mutation carriers become 
clinically symptomatic (defined as clinical dementia rating [CDR] > 0). 
The DIAN-MCE will include 4 measures that have well-demonstrated sensitivity to decline in 
preclinical and early stage symptomatic AD; most importantly, these measures have shown 
sensitivity to changes in the cognitively normal/preclinical stage of dominantly inherited AD in 
the DIAN-OBS cohort.  These 4 measures are:  1) The Delayed Recall score of the International 
Shopping List Test, 2) The Delayed Recall score of the Logical Memory IIa subtest from the 
Wechsler Memory Scale-Revised, 3) The Digit Symbol Substitution Test total score from the 
Wechsler Adult Intelligence Scale-Revised, and 4) The Mini-Mental State Examination total 
score.  The DIAN-MCE is unique, but has overlap with composite measures identified for other 
secondary prevention trials in AD, including the Anti-Amyloid in Asymptomatic Alzheimer’s (A4) 
trial (Donohue, Sperling et al. 2014) and the Alzheimer’s Prevention Initiative (API, Langbaum, 
Hendrix et al. 2014). 
 Rationale for Cognitive Run-in Assessments 
 
 
 
 

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 Rationale for Open-label Extension 
In dominantly inherited Alzheimer’s disease, subjects who carry the disease-associated mutation 
will ultimately develop dementia.  This trial is testing the hypothesis that the study drugs can 
change the course of amyloid injury and delay or prevent dementia.  Assuming that the 
observations of subjects during the trial show that the interventions demonstrate potential 
clinical benefit and are reasonably safe, an open-label extension for symptomatic subjects, and 
asymptomatic subjects who are confirmed mutation carriers, would allow for treatment at the 
earliest time point so that symptomatic subjects would be treated, and those with the gene may 
get maximal opportunity to benefit as well.  Thus, at the end of the double-blind treatment 
period, subjects may have the opportunity to receive active drug with appropriate safety 
monitoring; details are provided in section 3.10. 

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2 STUDY OBJECTIVE 
To assess the safety, tolerability, biomarker and cognitive efficacy of each study drug versus 
mutation positive placebos in subjects who are known to have an Alzheimer’s disease-causing 
mutations by determining if treatment with the study drug slows the rate of progression of 
cognitive impairment and improves disease-related biomarkers. 
3 STUDY DESIGN 
 Overall Design 
This study is a Phase II/III double-blind placebo-controlled, cognitive endpoint, multicenter study 
of disease modifying therapies in individuals at risk for dominantly inherited Alzheimer’s disease.  
Individuals who are at risk for dominantly inherited Alzheimer’s disease (known mutation 
carriers or those who are blind to their mutation status but have a 50% risk of being mutation 
carriers) AND who are between 15 years younger (−15) or 10 years older (+10) than the typical 
age at onset of dementia in their pedigree or gene type (APP, PSEN1, PSEN2) AND who are either 
cognitively normal (Clinical Dementia Rating™ [CDR]=0) or have mild symptoms of dementia 
(CDR 0.5 or 1) will be enrolled. 
Many subjects in this study will choose to remain blind to their genetic status.  These subjects 
and study staff will remain blind to their genetic status throughout the study.  Mutation negative 
subjects will not receive active study drug, but in order to maintain blinding as to genetic status, 
mutation negative subjects will be assigned to the placebo group and will participate in all study 
procedures and assessments.  Placebo PET tracers may be used if required by local regulations, if 
pre-approved by the sponsor.  Mutation-negative subjects will not be included in the primary 
efficacy or futility analyses.  These subjects will provide valuable biomarker data that will be 
useful for future studies in both DIAD and sporadic DAT.  Mutation positive subjects will be 
randomized into actively enrolling study drug arms and within a study drug arm the subject will 
be randomized at an overall ratio of 3:1 for active drug versus placebo.  Therefore, both 
mutation positive and negative subjects will be randomized to receive placebo for each study 
drug arm.  This is needed because the treatment administration routes and safety monitoring 
may be different for the different study drug arms.  Subjects and study staff will be blinded as to 
whether subjects are on active drug or placebo but will not be blinded as to the treatment route 
and interval.   
This study is an adaptive platform-based study, which allows flexibility to add a new compound 
to the same protocol, allowing subjects to be randomized to study drug arms open to 
enrollment, and to maintain a cohort of trial ready subjects with or at risk for DIAD mutations.  
Subjects have been enrolled to the gantenerumab or solanezumab study drug arms, with each 
enrolled subject randomized to active drug or the corresponding placebo (‘direct placebo’).  
Previously, DIAN-TU-001 also included an atabecestat arm. For further information relevant to 
this study drug arm, see earlier versions of the protocol. 

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All subjects enrolled to the gantenerumab and solanezumab arms will continue to be treated 
with active drug or placebo, while biomarker (e.g., positron emission tomography (PET) imaging, 
volumetric brain magnetic resonance imaging (MRI), cerebral spinal fluid (CSF), and plasma 
measures), clinical, cognitive, and safety assessments (including safety MRI scans, vital signs, 
electrocardiogram (ECG), clinical chemistry, and hematology) are monitored throughout the 
study period.  The active drug group will be given for up to a minimum of 204 weeks through a 
maximum of 364 weeks, based upon when the subject was randomized into the study.  Placebo 
will be given for up to a minimum of 204 weeks through a maximum of 364 weeks, based upon 
when the subject was randomized into the study. 
 
 
 
 
 
 
 
The primary efficacy hypothesis of the study is that the study drug group will have a slower rate 
of progression on the DIAN-MCE compared to the mutation-carrier placebo group after 
treatment for a minimum of 4 years.  That is, all subjects continue on double-blind treatment 
until every subject completes 4 years of treatment resulting in a range of treatment exposure 
beyond 4 years along with additional cognitive assessments, all of which contribute to the 
primary endpoint.  The biomarker endpoints and cognitive endpoints may be used to conduct 
interim analyses in any of the study drug arms.  The design includes the potential to conduct at 
least one interim analysis of the biomarker endpoints and up to two interim analyses of the 
cognitive endpoint.  The number and timing of interim analyses may vary for each study drug 
arm.  Details about the interim analyses are described in each drug-specific appendix.  If a study 
drug fails to demonstrate target engagement, as evidenced by meeting a pre-specified threshold 
at one of the interim analyses, the Data Safety Monitoring Board (DSMB) may recommend that a 
study drug arm either be stopped early or that the study dose be escalated, if dose escalation is 
deemed safe.  If a study drug achieved significant slowing of cognitive decline at the cognitive 
interim analysis, the study drug arm may be terminated early for efficacy. 
Study drug arms that demonstrate a potential clinical benefit may have an open-label extension 
period. 

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 Rationale for Study Design 
There are two unusual features of this study population that have influenced the study design.  
First, many individuals who are at risk for dominantly inherited Alzheimer’s disease do not want 
to know their mutation status.  The study design allows for enrollment of these individuals as it 
permits subjects and study staff to remain blinded to mutation status.  Mutation negative 
subjects will not be exposed to active study drug.  Mutation positive subjects will be randomized 
between study drug arms and placebo.  The placebo group of mutation positive individuals will 
be pooled among the treatment groups (‘mutation positive placebos’), increasing the statistical 
power of the study.  This use of a pooled placebo group enables a study of more than one 
therapy to be powered with fewer total subjects and allows more than 50% to be on an active 
drug, a feature often requested by potential research subjects.  Further, this platform study 
design also allows for flexibility and for the application of an “adaptive design” for which study 
drug is used.  For example, if a study drug failed early due to adverse events or lack of efficacy, a 
new compound could be added to the same protocol and new subjects could be randomized to 
the actively enrolling study drug arms 
. 
Secondly, families with mutations linked to DIAD are rare and subjects typically live at a 
significant distance from DIAN-TU sites.  Because subjects typically work and have family 
responsibilities, there is increased burden of travel and time spent on study activities.  Further, a 
high level of subject retention is essential for the success of the study.  These considerations play 
a significant role in study design.  Subjects who reside outside a reasonable distance from their 
‘host’ trial site will be asked to travel to the site only when needed for highly specialized 
assessments (e.g., PET scans, lumbar puncture (LP), and specialized cognitive testing; these occur 
at least annually).  Regular visits (e.g., for administration of study drugs) may be performed by 
trial-designated and GCP trained home health nurses or other trial-identified satellite sites.  For 
relevant study drug arms, the 3T safety MRIs that are not part of an Annual Visit may be 
performed at either the subject’s host DIAN-TU site or a trial-identified location qualified for the 
study near the subject’s home.  For all study drug arms, the annual MRI session will be 
performed at the subject’s host DIAN-TU site. 
A more traditional study design with separate biomarker and cognitive endpoint trials would be 
extremely difficult in this cohort for two reasons:  1)  The subject pool is very limited as families 
with DIAD causing mutations are rare and 2) a prolonged treatment period (≥ 4 years in this 
study) may be needed to determine if the study drugs can slow or prevent cognitive changes in 
a cohort where over half of the treated subjects are asymptomatic and may be up to 15 years 
younger than their estimated age at onset.  The inclusion of these cognitively normal subjects is 
very important, as they may be most likely to benefit from amyloid-modifying treatments. 
However, the subtle cognitive change in the asymptomatic mutation carriers limits the power 
to detect treatment effects when there are small numbers of subjects enrolled.  One method to 
improve the power to detect treatment effects is to include additional control subjects.  The 
DIAN Observational study (DIAN-OBS) has been following nearly the same protocol as DIAN-TU-

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001 in order to study the natural history of disease progression in DIAD.  Given the similarities 
of the protocol and the fact that the DIAN-OBS study has contributed approximately 40% of the 
subjects to the DIAN-TU-001, data will be used from DIAN-OBS subjects who meet the inclusion 
criteria for DIAN-TU-001 to track disease progression.  The DIAN-OBS data will be used as 
additional control subjects and will be combined with the placebo group to improve power. 
Rationale for Cognitive Run-in Period to Establish Trial Ready Cohort 
  
 
 
 
To determine the potential benefits for statistical power, a detailed simulation analyses was 
conducted in three study cohorts at risk for AD.  Across all datasets, including slopes and 
intercepts from pre-randomization periods as covariates resulted in the largest increases in 
statistical power for a 4-year simulated trial.  Statistical power increased by 5-11% depending 
upon randomization scenarios (3:1, 1:1) and the length of the pre-randomization period.  In 
addition, the use of pre-randomization cognitive testing will align the DIAN-TU with ongoing 
initiatives — the Trial Ready Cohort (TRC) for preclinical/prodromal AD (PAD) trials (TRC-PAD; 
NCT03638583) and the European Prevention of Alzheimer Dementia Longitudinal Cohort Study 
(EPAD LCS; NCT02804789) — that are developing trial-ready populations for AD prevention 
trials (Aisen et al., 2016). 
 
 
 
 
 
 
 
 
 
 
 

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 Number of Subjects and Sites 
Individuals will be recruited by host DIAN-TU sites and may also come from other sources such 
as referring partner sites, and the DIAN-EXR.  DIAN-TU sites are located globally.  The number of 
sites and locations may be expanded over the course of the study. 
Recruitment of mutation positive subjects is with baseline CDR 0 to 1 (inclusive) with no more 
than 50% CDR > 0 enrolled.  Mutation positive groups (active vs. placebo) will be balanced 
proportionally as to number of asymptomatic (CDR 0) and symptomatic (CDR > 0) subjects. 
For the gantenerumab and solanezumab arms, the recruitment goal was 52 mutation carriers for 
each study drug arm and 34 mutation carriers for the combined placebo group for a total of 138 
mutation carriers.  An estimated 72 non-carriers (mutation negative subjects who are unaware 
of their genetic status, estimated to be about 1/3 of total subjects) would also be recruited and 
will receive placebo.  Recruitment was closed once 52 mutation carriers were enrolled in each 
active drug group and 34 were enrolled in the mutation positive placebo group. 
 
 
 
 
 
The number of DIAN-TU sites is estimated to be approximately 40 sites globally.  The 
 
baseline study visit (V2) and annual visits for the 
 treatment period will be 
conducted at the DIAN-TU site.  Other visits (e.g., visits for dispensing/administration of study 
drugs and cognitive testing) may be performed at the DIAN-TU site or by trial-designated and 
GCP trained home health nurses or other trial-identified satellite sites.  For relevant study drug 
arms, regular interval 3T safety MRIs will be performed at either the host DIAN-TU site or a trial-
identified location qualified for the study near the subject’s home.  Whenever possible, satellite 
sites for imaging in the US will be sites in the Alzheimer’s Disease Cooperative Study (ADCS) 
and/or Alzheimer’s Disease Neuroimaging Initiative (ADNI) that have experience with AD 
imaging, assessment and therapeutic trials, and have been qualified by the trial’s MRI central 
reader.  Preliminary studies suggest that >70% of potential US subjects live within a 2-hour drive 
of an ADCS and/or ADNI site, so we anticipate the majority of scans will be performed at these 
sites.  When other sites are needed, satellite imaging sites that are able to complete and upload 
safety scans will be individually selected and qualified (see section 6.1.16). 

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 Subject Enrollment and Randomization 
Subjects will be recruited from or may be referred to a host DIAN-TU site for screening.  The 
complexity of the study and the likelihood that many subjects may live at a distance from the 
DIAN-TU site create additional challenges for enrollment.  Individuals interested in the study 
will be provided with an informed consent form (ICF) for review. 
If more than one study drug arm is enrolling, a main ICF will provide detailed information on 
study design, number and timing of visits and procedures, and the rationale for use of drugs 
targeting AD pathology.  The ICF will provide information on the route of administration, 
potential side effects associated with drugs that target amyloid-beta or tau, and study 
procedures.  The ICF will explain that subjects will be assigned randomly to a study drug arm 
and if more than one of the study drug arms is recruiting simultaneously, they will not be able 
to choose a specific study drug arm.  If only one drug is enrolling, one ICF may be utilized in the 
traditional fashion. 
 
 
 
 
 
 
 
 
 
Subjects (and their legally acceptable representative if the subject is cognitively impaired) will 
review the ICF and discuss with study staff on the phone or in-person.  The subject and/or 
representative will only sign the ICF after all questions have been answered.  The study partner 
will be provided with information on their role in the study and will sign the ICF; this may be 
part of the main ICF or a separate ICF, as required by local regulations. 
If enrolling directly into a study drug arm, after informed consent is obtained, each subject will 
be assigned a unique study number and screening visit (V1) procedures will be completed 
either in the subject’s home by a home health nurse, other trial-identified satellite site, or at 
the DIAN-TU site.  Appropriate documentation of informed consent and screening assessments 
will be monitored by the sponsor and/or sponsor designee.  The baseline visit (V2) at the DIAN-
TU site will be scheduled 2-8 weeks after completion of the screening visit procedures, and no 
earlier than 6 weeks after the genetics blood draw.  After all baseline measures have been 
completed, and adherence to inclusion and exclusion criteria has been verified, the subject will 
be randomized to a study drug arm via the Interactive Web Response System (IWRS, an 
interactive voice response system (IVRS) may be used at sites where IWRS is not feasible).  The 
subject and study staff at the site will know which study drug arm the subject was assigned but 

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will not know whether the subject was assigned to active drug or placebo.  If more than one 
study drug arm is enrolling subjects, the subject will review a supplemental drug-specific ICF for 
the assigned study drug arm that provides additional details of the frequency of side effects and 
risk/benefit information for that specific study drug. 
Subjects will receive their first dose of study drug after all visit procedures have been 
completed and the subject has been randomized.  If a subject decides not to continue in the 
assigned study drug arm after randomization but prior to dosing, they will be withdrawn from 
the study and may not be re-randomized to a different study drug arm. 
See details about subject randomization in each drug-specific appendix. 
 
 
 
 
 
 
 
 
 
 
 Primary Study Endpoints 
The primary efficacy endpoint is the DIAN-MCE which consists of 4 cognitive measures:  1) The 
Delayed Recall score of the International Shopping List Test, 2) The Delayed Recall score of the 
Logical Memory IIa subtest from the Wechsler Memory Scale-Revised, 3) The Digit Symbol 
Substitution Test total score from the Wechsler Adult Intelligence Scale-Revised, and 4) The 
Mini-Mental State Examination total score.   
A mixed-effects cognitive multivariate disease progression model (MDPM) with a proportional 
treatment effect will be used to assess statistical differences in the rate of decline, relative to 
the expected years from symptom onset, of the DIAN-MCE between each active drug and the 
mutation positive placebos and eligible DIAN-OBS subjects. 
 Additional Study Endpoints 
The safety and tolerability of the study drugs in individuals who have mutations causing 
dominantly inherited Alzheimer’s disease will be important endpoints throughout the study. 

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The biomarker endpoints used for the interim biomarker analyses are specific for each drug 
based on mechanism of action.  These are listed in each drug-specific appendix and/or drug-
specific SAP appendix. 
The ultimate goal of therapeutic interventions in DAT is to ameliorate or prevent the cognitive 
effects of the disease and to prevent the onset or slow the progression of disease symptoms.  
Four cognitive measures will be used in the DIAN-MCE as the primary endpoint (section 3.5).  
Additional clinical and cognitive measures may be included as additional endpoints (secondary 
or exploratory) if not already included in the primary outcome measures.  All measures may be 
included in development of more sensitive endpoints.  Cognitive endpoints may include testing 
administered via an electronic platform (Cogstate) and conventional psychometric testing. 
Additional outcome measures include comparisons between each drug and mutation positive 
placebos and eligible DIAN-OBS subjects for change in values between baseline and endpoint 
for the clinical and cognitive measures listed below if/as specified in the drug-specific SAP 
appendix. 
Clinical Measures 
Clinical measures to be obtained at the 
 baseline (V2), and annual visits for 
 the 
 treatment period will be administered at a host DIAN-TU site include: 
• Clinical Dementia Rating™ (CDR), including Clinical Dementia Rating Sum of Boxes™ 
(CDR-SB) and clinician’s diagnostic assessment 
• Geriatric Depression Scale (GDS) 
• Neuropsychiatric Inventory Questionnaire (NPI-Q) 
• Functional Assessment Scale (FAS) 
• Mini-Mental State Examination (MMSE) 
 
 
 
Complete Cognitive Battery 
Cognitive measures to be obtained at the baseline (V2) and annual visits for the treatment 
period will be administered at a host DIAN-TU site and include the iPad administered and 
conventional psychometric (pen/paper) tests listed below.  
 
 

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iPad Administered Cognitive Testing:  
• International Shopping List Test (12-Item Word List Learning): 3 learning trials, 
Immediate Recall, 30-min Delayed Recall (Cogstate) 
• Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-
min Delayed/Reversed Recall (Cogstate)  
 
 
 
 
 
 
 
 
 
 
 
 
Conventional Psychometric Testing (Pen/Paper):  
• Trailmaking Test parts A & B 
• WMS-R Digit Span 
• WAIS-R Digit-Symbol Substitution Test 
• Raven’s Progressive Matrices (Set A) 
• Category Fluency (Animals & Vegetables) 
• WMS-R Logical Memory (Immediate & Delayed Recall) 
Cognitive Battery Subset 
The subset of cognitive measures administered by the site or trial-certified cognitive rater at 
 
 treatment weeks 24 (V8), 76 (V21), 128 (V34), 180 
(V47), 232 (V60), 284 (V73), and 336 (V86) includes the iPad administered and conventional 
psychometric (pen/paper) tests listed below. 
 
 
In addition, the iPad administered battery of cognitive measures listed below will be 
administered by the site or trial-certified cognitive rater at 
 
 screening (V1) visit, to familiarize subjects with the iPad administered cognitive 
testing procedures. 
iPad Administered Cognitive Testing 
• International Shopping List Test (12-ltem Word List Learning): 3 learning trials, 
Immediate Recall, 30-min Delayed Recall (Cogstate) 
• Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 
30-min Delayed/Reversed Recall (Cogstate) 
 
 
 
 
 
 
 

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Conventional Psychometric Testing (Pen/Paper) (Not administered at 
 
treatment screening (V1) visit: 
• Trailmaking Test parts A & B 
• WMS-R Digit Span 
• WAIS-R Digit-Symbol Substitution Test 
• WMS-R Logical Memory (Immediate & Delayed Recall) 
• 
 
Additional secondary measures may be listed in each drug-specific appendix. Refer to the final 
SAP for drug-specific differentiation of endpoint classification based on the respective drug’s 
target and mechanism of action. 
For Cognitive Run-in Period and for Drug Arms Other Than Gantenerumab and Solanezumab 
The brief battery (home-based iPad cognitive testing) consisting of a brief subset of cognitive 
measures listed below administered on an iPad, will be administered approximately every 
6 months starting 3 months from Baseline (V2) for subjects randomized to an enrolling study 
drug arm, during home visits by a trial-certified cognitive rater.  These assessments will occur at 
treatment weeks 12 (V5), 32 (V10), 40 (V12), 64 (V18), 88 (V24), 116 (V31), 140 (V37), 168 
(V44), 192 (V50), 220 (V57), 244 (V63), 272 (V70), 296 (V76), 324 (V83), and 348 (V89).  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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For all study drug arms, the following additional biomarker endpoints may be assessed. Refer 
to the final drug-specific SAP appendix for drug-specific differentiation of endpoint classification 
based on the respective drug’s target and mechanism of action. 
• Change from baseline in amyloid load based on imaging with [11C]PiB-PET 
• Change in FDG-PET metabolism in specific regions of interest (e.g., precuneus) in treated 
group as compared with mutation positive placebos 
• Tau PET measures of neurofibrillary tangle (NFT) burden 
 
 
 
 
 
• Change in CSF amyloid-beta peptide concentrations 

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• Change of CSF biomarkers tau and ptau values 
• Change in Neurofilament Light chain (NfL) in plasma and CSF 
 
 
 
 
• Rate of brain atrophy as measured by cortical thickness of regions of interest (volumetric 
MRI) 
• Plasma amyloid-beta isoform analyses 
 
• CSF markers of neurodegeneration or AD 
• Plasma markers of neurodegeneration or AD 
 
 
 
 
• Other drug-specific biomarkers, as specified in each drug-specific appendix 
 
 
 
 Safety Endpoints 
This study will assess safety and tolerability in individuals at risk for dominantly inherited AD.  
Safety endpoints used will be the incidence and severity of treatment-emergent adverse events 
(TEAEs), serious adverse events (SAEs) and treatment discontinuations.  Analysis will be on an 
intent-to-treat basis.  Clinical laboratory evaluations, vital signs, and 12-lead ECGs will also be 
measured throughout the study. 
Amyloid-related imaging abnormalities (ARIA) are a safety endpoint in studies of DAT.  Based on 
the assigned study drug arm, this study may include MRI scans every few months to assess for 
ARIA changes.  ARIA can occur as either cerebral edema (ARIA-E) or as hemorrhages (ARIA-H), 
typically microhemorrhages, but larger hemorrhages and frank infarction have also been 
reported (Sperling, Salloway et al. 2012).  MRI scans will be analyzed for ARIA changes at the 
Mayo Clinic Aging and Dementia Imaging Research (Mayo-ADIR).  The number of 
microhemorrhages (ARIA-H, including both hemorrhages and hemosiderin deposits) and size of 

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areas of edema (ARIA-E) will be monitored at entry and throughout the trial.  Incidence of ARIA 
and comparison to placebo will be made. 
A report of new ARIA changes in a subject will trigger a review by the DIAN-TU Medical Director 
or designee, Project Arm Leader (PAL), and site principal investigator.  This review will include 
contact with the subject or caregiver to assess for any symptoms associated with the changes 
and discussion with the central readers.  The PAL, as a site independent neurologist, will help 
ensure consistency of decisions within a study drug arm across sites during the study.  See each 
drug-specific appendix for drug-specific ARIA algorithms.  The DIAN-TU Medical Director will 
ensure consistency across study drug arms and will have final decision-making authority on 
changes in dosing of study drug or safety monitoring; this decision should be received by the 
site within 7 days of the report of the new ARIA changes, but no later than the day prior to the 
planned administration of the next dose of medication.  A similar process will be followed if a 
follow-up MRI shows worsening of a previously reported ARIA. 
Additional assessments based on drug-specific safety concerns are detailed in each drug-
specific appendix (Appendices 3 and 4). 
An independent Data Safety Monitoring Board (DSMB) will assess safety data periodically 
throughout the study.  The DSMB will have timely access to data, including clinical laboratory 
values, ECGs, MRI results, and clinical and cognitive testing scores; this will include access to 
unblinded data when requested.  The DSMB will monitor the incidence of ARIA and comparison 
to placebo.  See section 7.9 and the DSMB charter for additional information. 
 Study Schedule 
The schedule of visits, including drug-specific testing and frequency of safety MRIs, for each 
drug is provided in each drug-specific appendix (Appendices 3 and 4). 
 Total Study Duration and Duration of Treatment 
  The treatment duration of each study drug 
arm may vary depending on the enrollment rate, the respective sample size, and the treatment 
time needed for the study drug to achieve its goal.  A study drug arm may be stopped early or 
revised (e.g., dose adjustment or treatment duration), based upon the results of the interim 
analyses or information from other clinical trials for the same drug, as outlined in each drug‐
specific appendix. 
For the gantenerumab and solanezumab arms, subjects will continue to receive blinded 
treatment until every subject randomized to either the gantenerumab or solanezumab blinded 
study drug arms has received a minimum of 4 years (208 weeks) of treatment or is withdrawn.  
Based on the time that was needed for full recruitment, the total duration of the gantenerumab 
and solanezumab arms is expected not to exceed 81 months (6.75 years), which allows 33 
months for enrollment and 48 months for treatment.  For subjects enrolled in the first month, 

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the duration of treatment will be approximately 80 months (32+48); for those enrolled in the 
last month, the duration of treatment will be 48 months; and for those enrolled in-between, 
the duration of treatment will be approximately from 48 months to 80 months.  On average, 
the duration of treatment per subject is about 64 months (5.3 years). 
The sponsor may choose at any time to limit treatment duration to 4 years (208 weeks) for a 
study drug arm even if some subjects have exceeded this limit at the time of the decision. 
 
 
After the final analysis is complete for a study drug arm, subjects may be eligible to continue or 
start treatment in the open-label extension period (section 3.10) if the study drug arm 
demonstrates clinical or cognitive benefit. 
 
 
 
]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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4 STUDY POPULATION AND SITES 
 
 
 
 Inclusion Criteria 
A subject may be included in the double-blind period if the answer to all of the following 
statements is “yes”. 
1. Written informed consent is signed and dated by the subject, study partner (if 
applicable) and/or by the subject’s legally acceptable representative according to local 
regulations for the core trial ICF and, if applicable, 
 the drug-specific 
ICFs. 
2. Subject is 18-80 years of age (inclusive). 
3. Women of childbearing potential, if partner is not sterilized, must agree to use effective 
contraceptive measures (e.g., hormonal contraception, intra-uterine device, sexual 
abstinence, barrier method with spermicide) from screening (V1) until 16 weeks after 
last dose of study drug. 

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4. Mutation status (must fulfill criteria a or b, based on estimated years from symptom 
onset [EYO]): 
a. −15 to +10 EYO (secondary prevention population): 
i. 
Subject is a carrier2 of a mutation in PSEN1, APP or PSEN2 gene that is 
associated with dominantly inherited Alzheimer’s disease3 OR at 50% risk for 
such a mutation (e.g., does not know their mutation status AND is a child or 
sibling of known mutation carrier) 
ii. 
Subject is within -15 to +10 years of the predicted or actual age at cognitive 
symptom onset. 
(a) For cognitively normal subjects, the predicted age at onset is determined 
based on their mutation type or family pedigree (refer to Global Manual 
of Operations for calculation of estimated age at onset). 
(b) For subjects with symptomatic Alzheimer’s disease (CDR 0.5 or 1 with 
clinical diagnosis of Alzheimer’s dementia), the age at onset is the 
subject’s actual age at symptom onset. 
Note: Subjects who are aware that they are mutation negative are not eligible 
for enrollment. 
b. Younger than −15 EYO (primary prevention population):  
i. 
Subject is a carrier4 of a mutation in PSEN1, APP or PSEN2 gene that is 
associated with dominantly inherited Alzheimer’s disease5 OR does not know 
their mutation status AND there is a mutation in their family pedigree) 
ii. 
Subject is younger than -15 years from predicted age of cognitive symptom 
onset based on their mutation type or family pedigree (refer to Global Manual 
of Operations for calculation of estimated age at onset). 
                                                     
2  Mutation genotype will be determined at the trial-designated CLIA-approved lab as part of the screening 
process.  Results of this testing will not be available to the DIAN-TU site or to the subject.  Subjects who ask to be 
informed of the test results will be referred for genetic counseling and will have testing ordered through a 
clinical laboratory; results will be sent to the genetic counselor who will disclose results to the subject.  Note that 
subjects who become aware that they are mutation negative will be excluded from the study.   
3  The sponsor will provide a list of mutations that are judged to be associated with dominantly inherited 
Alzheimer’s disease.  Site staff should confirm that the mutation in each potential subject’s family is on the 
current mutation list.   
4  Mutation genotype will be determined at the trial-designated CLIA-approved lab as part of the screening 
process.  Results of this testing will not be available to the DIAN-TU site or to the subject.  Subjects who ask to be 
informed of the test results will be referred for genetic counseling and will have testing ordered through a 
clinical laboratory; results will be sent to the genetic counselor who will disclose results to the subject.  Note that 
subjects who become aware that they are mutation negative will be excluded from the study.   
5  The sponsor will provide a list of mutations that are judged to be associated with dominantly inherited 
Alzheimer’s disease.  Site staff should confirm that the mutation in each potential subject’s family is on the 
current mutation list.   

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Note: If the at-risk parent is deemed a non-carrier at any time during the study, the 
subject will be withdrawn 
5. Cognitive status must fulfill criteria a or b, based on EYO: 
a. −15 to +10 EYO (secondary prevention population): Cognitively normal or with mild 
cognitive impairment or mild dementia, CDR 0 to 1 (inclusive).  If the number of 
mutation positive subjects with CDR>0 reaches 50% of the total enrollment for the 
secondary prevention population, the sponsor will close enrollment for symptomatic 
subjects (CDR>0) and will thereafter enroll only cognitively normal (CDR 0) subjects. 
 
6. Fluency in DIAN-TU trial approved language and evidence of adequate premorbid 
intellectual functioning. 
7. Adequate visual and auditory abilities to perform all aspects of the cognitive and 
functional assessments. 
8. Receiving stable doses of medication(s) for the treatment of non-excluded medical 
condition(s) for at least 30 days prior to 
 baseline visit (V2) with the 
exception of medications taken for episodic conditions (e.g., migraine abortive therapy, 
antibiotics and other medications for upper respiratory and gastrointestinal ailments), 
AND, if treated with cholinesterase inhibitors and/or memantine, all of the following 
conditions are also met: 
a. The subject has been taking these medications for at least 90 days prior to 
 
 baseline visit (V2) and has been on a stable dose for at least 2 months (60 
days) prior to 
 baseline visit (V2). 
b. The subject is free of any clinically important side effects attributable to the drug.  
Side effects that are intermittent, stable or well-tolerated by the subject are not 
exclusionary. 
9. Has a study partner who in the investigator's judgment is able to provide accurate 
information as to the subject's cognitive and functional abilities, who agrees to provide 
information at the study visits that require study partner input for scale completion, and 
who signs the necessary informed consent form, if applicable. 
10. Agrees not to donate blood or blood products for transfusion from screening (V1) for a 
study drug arm for the duration of the study and for one year after the final dose of 
study drug. 
 
 
11. In the opinion of the investigator, the subject will be compliant and have a high 
probability of completing the study. 
12. Able and willing to complete all study-related testing, evaluations, and procedures. 

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 Exclusion Criteria 
A subject will be excluded from the double-blind period if the answer to any of the following 
statements is “yes”. 
CNS Disorders 
1. Significant neurologic disease (other than AD) or psychiatric disease that may currently 
or during the course of the study affect cognition or subject’s ability to complete the 
study.  This would include disorders such as: recent or severe head trauma causing 
cognitive change, seizure disorder, neurodegenerative disease, hydrocephalus, 
cerebral/spinal hematoma, inflammatory disease, CNS infection (e.g., encephalitis or 
meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or 
hypoglycemic episodes) or endocrine disorder; psychiatric disorders such as 
schizophrenia, schizoaffective disorder, bipolar disorder or major depression, or any 
other psychiatric condition/disorder which could significantly interfere with the 
subject’s cooperative participation (e.g., prominent anxiety, agitation or behavioral 
problems).  Disorders that are controlled medically or remote history of these 
disorders (e.g., history of febrile seizures in childhood) that are not likely to interfere 
with cognitive function and compliance with study procedures are not exclusionary. 
2. At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 
months, current major depression (as defined in DSM-IV), or increased suicide risk 
based on 
 or screening (V1) C-SSRS.  Current stable mild depression or 
current use of antidepressant medications is not exclusionary. 
3. History of clinically evident stroke or history of clinically important carotid or 
vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral 
hemorrhage (including atrial fibrillation and anticoagulation, documented transient 
ischemic attack [TIA] in the last 12 months).  Low dose aspirin (≤ 325 mg daily) is not 
exclusionary. 
4. Alcohol or drug dependence sufficient to meet DSM-IV criteria currently or within the 
past 1 year. 
Imaging related exclusion criteria: 
5. History of brain MRI scan indicative of any other significant abnormality, including but 
not limited to more than 4 definite microhemorrhages, history or evidence of a single 
prior hemorrhage >1 cm3, 2 or more subcortical infarcts, evidence of a single prior 
cortical infarct >1 cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, 
vascular malformations, subdural hematoma, or space-occupying lesions (e.g., large 
arachnoid cysts or brain tumors, such as meningioma), hydrocephalus (other than 
hydrocephalus ex vacuo).  Minor or clinically insignificant imaging findings are not 
exclusionary. 

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Note:  For subjects who have participated in the DIAN Observational study, site staff 
should work with DIAN Observational Imaging Core to review results of MRIs done in the 
observational study so that those with preexisting exclusionary findings on MRI are not 
unnecessarily subjected to 
 screening (V1) and 
 baseline (V2) 
visit procedures. 
6. Presence of certain implanted medical devices, such as some pacemakers, aneurysm 
clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin or 
body which would preclude MRI scan. 
7. 
 
 
 
 
 
 
Cardiovascular Disorders 
8. Uncontrolled hypertension within 6 months prior to 
 screening (V1) 
(e.g., sustained systolic BP > 160 mm Hg or diastolic BP > 95 mm Hg). 
9. Myocardial infarction or other myocardial ischemic events within the last 2 years.   
10. Heart failure that results in limitation of physical activity (e.g., New York Heart 
Association [NYHA] functional classification stage 2 or higher). 
11. History of atrial fibrillation unless more than one year ago, and no structural lesions 
(e.g., atrial enlargement or cardiomyopathy) that would increase risk of stroke. 
12. 12-lead ECG: Clinically significant abnormalities including Bazett’s QTc interval greater 
than 450 msec for males and 470 msec for females; in subjects above 65 years of age: 
470 msec (AV-block I° allowed; RBBB allowed).  Site principal investigator or designated 
sub-investigator will be responsible for initial read on ECGs done at 
 
baseline (V2).  In the event that the central read becomes available after study drug is 
dispensed/administered and is exclusionary when the local read was not, the site 
principal investigator or designated sub-investigator, in consultation with the Medical 
Director or designee, will decide if the subject should continue in the study.  A 
discrepancy between the local and central read will not be considered a protocol 
deviation.  When there are differences in ECG interpretation between the investigator 
and the cardiologist at the central ECG laboratory, the investigator’s interpretation will 
be used for study entry and immediate subject management.  Interpretations from the 
cardiologist at the central ECG laboratory will be used for data analysis and report 
writing purposes. 

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Hepatic / Renal Disorders 
13. Alanine aminotransferase (ALT) ≥ 2 times the upper limit of normal or aspartate 
aminotransferase (AST) ≥ 3 times the upper limit of normal or total bilirubin ≥ 2 times 
the upper limit of normal. 
14. Creatinine clearance lower than 30 mL/min according to Cockcroft-Gault formula (if 
confirmed at re-test). 
15. Clinically significant abnormalities in urinalysis. 
Infections/Immune Disorders 
16. History of Human Immunodeficiency Virus (HIV) infection, history of Hepatitis B 
infection within the past year, history of Hepatitis C infection which has not been 
adequately treated or history of spirochete infection of the central nervous system 
(CNS), (e.g., syphilis, lyme or borreliosis). 
17. Known allergies, hypersensitivity, intolerance to study drug or its excipients (see current 
Investigator’s Brochures) or sensitivity to study-drug specific PET imaging agents. 
18. Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within 
90 days prior to the 
 baseline (V2) visit (topical and nasal 
corticosteroids and inhaled corticosteroids for asthma are permitted) or 
chemotherapeutic agents for malignancy within the last 3 years. 
Metabolic/Endocrine Disorders 
19. Current clinically significant abnormalities of thyroid function studies, clinically 
significant deficiency in B12. 
20. HgbA1c >8% (retesting is permitted if slightly elevated) or poorly controlled insulin-
dependent diabetes (including hypoglycemic episodes).  Subjects may be rescreened 
after 3 months to allow optimization of diabetic control. 
21. Morbid obesity with significant comorbidities or that would preclude MRI imaging. 
Co-Medications 
22. Current chronic use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban or 
apixaban) or of clopidogrel is exclusionary.  Limited (occasional or isolated) use of 
anticoagulants / antiplatelet compounds in cases such as surgical procedures, as well as 
daily use of low dose (≤ 325 mg) aspirin is not exclusionary. 
23. Have been exposed to a monoclonal antibody targeting beta amyloid peptide within the 
past six months. 
24. Received any other investigational treatment within 3 months or 5 half-lives of 
 
 screening (V1), whichever is longer. 

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25. Ever participated in a study of an active vaccine which was being evaluated to prevent 
or postpone cognitive decline. 
Note: Use of approved treatments for AD and other medications is permitted in this study in 
accordance with the guidelines in Concomitant Medications, section 5.3 below. 
Other 
26. Lack of sufficient venous access. 
27. Clinically relevant abnormalities in hematology, coagulation studies or clinical chemistry. 
28. History of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin 
carcinoma, prostate cancer or carcinoma in situ with no significant progression over the 
past 2 years. 
29. Any other medical condition that could be expected to progress, recur, or change to 
such an extent that it could bias the assessment of the clinical or mental status of the 
subject to a significant degree or put the subject at special risk. 
30. Currently, or within the last month prior to 
 screening (V1), participated in 
a clinical trial including a nonpharmacological trial with a key objective of improving 
cognition. 
31. Positive urine or serum pregnancy test or plans or desires to become pregnant during 
the course of the trial. 
32. Currently breast feeding.  Subjects must agree to refrain from breastfeeding during their 
participation in the trial and until 16 weeks after the last dose of study drug. 
33. Unable to fully complete 
 baseline visit (V2) procedures with 
appropriate cognitive and clinical scores for eligibility (e.g., mild dementia). 
 Subject Recruitment and Screening 
This study will recruit subjects from the DIAN Observational study, DIAN-TU sites, DIAN-TU 
partner sites, DIAN-EXR, and families identified by the sites.  These individuals will be recruited 
by and/or referred to a host DIAN-TU site for screening.  A list of screening labs and 
assessments for the
 
 double-blind treatment period is included in section 6.3.2. 
 Discontinuation/Early Withdrawal of Subjects 
4.4.1 Criteria for Discontinuation 
Subjects could be discontinued from the double-blind period or OLE for any of the following 
reasons: 

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1. Subjects would be discontinued from this study if they were involved in any other 
clinical trial or other research judged not to be scientifically or medically compatible 
with this study.  Participation in any other concurrent clinical trial that studies an 
investigational drug or any procedures to improve cognition is not permitted. 
2. Site principal investigator, Medical Director, PAL, or Medical Monitor decides subject 
should be discontinued, e.g., after an SAE or other clinically significant event or 
laboratory finding.  See each drug-specific appendix for any drug-specific 
discontinuation criteria related to adverse events and laboratory findings. 
Decisions regarding subjects who have ARIA AEs will be made based on both imaging 
and clinical factors; decisions will be made by the Medical Director following discussion 
between site principal investigator or designated sub-investigator, Medical Director 
and/or designee, and Project Arm Leader using drug-specific guidelines in Appendices 3 
and 4. 
3. Subject or subject research proxy (if subject is cognitively impaired and unable to 
provide their own consent) decides to withdraw consent, including declining to consent 
to any protocol amendments. 
4. Subject becomes pregnant. 
5. Subject non-compliance, based on decision of site study staff or Medical Monitor.  For 
parenteral drugs administered every 4 weeks, this includes subjects who fall below 75% 
compliance with respect to dosing, e.g., those who miss more than 7 study drug doses 
during the four-year study or who miss more than 3 consecutive doses of study drug.  
For daily oral administration, subject non-compliance is to be determined by the 
principal investigator in collaboration with the study medical staff after review of the 
subject’s study drugs usage.  Determination of non-compliance would not apply to 
doses that are missed or reduced when the site principal investigator and Medical 
Director decide that changes in study drug dosing are necessary for medical or safety 
reasons.
 
 
6. Subject can no longer contribute to the collection of key outcomes data.  Thus, a subject 
who cannot contribute to both the biomarker endpoint and cognitive endpoint during 
the first 2 years of the study or the cognitive endpoint after the first 2 years of the study 
should be discontinued from the double-blind treatment period but is eligible for 
continued clinical and/or cognitive follow-up and/or OLE* (refer to section 6.3.7). 
7. Known negative mutation carrier status.  For example, if a subject enters the study 
unaware of their mutation status, but later learns that they are mutation negative, they 
would be discontinued from the study. 

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8. For subjects in the primary prevention population:  if a subject enters the study based 
on their family pedigree, but later learns that the at-risk parent is a non-carrier, they 
would be discontinued from the study. 
9. For subjects administered [18F]AV-1451 tau PET tracer, the following additional 
discontinuation criteria apply: 
a. Participants who exhibit hypersensitivity to [18F]AV-1451 or any of its excipients 
are to be discontinued from this protocol addendum and are not to have 
another [18F]AV-1451 dose administered. 
b. Discontinuation or Holding of [18F]AV-1451 dose for participants who take 
medications that prolong QT interval: 
i. Participants who begin taking a medication known to prolong QT interval 
prior to the baseline [18F]AV-1451 scan will be discontinued. 
ii. Participants who begin taking a medication known to prolong QT interval 
after the baseline scan and continue to take medication at the time of the 
next scheduled [18F]AV-1451 scan will be discontinued. 
iii. If a participant receives a course of a QT prolonging medication and has 
stopped taking the medication prior to a scheduled [18F]AV-1451 scan, 
the advisability of administering the next scheduled dose of [18F]AV-1451 
and performance of the [18F]AV-1451 PET scan or holding the dose of 
[18F]AV-1451 should be considered by the Site principal investigator in 
consultation with the Sponsor 
 
If a subject discontinues early from the double-blind treatment period, every effort will be 
made to complete all study assessments, as applicable, at an Early Termination visit.  These 
assessments would not be completed for subjects who are withdrawn because they become 
unblinded to genetic status and are found to be mutation negative. 
 
 
*Any subject that discontinues from treatment due to safety reasons or inability to continue 
treatment and/or key study procedures will be encouraged to continue with any clinical or 
cognitive measures able to be performed based upon the assessment schedule.  The 
assessments will be determined based on discussion with the site principal investigator and 
sponsor. 
4.4.2 Replacement of Subjects  
Enrollment for each study drug arm will be ongoing until all groups within the study drug arm 
are filled.  Subjects will be replaced only when they withdraw from the study before the first 
dose of study drug is dosed/administered. 

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 Transfer of Subjects Between Sites  
A subject may request a transfer to a different DIAN-TU site if they relocate or if transfer to a 
new site will enable improved compliance with all study visits and procedures.  Should the trial 
be closed at a DIAN-TU site, subjects from the closing site would be offered the option of 
remaining in the study and transferring to another site to complete study procedures.  Subjects 
may have some study procedures performed at other DIAN-TU sites if the procedure cannot be 
performed at the host DIAN-TU site (e.g., due to equipment failure).  These subjects would 
remain enrolled at their host DIAN-TU site. 
 Expectations and Withdrawal of Sites 
Sites are expected to fulfill all study obligations.  DIAN-TU sites that fail to fulfill study 
obligations may be terminated from the study.  While a site is on probationary status or if a site 
is terminated, subjects at that site will be offered the option of transferring to a different DIAN-
TU site on a temporary or, if the site is terminated, permanent basis.  After obtaining signed 
release from subjects, copies of all source documents should be made available to the new site 
as rapidly as possible and at least within 30 days after probationary status begins. 
5 STUDY DRUGS 
See each drug-specific appendix for drug-specific background, preclinical and clinical data, 
rationale for specific biomarkers endpoints to assess target engagement, risks/benefits and 
specifics of drug packaging, preparation, administration, compliance, analysis issues, and drug-
specific adverse events, and schedule of visits. 
The following information on blinding, concomitant medications, and treatment compliance 
applies to all drugs. 
 Blinding 
Subjects and study staff will remain blinded as to whether subjects are on active drug or 
placebo.  Subjects and staff will not be blinded as to the treatment route and interval.  Although 
it is possible that study staff preparing parenterally administered compounds could be 
inadvertently unblinded, procedures are designed to reduce the risk of inadvertent unblinding 
and to ensure that study staff who might become unblinded (e.g., pharmacists) have minimal 
contact with other study staff and no direct contact with subjects and do not participate in 
other study assessments.  Research staff that do home or remote visits may have one home 
health nurse prepare and administer study drug while the other home health nurse conducts 
the study procedures.  The procedures taken to maintain blinding are detailed in each drug-
specific appendix. 
During double-blind periods, genetic status will not be disclosed to either the subject or study 
staff.  Mutation positive subjects may already be aware of their genetic status and choose to 

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disclose this to study staff.  The mutation positive subjects will be encouraged not to disclose 
their genetic status to study staff.  For subjects who have not been provided with their 
mutation status, the staff will be encouraged not to make assumptions about genetic status or 
group assignment within a study drug arm when adverse events (AEs) are reported.  Genetic 
status will be confirmed for entry into any OLE period. 
 Breaking the Blind 
With the exception of the periodic DSMB data review or required regulatory reporting for 
expedited reports by designated safety personnel who do not have contact with study staff or 
subjects, the study blind will not be broken until all subjects in a blinded study drug arm have 
completed the double-blind treatment period and the database for that study drug arm is 
locked.  Only in the case of an emergency, when knowledge of the study drug is essential for 
the immediate clinical management or welfare of a specific subject, may the investigator 
unblind a subject’s treatment assignment. 
Prior to any unblinding, the investigator is strongly advised to discuss options with the Medical 
Director or appropriate sponsor study personnel or designee.  As soon as possible, and without 
revealing the subject’s study drug assignment (unless important to the safety of subjects 
remaining in the study), the investigator must notify the sponsor if the blind is broken for any 
reason and the investigator was unable to contact the sponsor prior to unblinding.  The 
investigator will record in source documentation the date and reason for revealing the blinded 
treatment assignment for that subject. 
 Concomitant Medications 
All concomitant medication taken during the study must be recorded on the Concomitant 
Medication electronic case report form (eCRF).  Subjects will be instructed to consult the 
investigator or other appropriate study personnel at the site before initiation of any new 
medications or supplements and before changing dose(s) of any current concomitant 
medications or supplements. 
To approximate standard of care for AD, use of approved treatments for AD is permitted in this 
study, and no AD medications are explicitly excluded from use.  This section provides additional 
guidance on managing concomitant medication use during the trial. 
Allowed Medications.  Use of approved treatments for AD (including donepezil [Aricept], 
rivastigmine [Exelon], galantamine [Razadyne, RazadyneER], tacrine [Cognex], and 
memantine [Namenda]) is permitted during the study, provided that such medications have 
been given for at least 90 days and the dose has been unchanged for 2 months (60 days) before 
 Visit 2.  Doses of these medications should remain constant throughout the 
study. 

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If a subject has recently stopped acetylcholinesterase inhibitors (AChEIs) and/or memantine, he 
or she must have discontinued treatment at least 90 days before 
 Visit 2.  Other 
vitamins or nutraceuticals given for their possible effects on AD may be continued on stable 
doses beginning 90 days before 
 Visit 2. 
Starting, stopping, or changing doses of AChEIs and/or memantine during the study could 
interfere with outcome measures and may therefore result in discontinuation of the subject 
from the study. 
Before a subject starts, stops, or changes doses of AChEIs and/or memantine or other 
treatments for their AD, the sponsor or designee should be contacted to determine whether 
or not the subject should continue in the study and whether or not clinical outcome measures 
should be performed.  If documentation of sponsor discussion and approval in advance of 
starting, stopping, or changing doses is in place, this will not be considered a protocol 
deviation. 
If changes are made without prior contact with the sponsor or designee, the principal 
investigator, once informed of these changes, should contact the sponsor or sponsor’s 
designee to discuss and jointly determine whether or not the subject should continue in the 
study and whether or not clinical outcome measures should be performed.  It will be 
considered as a protocol deviation if discussion and sponsor approval prior to the start, stop, 
or modification of such medications were not in place 
Non-medication treatments for AD such as psychotherapy are permitted but are subject to the 
same restrictions as medication treatment taken for AD. 
Other concomitant medications that affect CNS function may be given if the dose remains 
unchanged throughout the study.  Doses of these compounds should remain constant from 
4 weeks before 
 before randomization (Visit 2). 
To avoid effects on cognitive measures, subjects should not stop receiving any medications that 
affect CNS function during the study, add any to the treatment regimen, or change doses of 
these medications.  If unforeseen starting, stopping, or changing of stable doses of these drugs 
occurs during the study, the Medical Director or designee must be contacted to determine 
whether or not the subject should continue in the study and whether or not outcome measures 
should be performed. 
Use of benzodiazepines for treatment on an as-needed basis for insomnia or daily dosing as 
anxiolytics is permitted.  Use of sedatives or hypnotics should be avoided for 8 hours before 
administration of the cognitive tests unless they are given chronically. 
 Treatment Compliance 
Compliance will be monitored for all drugs and recorded on study documents.  See each drug-
specific appendix for specific compliance monitoring for each study drug. 

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6 STUDY PROCEDURES 
 Procedures 
6.1.1 Subject Informed Consent 
Prior to any study procedures or study-related activities, an IRB or IEC approved Informed 
Consent Form (ICF) must be signed and dated by the subject (and/or caregiver/legally 
acceptable representative if the subject is cognitively impaired) and by the study partner (if 
required).  Study staff must document the informed consent process in the subject’s source 
document.  A copy of the signed and dated ICF will be provided to the subject and study 
partner. 
Because of the complexity of this study design, informed consent may occur in two steps when 
more than one drug is recruiting simultaneously. 
 
 
 
 
 
 
 
 
 
 
 
For subjects enrolling into a treatment period, a main ICF may be used.  The main ICF will 
include a description of the overall study including an overview of possible side effects of the 
study drugs and differences between study procedures for the different study drug arms.  
Subjects signing the main ICF agree to screening and randomization and indicate their intention 
to enter the study.  After randomization, a supplemental study drug arm-specific ICF document 
may be reviewed with and signed by the subject (and/or caregiver/legally acceptable 
representative if the subject is cognitively impaired).  This supplemental ICF will contain 
additional details about the procedures, risks and benefits of the specific study drug arm.  
Subjects and their caregivers will have the opportunity to review the main and all supplemental 
ICFs before they sign the main study informed consent.  This two-step approach is needed to 
keep the ICF concise as subjects will only be assigned to one study drug arm, and also keeps 
confidential drug information in separate documents.  In cases where only one drug is enrolling, 
one informed consent may be used in a more traditional fashion. 
The ICFs must be written in a language fully understood by the prospective subject, study 
partner, and caregiver/legally acceptable representative (if the subject is cognitively impaired).  
The investigator or designee shall give the subject adequate opportunity to read the ICF before 

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it is signed and dated.  Information will be given in both oral and written form, whenever 
possible, and in the manner deemed appropriate by the IRB/IEC.  Subjects must also be given 
ample opportunity to inquire about details of the study. 
Study drug arms that demonstrate potential clinical benefit may have an open-label extension 
period.  Eligibility criteria must be met and a new written informed consent form will be 
obtained from the subject, study partner (if applicable) and/or by the subject’s legally 
acceptable representative accordingly. 
The opportunity to donate post-mortem brain tissue will be discussed.  Interested subjects will 
be provided additional details and a brain donation informed consent will be signed.  The DIAN-
TU-Neuropathology Core (DIAN-TU-NPC) will conduct a neuropathologic assessment of each 
subject recruited to the DIAN-TU who consents to a brain donation and comes to autopsy.  Each 
participating DIAN-TU center will coordinate with the DIAN-TU-NPC to ensure that a brain 
donation is successful and that tissue will be preserved (freezing one half of the brain and fixing 
the other hemisphere in formalin) and subsequently transported to the DIAN-TU-NPC.  To 
ensure standardized methods and uniform assessment of tissue across DIAN-TU sites, the DIAN-
TU sites and NPC will undertake a neuropathologic assessment as described in the DIAN-TU-
NPC manual. 
6.1.2 Family History/Age at Onset Assessment/Demographics/Study Partner Information 
Family history, specifics of family mutation and age at onset assessment as well as demographic 
and study partner information will be collected during the 
 
treatment screening period (V1) and confirmed at the 
 baseline visit (V2).  See the 
Global Manual of Operations for details of the age at onset assessment and the required 
family/pedigree genetic mutation documentation. 
6.1.3 Medical/Treatment History, Concomitant Medications, Adverse Event Assessment 
At all visits, the subject’s clinically significant medical history and names and dosages of all 
medications will be reviewed.  Medications taken within 90 days of any screening visit (
 
V1) will be obtained at the respective visit (
V1) and reviewed at all 
subsequent visits.  Prior medications taken for dementia and any interval changes in 
medications including over-the-counter medications should be reviewed at every visit.  Use of 
alcohol, caffeine, and abused substances will be reviewed.  Interval history and presence and 
severity of any adverse events will be documented at follow-up visits. 
6.1.4 Clinical Assessment 
The clinical assessment is performed by interviewing the study partner and subject at 
 
baseline (V2), and annual visits for 
the 
 treatment period;
 
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Audio recordings of some assessments will be made for quality control; see Global Manual of 
Operations for details.  The following test instruments will be administered: 
a. Clinical Dementia Rating (CDR) and calculation of CDR-SB.  CDR-SB includes 
supplemental boxes for language and behavior. 
b. Assessment of clinical diagnosis (Clinician judgment of symptoms) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other assessments (e.g., MMSE, FAS, GDS, NPI-Q) or in 
cognitive testing. 
c. Geriatric Depression Scale (GDS) 
d. Functional Assessment Scale (FAS) 
e. Neuropsychiatric Inventory Questionnaire (NPI-Q) 
f. Mini-Mental State Examination (MMSE) 
See the Global Manual of Operations for details of administration.  All staff administering 
these batteries must be appropriately trained and certified as specified in the Global Manual 
of Operations for the trial. 
6.1.5 Physical and Neurological Examination 
Physical examination will include skin, head, eyes, ears, nose and throat, respiratory, 
cardiovascular, abdomen, lymph nodes and musculoskeletal. 
A complete neurological examination will also be completed.  At visits after 
 
baseline, any clinically significant changes will be documented and reported. 
6.1.6 Vital Signs 
 
 
During the treatment period, blood pressure, heart rate, respiratory rate and temperature will 
be collected at all visits.  Height will be measured at baseline and at annual visits only and 
weight will be measured approximately every 3 months starting at baseline.  Weight may be 
obtained at a medical facility where subjects receive safety MRIs or at the subjects’ home. 
6.1.7 Electrocardiogram 
A standard 12-lead ECG or a triplicate ECG will be performed at the indicated visits based on the 
 study drug arm requirements.  Refer to each drug-specific appendix for more 
details. 
 

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For the treatment periods, a central read vendor will be utilized.  The site principal investigator 
or designated sub-investigator will be responsible for initial read on ECGs done at baseline (V2).  
In the event that the central read becomes available after study drug is administered and is 
exclusionary when the local read was not, the site principal investigator or designated sub-
investigator, in consultation with the Medical Monitor or Medical Director, will decide if the 
subject should continue in the study.  A discrepancy between the local and central read will not 
be considered a protocol deviation.  When there are differences in ECG interpretation between 
the investigator and the cardiologist at the central ECG laboratory, the investigator’s 
interpretation will be used for study entry and immediate subject management. 
Interpretations from the cardiologist at the central ECG laboratory will be used for data analysis 
and report writing purposes.  ECGs done at visits conducted at sites other than the DIAN-TU site 
may be done at a sponsor approved local site or by a home health nurse.  These will be sent to 
the central reader and will also be available to the host DIAN-TU site. 
6.1.8 C-SSRS 
The Columbia Suicide Severity Rating Scale (C-SSRS) will be administered at screening (V1), 
baseline (V2) and approximately every 3 months thereafter for the first 2 years (until V28 
[week 104]) during the treatment period.  The C-SSRS will be administered approximately every 
6 months for years 3 and 4, and then annually for the remaining duration of the study.   
 
6.1.9 Genetic Testing  
Determination of mutation status for DIAD causing variants (APP, PSEN1, PSEN2) and APOE 
genotype will be performed in the trial-designated CLIA-approved laboratory at 
 
screening (V1).  The results from the CLIA-approved laboratory will be used for purposes of 
the DIAN-TU-001 study (e.g., for randomization) but will not be communicated to the subjects 
or sites.  Subjects who wish to learn their DIAD mutation status would be referred for genetic 
counseling and testing. 
Blood samples for provenance3F6 testing will be obtained at the 
 baseline visit.  
 
For an open-label extension (OLE) period, if the subject does not know their genetic status and 
is interested in joining the OLE, the clinical genetic report generated from the study’s genetic 
testing at trial entry can be provided to the appropriate party managing the genetic counseling 
and disclosure for the subject, i.e., the PI or genetic counselor. 
                                                     
6 Provenance testing is performed for quality assurance purposes to ensure that genetic blood sample obtained at 
baseline visit is from the same individual as the sample obtained at the screening visit.   

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6.1.10 Clinical Laboratory Tests 
Clinical laboratory testing includes hematology with differential, chemistry (including liver 
enzyme tests and electrolytes), and urinalysis (macro and micro).  In addition, TSH, B12 levels, 
hemoglobin A1c, PT, PTT, and INR are obtained only at the 
 screening visit (V1).  
Refer to the central laboratory manual for a complete list of analytes to be tested. 
Clinical laboratory samples will be obtained and sent to a central laboratory for analysis. 
 
 
 Laboratory values obtained at screening (V1) must be reviewed prior to 
completion of baseline (V2) biomarker measures (PET imaging, vMRI, LP-CSF).  The site principal 
investigator or designated sub-investigator must review all laboratory results and document 
any clinically meaningful abnormal results as an AE; see section 7.1.1 for criteria to determine if 
an abnormal result is clinically meaningful.  If results from the central laboratory for coagulation 
studies are unavailable at the baseline visit, results from a local laboratory may be used to 
confirm that a subject is able to continue with baseline visit procedures, including 
randomization and study drug dosing.  Central lab samples should be sent and used for study 
reporting purposes.  Any clinically meaningful abnormal result that occurs during the course of 
the study (after screening) should be repeated within an appropriate time frame (as 
determined by the site principal investigator or designated sub-investigator and/or Medical 
Director or designee). 
Refer to section 7 (Safety and Adverse Events) for further details regarding adverse events. 
Pregnancy testing – women of childbearing potential only 
 
uring the treatment period, serum pregnancy testing will be 
performed at screening (V1), V54, and V93 and urine pregnancy testing will be performed at all 
other visits.  Pregnancy tests must be confirmed as negative prior to dosing with study drug.  
Urine pregnancy test must be completed and confirmed as negative either the day of or the day 
prior to any PET scan. 
NOTE:  Women who have undergone tubal ligation are required to have pregnancy testing 
performed as scheduled at all treatment visits.  In cases where urine collection proves difficult 
based on a subject’s symptom progression, e.g., incontinence, alternative methods for 
pregnancy testing may be used with prior sponsor approval. 
6.1.11 Drug-specific Testing 
There will be specific laboratory tests for each study compound (e.g., drug levels for 
pharmacokinetics [PK], immunological monitoring for immunotherapy including anti-drug 
antibodies [ADA]).  Frequency and specific visit requirements will be specified in each drug-
specific appendix.  Refer to the central laboratory manual and the Global Manual of Operations 
for additional details on specific sample collection and processing procedures. 

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6.1.12 Stored Samples (Plasma and/or Serum and DNA) – Treatment Period Only 
Selected samples (e.g., plasma and/or serum and DNA), will be collected and stored for future 
use so that testing for as yet undiscovered biomarkers can be performed (including, but not 
limited to, protein biomarker identification, single-gene or genome-wide analyses, epigenetics).  
Stored samples may also be used to address regulatory inquiries or for additional monitoring of 
anti-drug antibodies or other drug-specific analyses. 
Type of samples to be collected, frequency, and specific visit requirements are specified in the 
drug-specific schedule of visits.  Refer to the central laboratory manual for additional details on 
specific sample collection and processing procedures. 
The biomarkers chosen as endpoints for this study were based on currently available data, but 
new biomarkers are likely to emerge in the coming years.  These samples will be used for future 
studies on the mechanism of action of Alzheimer’s treatments and other studies related to 
neurodegenerative disorders under the supervision of Washington University and the DIAN-TU.  
These samples will be stored using the subject identification number; samples will be stored 
indefinitely unless otherwise specified.  Collection and storage of these samples is mandatory 
unless prohibited by local laws. 
6.1.13 Study Drug Administration 
For study drugs with parenteral administration (IV or SC), the first dose of study drug will be 
given at the host DIAN-TU site.  For subjects who live at a distance from the host DIAN-TU site, 
subsequent doses may be administered by the trial-designated home health nurses or at other 
trial-identified locations.  Study staff who administer study drugs should have training and 
supplies necessary to treat allergic reactions including anaphylaxis.   
Details of study drug administration or dispensing should be recorded; see Global Manual of 
Operations for details. 
Requirements for monitoring subjects after study drug administration are detailed in each drug-
specific appendix. 
For the study drug administration visits following the occurrence of a safety MRI, the site 
principal investigator or designated sub-investigator must review the MRI central read prior to 
proceeding with the subsequent dose administration for parenterally administered treatments. 
6.1.14 Cognitive Testing 
The Complete Cognitive Battery will be performed annually at the host DIAN-TU site.  The 
cognitive testing should be performed early in the day before other invasive or stressful 
procedures.  See DIAN Trials Unit Cognition Core Procedures Manual for additional details and 
suggested timing for administration of cognitive testing. 
A subset of the testing battery (the Cognitive Battery Subset) will be performed approximately 
every 6 months.  See DIAN Trials Unit Cognition Core Procedures Manual for details of 

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administration.  All staff administering these batteries must be appropriately trained and 
certified as specified in the DIAN Trials Unit Cognition Core Procedures Manual.  The following 
tests will not be administered at any visit to subjects who are a CDR of 1 at their 
 
baseline (V2) visit: Groton Maze Learning Test, Behavioral Pattern Separation Object Task, and 
MAC-Q. 
Additional cognitive assessments between annual visits may be added to the schedule of visits 
based on the study drug arm (see each drug-specific appendix). 
  
 
 
 
 
 
 
 
 
 
In all study drug arms: The iPad administered cognitive tests listed below will be administered 
by a trial-certified cognitive rater at the 
 
screening visit (V1) to familiarize subjects with the test procedures.
 
 
 
iPad Administered Cognitive Testing:  
• International Shopping List Test (12-Item Word List Learning): 3 learning trials, 
Immediate Recall, 30-min Delayed Recall (Cogstate) 
• Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-
min Delayed/Reversed Recall (Cogstate) 
 
  
 
 
 
 
 
 
 
 
 

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Complete Cognitive Battery (annual visits) 
Cognitive measures to be obtained at the 
 
 
baseline visit (V2) and at treatment weeks 52 (V15), 104 (V28), 156 (V41), 208 (V54), 260 (V67), 
312 (V80), and 364 (V93) include iPad administered and conventional psychometric (pen/paper) 
tests listed below. 
 
 
iPad Administered Cognitive Testing:  
• International Shopping List Test (12-Item Word List Learning): 3 learning trials, 
Immediate Recall, 30-min Delayed Recall (Cogstate) 
• Groton Maze Learning Test*: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-
min Delayed/Reversed Recall (Cogstate) 
 
 
 
 
 
 
 
 
 
 
 
 
Conventional Psychometric Testing (Pen/Paper):  
• Trailmaking Test parts A & B 
• WMS-R Digit Span 
• WAIS-R Digit-Symbol Substitution Test 
• Raven’s Progressive Matrices (Set A) 
• Category Fluency (Animals & Vegetables) 
• WMS-R Logical Memory (Immediate & Delayed Recall) 
*These tests should not be administered at any visit to subjects who are a CDR of 1 at their 
 baseline (V2) visit. 
 
  
 
 
Cognitive Battery Subset (every six [6] months when not annual): 
A subset of the complete cognitive battery will be administered at 
 
 treatment weeks 24 (V8), 76 (V21), 128 (V34), 180 (V47), 232 (V60), 284 (V73), 
and 336 (V86) and include the iPad administered and conventional psychometric (pen/paper) 
testing listed below. 

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iPad Administered Cognitive Testing:  
• International Shopping List Test (12-Item Word List Learning): 3 learning trials, 
Immediate Recall, 30-min Delayed Recall (Cogstate) 
• Groton Maze Learning Test: Timed Chase Task, 5 learning Trials, Immediate Recall, 30-
min Delayed/Reversed Recall (Cogstate)* 
 
  
 
 
 
 
 
Conventional Psychometric Testing (Pen/Paper):  
• Trailmaking Test parts A & B 
• WMS-R Digit Span 
• WAIS-R Digit-Symbol Substitution Test 
• WMS-R Logical Memory (Immediate & Delayed Recall) 
 
 
 
*These tests should not be administered at any visit to subjects who are a CDR of 1 at their 
 baseline (V2) visit. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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6.1.15 Baseline and Annual Magnetic Resonance Imaging (MRI)  
For all drug arms, MRIs performed at the host DIAN-TU site at annual visits including 
 
baseline [V2], and the week 52 [V15], 104 [V28], 156 [V41], 208 [V54], 260 [V67], 312 [V80], 
and 364 [V93] visits, will include structural and functional MRI and other additional MRI 
endpoints in addition to sequences for safety monitoring.  All MRIs, including safety MRI scans 
performed off site, if applicable (see section 6.1.16 below), will utilize standardized sequences 
that include fluid-attenuation inversion recovery (FLAIR) and T2*-weighted gradient-recalled-
echo (GRE) sequences.  Additional scheduled safety MRI assessments between annual visits 
may be scheduled based on study drug arm (see each drug-specific appendix). 
MRIs use a standardized protocol specified by the DIAN-TU Imaging Core (see MRI Technical 
Manual for specific sequences).  The DIAN-SHORT protocol, a core set of MR sequences 
necessary for safety MR and PET processing, will be used for off-site MRIs and may be used at 
the host site for those whom, in the estimation of the site principal investigator, would not be 
able to complete the full-length protocol (e.g., subjects who are unable to remain still for the 
full MR session, approximately 45 minutes in duration).  MRI should be performed before 
lumbar puncture (if on the same day) or scheduled to be on a different day than the lumbar 
puncture. 
Scanners will be evaluated and qualified by the Mayo-ADIR Clinic prior to subject scanning, and 
ongoing quality control of the MRI scans will be performed at the Mayo-ADIR Clinic. 
MRIs will be uploaded to the trial-designated imaging data management system (DIAN Central 
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Images should be uploaded within 24-48 hours of scan completion; failure to upload the images 
within 3 working days of receipt of the images will be considered a protocol deviation.  Images 
from the 
 baseline MRI (V2), and all annual visit MRIs should be 
uploaded immediately after these scans are completed as the findings of these MRIs can 
impact inclusion in the study (
 baseline [V2] MRI) and thereafter alter 
dispensing/administration of next dose(s) of study drug. 
Volumetric analysis of the baseline and the annual MRIs will be performed by Washington 
University and will include measures of hippocampal volume, ventricular volume and whole 
brain volume.  Site investigators will not receive results of the volumetric analysis.  All MRI 
scans will be analyzed for amyloid-related imaging abnormalities (ARIA) and for incidental 
findings at the Mayo-ADIR Clinic; this includes safety MRIs (see section 6.1.16 below).  Findings 
on the baseline MRI will determine eligibility; therefore, results of the baseline read will be 
made available before randomization and first dispensing/administering of study drug.  ARIA 
findings during the study may result in a change or halting of study drug dosing; see each drug-
specific appendix for additional information.  See Global Manual of Operations for additional 
details and MRI Technical Manual for technical information. 
 
6.1.16 Safety Magnetic Resonance Imaging (MRI) 
Safety MRIs on 3T scanners will be done primarily to monitor for ARIA.  Safety MRIs may be 
done at the host DIAN-TU site or, for subjects who live at a distance from the host DIAN-TU site, 
at a site closer to the subject’s home in order to reduce subject travel burden.  When not 
performed at the DIAN-TU site, safety MRIs may be performed at an ADNI/ADCS site if possible 
or at a 3T scanner near the subject’s home.  Local centers not previously qualified as a DIAN, 
ADCS or ADNI-equivalent site will be pre-qualified for the DIAN-TU trial protocol by the 
Mayo-ADIR Clinic.  With the exception of the MRIs done at the DIAN-TU site during annual 
visits, safety MRIs should be performed on the same scanner throughout the trial. 
Standardized sequences will be used for these scans and will include fluid-attenuation inversion 
recovery (FLAIR) and T2*-weighted gradient-recalled-echo (GRE) sequences.  See MRI Technical 
Manual for additional information.  Satellite sites will ship MRI images on CD to the host DIAN-
TU site, preferably within 24-48 hours and at the most within 3 working days.  The host DIAN-
TU site should upload the images to the imaging data management system (DCA) within 2 
working days of receipt.  Satellite sites may directly upload images to the DCA only by prior 
agreement with Washington University.  Sites must ensure that study visits are scheduled so 
that MRI images are uploaded and available for central read at least 10 working days before 
next administration of study drug for parenterally administered drugs. 
A central read for safety purposes (e.g., analysis of ARIA) will be completed at the Mayo-ADIR 
Clinic within 1 week (5 working days) of upload for routine exams, for the gantenerumab and 
solanezumab arms; and within 24 hours for the MRIs done for all drug arms at 
 

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, baseline (V2), and the 
week 52 (V15), 104 (V28), 156 (V41), 208 (V54), 260 (V67), 312 (V80), and 364 (V93) visits. 
 
   
The central read results will be communicated to site principal investigators (site PIs) or 
designated sub-investigator, Project Arm Leader (PAL), and Medical Director or designee.  This 
communication will occur at least one week before the next scheduled drug 
dispensing/administration.  Extent of ARIA-E and presence of definite and possible ARIA-H 
changes will be reported; reports including significant or new definite findings will be flagged 
for review by site principal investigator or designated sub-investigator, PAL, and sponsor 
Medical Director or designee.  The site principal investigator or designated sub-investigator will 
review the findings and drug-specific guidelines for dosing adjustment (see each drug-specific 
appendix) with the PAL.  The PAL will confer with the Medical Director or designee who has 
final authority on dose adjustment decisions (e.g., extra study visit, repeat or more frequent 
safety MRIs, suspension of study drug administration or dose adjustment; see each drug-
specific appendix for discussion of ARIA-related interventions).  The Medical Director has the 
final decision on whether a dose is released for treatment.  See Global Manual of Operations 
for further details on communication between the site principal investigator or designated sub-
investigator, PAL, and Medical Director or designee.  See MRI Technical Manual for technical 
information. 
When an imaging visit precedes a visit where study drug is parenterally administered, it is the 
responsibility of the DIAN-TU site principal investigator or designated sub-investigator to review 
the central read safety MRI results before study drug administration and communicate any 
changes in study drug administration to the site staff or home health nurse preparing and 
administering the study drug. 
Local read for safety MRIs is not required for purposes of this study but should be performed if 
needed in accordance with local requirements.  Should a local read be obtained and be 
different from the central read, central read has priority for study purposes. 
6.1.17 Lumbar Puncture (LP) – Cerebrospinal Fluid (CSF) 
Cerebrospinal fluid (CSF) analysis for biomarkers will be performed at baseline (V2) and at week 
52 (V15), 104 (V28) and 208 (V54) visits.  CSF will be obtained by lumbar puncture (LP) 
performed at the host DIAN-TU site. 
 
 
 

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A sample of CSF will be sent to a local lab for cell counts and differential as well as glucose and 
protein measurement; each site should confirm with their local lab the volume of CSF needed 
for these studies.  CSF biomarkers are the biomarker endpoint for some of the study drug arms.  
At least 15-20 mL CSF should be sent for biomarker analysis; this is in addition to the CSF 
obtained for the local lab studies.  If less than 15 mL is collected for biomarker analysis at the 
baseline visit, contact the sponsor prior to dispensing/administration of study drug to 
determine if subject is eligible to remain in the trial.  See central laboratory manual and the 
Global Manual of Operations for additional details regarding LP and collection, processing and 
shipping of CSF samples. 
The LP should be performed in the morning, at approximately 8 am local time, under fasting 
conditions (water is allowed and encouraged).  LPs should be conducted as close to the 
baseline collection time as possible at each subsequent visit.  CSF should be collected using the 
traditional gravity drip method.  Sites should obtain approval from the sponsor, before LP is 
performed, for the use of alternative methods or needles (e.g., aspiration if using a very small 
gauge needle, use of a needle type/size other than the sponsor mandated needle outlined in 
the Global Manual of Operations and provided to the sites for use).  If LP proves technically 
difficult, early referral for LP under fluoroscopy is expected. 
6.1.18 Positron Emission Tomography  
 
 
For all study drug arms, PET imaging with selected tracers will be performed at baseline (V2), at 
the week 52 (V15), 104 (V28), and 208 (V54) visits of the double-blind period, and potentially at 
baseline and annually during the open-label extension contingent on results of the double-blind 
period. 
 
 
 
 
The type of PET imaging is drug-specific (see each drug-specific appendix) any may include one 
or more of the following: 

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Pittsburgh Compound B ([11C]PiB-PET) PET Imaging – Gantenerumab and Solanezumab Arms 
Only 
[11C]PiB-PET imaging will be performed at the host DIAN-TU site at baseline (V2) and at the 
weeks 52 (V15), 104 (V28), and 208 (V54) visits of the double-blind period, 
 
 
 
 
[11C]PiB-PET imaging may be performed at other trial-qualified sites if the host DIAN-TU site is 
unable to perform PET imaging.  For each subject, the same scanner should be used for all 
[11C]PiB-PET imaging sessions.  See PET Technical Procedures Manual for additional details.  
[11C]PiB-PET manufacturing and imaging protocols will be standardized across all participating 
sites.  Certus International will audit and qualify [11C]PiB manufacturing and conduct ongoing 
QC of PiB batch records.  The University of Michigan will provide quality control on [11C]PiB-PET 
images.  Images will be uploaded the imaging data management system, DCA.  Image 
processing and analyses will be performed by Washington University. 
For women of childbearing potential, a urine pregnancy test must be completed and confirmed 
as negative before the first PET scan.  If PET scans are spread over more than one day, a urine 
pregnancy test should be completed either the day of or day prior to any PET scan. 
Scan Acquisition: Subject preparation consists of intravenous catheterization followed by the 
bolus injection (over 10-60 sec) of [11C]PiB at dosage: 8-18 mCi.  There are two acceptable 
procedures for obtaining the [11C]PiB-PET scans.  In one approach, a 30-minute scan will be 
started 40 minutes post-[11C]PiB-PET injection.  The other approach involves a 70-minute 
dynamic scan that is started at the time of PiB injection.  Further details of the PiB-PET scan 
acquisition are outlined in the PET Technical Procedures Manual. 
Subjects should be scanned on the same scanner at weeks 52 (V15), 104 (V28), and 208 (V54) 
visits as was utilized at the baseline visit, unless the subject changes DIAN-TU sites.  In the event 
an issue arises where a scanner becomes unavailable, a site may get sponsor approval to be 
scanned on another DIAN-TU approved scanner if there is one available to them and it is 
allowable per IRB/IEC guidelines. 
Florbetapir PET Imaging – Gantenerumab and Solanezumab Arms Only 
For the gantenerumab and solanezumab arms only, PET imaging with florbetapir F18 (an [18F] 
amyloid imaging agent, Avid Radiopharmaceuticals, Inc.) will be performed at baseline, week 
104 (V28), and week 208 (V54) visits at the host DIAN-TU site.  Florbetapir PET imaging may be 
performed at other trial-qualified sites if the host site is unable to perform PET imaging.   
For each subject, the same scanner should be used for all florbetapir-PET imaging sessions.  For 
US sites, Avid Radiopharmaceuticals, Inc. will provide florbetapir 18F and will provide 

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certification of imaging centers for performance of florbetapir 18F imaging.  Images will be 
uploaded to the imaging data management system, DCA.  Image analyses will be performed by 
Washington University.   For global sites, florbetapir 18F amyloid imaging will be performed in 
compliance with local regulations.  Florbetapir 18F imaging may be optional for some global 
sites based on its availability at the discretion of the sponsor. 
For women of childbearing potential, a urine pregnancy test must be completed and confirmed 
as negative before the first PET scan.  If PET scans are spread over more than one day, a urine 
pregnancy test should be completed either the day of or one day prior to any PET scan. 
Scan Acquisition: See PET Technical Procedures Manual for additional details.  Subject 
preparation consists of intravenous catheterization followed by the bolus injection (over 
10-60 sec) of 10 mCi of florbetapir 18F.  Doses administered that are within 10% of the protocol-
required dose per standard clinical practice will not be considered a protocol deviation.  There 
are two acceptable procedures for obtaining the florbetapir 18F PET scans.  In one approach, 
approximately 40 minutes after injection, the subject will be positioned in the scanner to 
undergo a scan lasting 20 minutes.  The scan will start 50 minutes after injection (note the 
temporal difference from PiB-PET).  In the second approach, the subject will be positioned in 
the scanner at the time of injection and a 70-minute scan will be obtained starting at the time 
of injection. 
Fluorodeoxyglucose PET (FDG-PET) – Gantenerumab and Solanezumab Arms Only 
For the gantenerumab and solanezumab arms only, uptake of 2-[18F]fluoro-2-deoxy-D-glucose 
(FDG-PET) will be performed for subjects enrolled in selected study drug arms at baseline (V2) 
and at the weeks 52 (V15), 104 (V28), and 208 (V54) visits of the double-blind period, 
 
  
 
 
FDG-PET will be done at the host DIAN-TU sites using DIAN-TU protocol as specified in the PET 
Technical Procedures Manual.  FDG-PET imaging may be performed at other trial-qualified sites.  
For each subject, the same scanner should be used for all FDG-PET imaging sessions.  Subjects 
should be fasting for 4 hours before the FDG-PET is performed.  The University of Michigan will 
provide quality control on FDG-PET images.  Images will be uploaded to the imaging data 
management system, DCA.  Image analyses will be performed by Washington University. 
For women of childbearing potential, a urine pregnancy test must be completed and confirmed 
as negative before any PET scan.  If PET scans are spread over more than one day, a urine 
pregnancy test should be completed either the day of or day prior to any PET scan. 

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Scan Acquisition:  Typically, the PiB-PET scans will precede the FDG scans on the same day; 
however, this arrangement is for convenience to the subject and coordinators but is not a 
requirement (see Global Manual of Operations for schema).  After completion of PiB-PET 
scanning, subjects will be moved to a dimly lit, quiet room and 5 mCi of FDG will be injected as 
a bolus.  Doses administered that are within 10% of the protocol-required dose per standard 
clinical practice will not be considered a protocol deviation.  About 20 minutes later, subjects 
will be repositioned in the PET scanner, and FDG PET scans will be acquired in dynamic, 3D 
mode beginning 30 min (+/- 30 seconds) after injection of FDG for 30 min (consisting of 6 x 5 
min frames).  Details of the PET scan acquisitions are outlined in the PET Technical Procedures 
Manual. 
Tau PET Imaging  
The DIAN-TU-001 trial provides a critical opportunity to investigate the potential for tau 
imaging to enhance basic understanding of the evolution of tau pathology during the 
Alzheimer’s disease process, to understand the relationship between tau imaging and tau 
measurements in CSF and may support a role for tau imaging as a new surrogate biomarker. 
 
For all study drug arms, tau scans will be performed at the host DIAN-TU site at baseline (V2), 
and week 52 (V15), 104 (V28), and 208 (V54) visits.  Refer to the below individual tracer details, 
drug-specific appendices, and any active protocol addenda for the individual tracer to be used 
and schedule to be followed. 
 
 
 
[18F]AV-1451 PET – Gantenerumab and Solanezumab Arms Only 
The gantenerumab and solanezumab arms utilize the [18F]AV-1451 tracer (Avid 
Radiopharmaceuticals, Inc.).  Since not all sites have access to [18F]AV-1451 necessary to 
perform the tau PET scan, this measure is included as an addendum for the double-blind period 
rather than as part of the main study protocol. 
Avid Radiopharmaceuticals, Inc. will provide [18F]AV-1451 and will provide certification of 
imaging centers for performance of [18F]AV-1451 imaging.  Images will be uploaded to the 
imaging data management system, DCA.  Image analyses will be performed by Washington 
University.  Specific imaging acquisition protocols designed to ensure consistency across sites 
will be provided in a technical manual.  The scanning technologist will be blinded to the 

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subject’s treatment assignment (e.g., whether subject is on active or placebo treatment in the 
DIAN-TU-001 study). 
Women of childbearing potential are to have a confirmed negative pregnancy test (HCG) on the 
day of [18F]AV-1451 PET imaging session, before [18F]AV-1451 dose administration. If PET scans 
are spread over more than one day, a pregnancy test should be completed either the day of or 
one day prior to any PET scan. 
Scan Acquisition: See PET Technical Procedures Manual for additional details. PET/CT is the 
preferred imaging modality for [18F]AV-1451 imaging.  In the event an issue arises where a 
scanner becomes unavailable, a site may get sponsor approval to be scanned on another DIAN-
TU approved scanner if there is one available to them and it is allowable per IRB/IEC guidelines.  
There are two acceptable procedures for obtaining the [18F]AV-1451 PET scans: 
1. The preferred option will be for subjects to receive a single IV bolus injection of 
approximately (240 MBq) 6.5 mCi of [18F]AV-1451 injection followed by a saline flush.  
Scanning will start at the same time as the injection and continue for a total of 105 
minutes.  If needed, the subject may take up to a 15-minute break after the first 60 
minutes of scanning, and scanning should resume immediately after the break. 
2. For subjects that are not able to tolerate or who do not wish to undergo the full-length 
scan, a continuous 30-minute brain scan (6 acquisitions of 5-minute duration) should be 
performed with scanning to start approximately 75 minutes following injection. 
3. DOSE PREPARATION: To allow for a convenient injection volume of greater than 1 mL, 
[18F]AV-1451 may be diluted aseptically with sodium chloride 9 mg/mL (0.9%) solution 
for injection to a maximum dilution of 1:5 by the end-user.  Diluted product should be 
used within 3 hours of dilution. 
The injection site will be observed for evidence of inflammation or damage to the surrounding 
tissue where the dose was injected and the subject will be requested to void after completion 
of the PET scans.  Subjects will be observed continuously for signs of adverse events (AE) or 
serious adverse events (SAE). 
 
 
 
 
 
 
Information on the tau PET tracer and additional details regarding tau PET scanning, including 
pre- and post-imaging procedures, will be included in the PET Technical Procedures Manual.   

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7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Figure 3 below provides a general visual representation of the DIAN-TU-001 study visit flow.  
Note that the figure does not contain all assessments to be performed during the study but is 
intended to present an overview of the study chronology.  Figure 3 shows the visit flow for 
subjects who live at a distance from a DIAN-TU site and have many study visits performed at 
home.  These visits can be performed at the host DIAN-TU site for subjects who live nearby or, 
for subjects who live at a distance from the host DIAN-TU site, in the subject’s home or another 
trial-identified location more convenient for the subject.  Visits performed in the home or other 
sites will be performed by a GCP trained home health nurse who has been trained in DIAN-TU 
procedures. 

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Figure 3 
Overview of Subject Visit Flow 
 
 Study Visits 
The schedule of visits for 
the secondary 
prevention treatment period screening and baseline visits, Appendix 2.  The schedule of visits, 
including drug-specific tests and frequency of safety MRIs, for each drug arm is provided in each 
drug-specific appendix (Appendices 3 and 4).  All information on timing of visits refers to 
calendar days.  The sequence and timing of visit procedures is very important.  Detailed 
requirements and suggested timing of events are detailed in the Global Manual of Operations.  
 
  The specific date during the 
baseline visit (V2) when the first dose of study drug is administered should be used to 
determine timing of subsequent visits during the treatment period and for calculating time 
between the screening and baseline visits. 

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6.3.2 Screening (Visit 1)  
The screening period that immediately precedes enrollment into a study drug arm may last up 
to 8 weeks, starting at the collection of the first screening procedure (e.g., clinical laboratory, 
cognitive testing). 
 
 
 
 
 
Location: Visit 1 procedures may be accomplished at the DIAN-TU site or at the subject’s home 
or other trial-identified location with the trial-designated home health nurse.  This visit also 
includes telephone calls with the DIAN-TU site staff.  The subject may be contacted by their 
host DIAN-TU site by telephone or during a regular DIAN Observational study visit.  The subject 
is given the opportunity to review the informed consent form(s), ask question and obtain 
answers, and sign the main ICF (if multiple drug arms are enrolling) or the stand-alone ICF. 
Time/Timing:  Informed consent must be obtained before any other study procedures.  
Informed consent, family history, demographic information and medical and treatment history 
may be obtained before the 8-week screening period begins.  Informed consent should be 
obtained from both subject and study partner.  Unless otherwise specified, all other Visit 1 
procedures may occur throughout the screening period (2-8 weeks before baseline [V2]).  
IMPORTANT: Results from screening clinical laboratory tests and genetic testing must be 
available before baseline (V2); blood draw for genetic testing must be completed at least 6 
weeks before V2 to ensure genetic results are available for baseline randomization.  
 
  The screening visit in the home ensures 
subject eligibility before travel (if applicable) to the DIAN-TU site for baseline testing and 
randomization. 
Procedures (all can be performed by DIAN-TU site staff or trial-designated and trained home 
health nurse or other staff except as noted-see Global Manual of Operations and DIAN Trials 

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Unit Cognition Core Procedures Manual for additional details on order and timing of 
procedures): 
• Obtain informed consent (DIAN-TU site staff should be available to answer questions) 
• Obtain or confirm family history and determine parental estimated age at onset or 
subject’s actual age at onset (DIAN-TU site staff),
.  
Estimated age at onset should be determined as outlined in the Global Manual of 
Operations. 
• Verify documentation of subject’s trial eligible mutation status OR confirm via family 
pedigree and mutation documentation (proband) that the subject is at 50% risk for a 
trial-eligible mutation,
 
• Collect demographic information and study partner information, 
 
 
• Obtain medical and treatment history, including assessment/recording of pre-existing 
conditions or adverse events; 
 
. 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature).  Weight is 
not required at this visit but the subject’s self-reported weight may be noted if required 
for laboratory tests. 
• Blood draw: 
o genetic testing (NOTE: genetic testing blood sample must be obtained at least 
6 weeks prior to Visit 2 to ensure availability for baseline randomization; 
 
.) 
o clinical laboratory tests, including TSH, B12, hemoglobin A1c, PT, PTT, and INR 
o serum pregnancy test for women of childbearing potential 
• Urine collection for urinalysis 
• Administration of C-SSRS 
• Cognitive testing (Screening Cognitive Battery), 
  
See section 6.1.14 
• 
 
 
A study-specific subject identification number is assigned to the subject by the interactive web 
response system (IWRS), 
 
.  Visit 2 is not scheduled to occur until the results of the clinical 
laboratory tests are available and the results of genetic testing are entered in IWRS.  
 
  Results of genotyping of APOE and DIAD-
associated genes (APP, PSEN1, and PSEN2) are not sent to the site to ensure genetic blinding is 
maintained during double-blind treatment periods, however may be provided for OLE 
qualification as specified in section 6.1.9. 

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6.3.3 Baseline (Visit 2/First Dose) 
Location: Host DIAN-TU site. 
Time/Timing:  Approximately a 3-4 day visit that is scheduled 2-8 weeks after the screening visit 
and at least 6 weeks after the genetic sample draw, 
 
.  This visit can only take place after results from safety screening labs are 
documented as consistent with inclusion/exclusion criteria before Visit 2 occurs.  Genotyping 
results will need to be confirmed as received and having completed analysis but no results will 
be provided or reviewed by site staff.  The study partner participates in some of the procedures 
at Visit 2 and other annual visits at the DIAN-TU site.  If possible, the study partner should 
accompany the subject to the DIAN-TU site for these visits.  If this is not possible, the study 
partner procedures can be completed via telephone.  The sequence and timing of visit 
procedures is very important.  Detailed requirements and suggested timing of events at Visit 2 
and at subsequent annual visits (V15, V28, V41, V54, V67, V80, and V93) are detailed in the 
Global Manual of Operations.  Baseline visit procedures may be scheduled over a longer time 
period of up to 2 weeks for subjects who live near the study site or in the event that some study 
procedures (e.g., PET imaging) are done at a different DIAN-TU site. 
Notes: Although participating in the DIAN-TU study does not require that subjects know 
whether they have a mutation associated with dominantly inherited Alzheimer’s disease, it will 
be recommended that all subjects undergo genetic counseling prior to starting assigned study 
drug.  Subjects in the study might guess (correctly or incorrectly) whether they are on active 
drug because specific side-effects may occur more often with the active drug compared to the 
placebo therapy, therefore disclosing mutation status. 
The date during Visit 2 when the first dose of study drug is dosed/administered should be used 
for determining the timing of all subsequent visits. 
Procedures: 
• In-person review of informed consent for subjects who provided consent over the 
telephone 
• Medical/treatment history, including: 
o Concomitant medications 
o Assessment /recording of pre-existing conditions or adverse events 
• Urine pregnancy testing for women of childbearing potential 
• Blood draw for the following:  
o provenanceF7 testing of Screening genetic sample [to confirm specimen identity]; 
 
o clinical laboratory tests (hematology, chemistry, urinalysis) 
o pharmacokinetic (PK) samples 
                                                     
7 Provenance testing is performed for quality assurance purposes to ensure that blood sample obtained at baseline 
visit is from same individual as sample obtained at screening visit. 

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o stored plasma and/or serum and/or DNA 
o baseline drug-specific tests (as outlined in the drug-specific appendices) 
• Urine collection for urinalysis 
• Administration of C-SSRS 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• Physical and neurological examinations 
• Clinical assessments:  CDR, calculation of CDR-SB, NPI-Q, GDS, FAS, MMSE, and 
assessment of clinical diagnosis and clinician judgment of symptoms. 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing 
• 12-lead ECG 
• Baseline Cognitive testing (per section 6.1.14) 
• MRI to be performed on 1st day and uploaded immediately to ensure reading obtained 
prior to randomization and dosing.  This MRI includes safety MRI sequences.  ARIA 
findings on this MRI may affect eligibility for the trial for some drug arms.  MRI should 
be performed before lumbar puncture (if on the same day) or scheduled to be on a 
different day than the lumbar puncture 
• Lumbar Puncture (LP) for CSF collection should be performed at approximately 8 am 
local time, under fasting conditions (water is allowed and encouraged).  Site staff should 
contact the subject 24-48 hours after the LP to assess for adverse effects of the LP.   
• PET imaging (see each drug-specific appendix for details) 
• See each drug-specific appendix for additional assessments which may be required 
• Final verification that all inclusion and no exclusion are met (including receipt of MRI 
read) 
• Randomization in IWRS system 
• Supplemental drug-specific informed consent reviewed and signed, if not a stand-alone 
consent 
• Drug arms other than gantenerumab and solanezumab: Reminder regarding ARC 
smartphone-based cognitive assessment completion 
• Study drug dosing and post-dose monitoring/evaluation as specified in each drug-
specific appendix 
After all baseline measures have been completed and adherence to inclusion and exclusion 
criteria has been verified, randomization and assignment to study drug arm is completed using 
the IWRS during this visit.  Randomization cannot occur until results of baseline (V2) CDR are 
entered into the IWRS system.  After randomization, subject and legally acceptable 
representative (if the subject is cognitively impaired) should review and sign the supplemental 
drug-specific informed consent form (if applicable); study staff should be available to answer all 

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questions regarding the study.  Study drug should not be administered until MRI is read to 
confirm eligibility (if required for specific study drug, e.g., number of microhemorrhages), 
pregnancy test is confirmed negative, and any other drug-specific inclusion/exclusion criteria 
have been verified. 
6.3.4 Double-blind Treatment Period 
The double-blind treatment period for each study drug arm will vary based on when the subject 
was enrolled and may last from 4 up to 7 years (364 weeks [V93]) or until early termination, 
whichever is sooner.  Subjects will continue treatment with the assigned study drug until every 
subject randomized to that study drug arm has received a minimum of 4 years (208 weeks) of 
treatment or is withdrawn.  After the double-blind treatment period is completed, subjects may 
be eligible to continue treatment in an open-label extension if the study drug arm 
demonstrates a potential for clinical benefit. 
Location:  Monthly procedures/contacts may be accomplished at/by the DIAN-TU site, at the 
subject’s home, or other trial-identified location with the trial-designated home health nurse.  
Annual visits will take place at the host DIAN-TU site. 
Time/Timing:  Every 4 weeks (+/- allowed visit window) until the last subject in a study drug arm 
has completed their year 4 visit, or the study drug arm has been terminated.   Refer to the drug-
specific appendices for allowable visit windows. 
Visit duration depends on specific visit and study drug (e.g., infusion time, observation time 
after infusion).  Note that annual visits may take place over 3-4 days.  For subjects who live near 
the study site, these visit procedures may be scheduled over a longer time period of up to 2 
weeks. 
Procedures: See each drug-specific appendix for the specific assessments that are required at 
each visit.  Procedures may include any of the following: 
• Medical/treatment history, including: 
o Concomitant medications 
o Assessment /recording of adverse events 
• Urine pregnancy testing, if applicable 
• Laboratory sample collection (e.g., drug-specific tests, stored plasma and/or serum, and 
clinical safety assessment as outlined in the drug-specific appendices) 
• Administration of C-SSRS 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• Physical and neurological examinations 

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• Clinical assessments: 
o CDR, including calculation of CDR-SB 
o NPI-Q 
o GDS 
o FAS 
o MMSE 
o Assessment of clinical diagnosis and clinician judgment of symptoms 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• 12-lead ECG 
• Cognitive testing  
• MRI (should be performed before lumbar puncture, if on the same date)  
• Lumbar Puncture (LP) for CSF collection (water is allowed and encouraged).  Site staff 
should contact the subject 24-48 hours after the LP to assess for adverse effects of the 
LP. 
• PET imaging  
• Study drug administration 
• Site phone call (not required after all off-site visits but direct site-subject contact should 
occur at least once every 3 months throughout the study): the DIAN-TU site coordinator 
calls subject and addresses any concerns, discusses scheduling of safety MRI and/or next 
visits, and encourages compliance. 
6.3.5 End-of-Treatment / Safety Follow-up Visit 
The double-blind treatment period for each subject may vary based on when the subject was 
enrolled and may last from 4 (208 weeks [V54]) up to 7 years (364 weeks [V93]) or until early 
termination, whichever is sooner.  Subjects will continue treatment with the assigned study 
drug until every subject randomized to the study drug arm has received a minimum of 4 years 
(208 weeks) of treatment or is withdrawn, at which time study treatment will be discontinued 
for all subjects in the study drug arm and all subjects should be scheduled for an end-of-
treatment/safety follow-up visit.  Based on the date of the last subject randomization 
(December 2015), the last subject will have received 4 years treatment and all double-blind 
treatment visits will be concluded by November 2019.  Any visits scheduled to occur on or 
before the sponsor-specified cut-off date (November 2019) should be conducted as usual and 
will be the final dosing visits for all subjects.  All subjects will then be scheduled for their 
respective end-of-study or safety follow-up visit relative to the subject’s last dose within their 
drug-specific visit window. 
Location: Procedures/contacts may be accomplished at the DIAN-TU site or subject’s home or 
other trial-identified location with the trial-designated home health nurse. 

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Timing:  The end of treatment/safety follow-up visit should be performed between 4 and 12 
weeks (+/- 7 days) after the subject’s last dose of double-blind treatment.  The sequence and 
timing of visit procedures is very important and are detailed in the Global Manual of 
Operations. 
Procedures may include any of the following: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight)  
• 12-lead ECG 
• Administration of C-SSRS 
• Laboratory sample collection (e.g., drug-specific tests, and clinical safety assessment as 
outlined in the drug-specific appendices) 
• Urine collection for urinalysis  
Any procedures done after the last dose, but before the safety follow-up visit, may not need to 
be repeated.  See each drug-specific appendix for the specific assessments that are required 
at each visit. 
6.3.6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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measures (e.g., drug-specific tests, stored plasma and/or serum) per drug-specific 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 

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• 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.3.7 Early Termination/Post-treatment Follow-up 
If a subject withdraws, is terminated from the study prior to completion of the double-blind 
treatment period, or is in a study drug arm that is stopped prior to the end of the double-blind 
treatment period, every effort should be made to schedule an early termination visit.  PET 
imaging studies may be omitted if early termination occurs less than 6 months after the 
previous PET imaging or if precluded by local regulations/dosimetry limits.  Other procedures 
may also be eliminated on a case-by-case basis, as determined by the sponsor or if not required 
based on the study drug arm procedures or study period. 
Any subject that meets study drug discontinuation criteria per section 4.4.1 (excluding subjects 
who are known mutation negative) will be encouraged to continue participation in any of the 
scheduled clinical, cognitive, and/or biomarker assessments that are able to be performed even 
though dosing has concluded.  The determination of which assessments to be 
attempted/completed will be decided with the site principal investigator and sponsor based on 
the subject’s capabilities, the benefit to the study, and the risk associated with continued 
participation at the time of study drug discontinuation.  The level of continued participation 
may change if/as the subject’s status changes. 
Location:  DIAN-TU site or at the subject’s home or other trial-identified location with the trial-
designated home health nurse 
Time/Timing:  The early termination visit may occur at any time during the study.  
Approximately a 3-4 day visit.  For subjects who live near the study site, these visit procedures 
may be scheduled over a longer time period of up to 2 weeks. 
Procedures: See each drug-specific appendix for the specific assessments that are required at 
each visit.  Procedures may include any of the following: 
• Medical/treatment history, including: 
o Concomitant medications 

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o Assessment /recording of adverse events 
• Laboratory sample collection (baseline drug-specific tests, stored plasma and/or serum, 
and clinical safety assessment) 
• Administration of C-SSRS 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• Physical and neurological examinations 
• Clinical assessments: 
o CDR including calculation of CDR-SB 
o NPI-Q 
o GDS 
o FAS 
o MMSE 
o Assessment of clinical diagnosis and clinician judgment of symptoms.   
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• 12-lead ECG 
• Cognitive testing  
• MRI (structural and functional) (should be performed before lumbar puncture, if on the 
same date)  
• Lumbar Puncture (LP) for CSF collection (water is allowed and encouraged).  Site staff 
should contact the subject 24-48 hours after the LP to assess for adverse effects of the 
LP. 
• PET imaging  
• Drug reconciliation as specified in each drug-specific appendix 
 Termination of the Study 
The sponsor may terminate the study or study-drug arm, 
 at any time.  
Furthermore, if it becomes apparent that subject enrollment is unsatisfactory with respect to 
quantity or quality, or that data recording is inaccurate or incomplete on a chronic basis, the 
sponsor has the right to terminate the study and remove all study materials from the 
investigational site.  A written statement will be provided to the investigator, IRB/IEC, and 
regulatory authorities, if required.  If any SAEs are reported as part of the reason for early 
termination of the study, all documentation relating to the event(s) reported to regulatory 
authorities must be obtained and filed appropriately.  The DSMB may recommend termination 
of the study or study drug arm but final decisions will be made by the sponsor. 
 

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7 SAFETY AND ADVERSE EVENTS  
 Definitions 
7.1.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered 
study drug, whether or not considered drug related.  An adverse event can be any unfavorable 
and unintended sign (including abnormal laboratory findings), symptom, or disease temporally 
associated with the use of the study drug, whether or not considered related to study drug.  An 
adverse event can arise from any use of the drug and from any route of administration, 
formulation, or dose including an overdose. 
Any medical condition that is present at the time the subject is consented but does not 
deteriorate should not be reported as an AE.  However, if it deteriorates or worsens 
significantly at any time during the study, it should be recorded as an AE. 
Clinically meaningful (for a given subject) changes in physical examination findings and 
abnormal objective test findings (e.g., laboratory, vital signs, ECG, imaging (e.g., definite new 
ARIA changes) should also be recorded as AEs.  The criteria for determining whether an 
abnormal objective test finding should be reported as an AE are as follows: 
1. Test result is associated with accompanying symptoms or is of clinical concern 
2. Test result requires additional diagnostic testing or medical/surgical intervention 
3. Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy 
4. Test result leads to any of the outcomes included in the definition of a SAE 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
meet criteria 2 above for reporting as an AE.  Any abnormal test result that is determined to be 
an error does not require reporting as an AE. 
NOTE: The following are not considered AEs or SAEs: 
• Preplanned surgeries or procedures:  Preplanned procedures (surgeries or therapies) 
that were scheduled prior to signing of informed consent are not considered AEs.  
However, if a preplanned procedure is performed early (e.g., as an emergency) due to a 
worsening of the pre-existing condition, the worsening of the condition should be 
captured appropriately as an AE.  Complications resulting from any planned surgery 
should be reported as AEs. 
 
• Elective surgeries or procedures:  Elective procedures performed where there is no 
change in the subject’s medical condition should not be recorded as AEs, but should be 
documented in the subject’s source documents.  Complications resulting from an 
elective surgery should be reported as AEs or SAEs (depending on the severity). 

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• Insufficient clinical response (lack of efficacy):  Insufficient clinical response, efficacy, or 
pharmacologic action, should NOT be recorded as an AE.  The principal investigator 
must make the distinction between exacerbation of pre-existing illness and lack of 
therapeutic efficacy. 
7.1.2  Serious Adverse Event 
If any adverse event meets any of the following criteria in the view of either the investigator or 
sponsor, it is to be reported to the safety group as a serious adverse event (SAE) within 24 
hours of occurrence or notification of the site: 
• Death of subject.  An event that results in the death of a subject. 
• Life-Threatening.  An event that, in the opinion of the investigator, would have resulted 
in immediate fatality if medical intervention had not been taken.  This does not include 
an event that would have been fatal if it had occurred in a more severe form. 
• Inpatient Hospitalization.  An event that results in the admission to the hospital for any 
length of time.  This does not include an emergency room visit or admission to an 
outpatient facility. 
• Prolongation of existing hospitalization.  An event that occurs while the study subject is 
hospitalized and prolongs the subject’s hospital stay. 
• A persistent or significant disability/incapacity.  An event that results in a condition 
that substantially interferes with the activities of daily living of a study subject.  
Disability is not intended to include experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., 
sprained ankle). 
• Important medical event requiring medical or surgical intervention to prevent serious 
outcome.  An important medical event that may not be immediately life-threatening or 
result in death or hospitalization, but based on medical judgment may jeopardize the 
subject and may require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of subject, life-threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity).  Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse. 
• Congenital anomaly/birth defect.  An anomaly detected at or after birth, or any 
anomaly that results in fetal loss. 
• Suspected Hy’s law case (should be reported as serious unexpected adverse event). 
 Adverse Event (AE) Severity 
The intensity of the AE will be rated by the investigator as mild, moderate or severe using the 
following criteria: 

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Mild:  an event that is transient and easily tolerated by the subject; requires minimal or no 
treatment and does not interfere with the subject’s daily activities. 
Moderate:  an event that causes the subject discomfort and may cause some interference 
in the subject’s usual activities. 
Severe:  an event that causes considerable interference with the subject’s usual activities, 
may require drug therapy or other treatment, and may be incapacitating or life-
threatening. 
 Relationship to Study Drug 
The relationship of an AE to study drug, imaging agents (e.g., [11C]PiB and 18F tracers) and or 
study procedures should be assessed by the principal investigator using the following guidance: 
Definite.  An event, including laboratory test abnormality, which: 
a. Occurs within a reasonable temporal sequence to administration of study drug, 
b. Cannot be explained by concurrent disease or other drugs or chemicals 
c. Improves or disappears on stopping or reducing study drug (dechallenge) 
d. Reappears on repeated exposure to study drug (rechallenge)   
e. Is an unusual event that is known to be associated with the drug or this class of 
compound, and cannot be explained by other therapy or the subject’s physical 
condition. 
Probable/Likely.  An event, including laboratory test abnormality, which: 
a. Occurs within a reasonable temporal sequence to administration of study drug,  
b. Unlikely to be attributed to concurrent disease or other drugs or a clinically reasonable 
response on withdrawal (dechallenge) 
c. Rechallenge was not attempted. 
Possible.  An event, including laboratory test abnormality, which: 
a. Occurs within a reasonable temporal sequence to administration of study drug, but 
b. Could also be explained by concurrent disease or other drugs or chemical  
c. Information on drug withdrawal may be lacking or unclear. 
Unlikely.  An event, including laboratory test abnormality, which: 
a. Occurs with a temporal relationship to administration of study drug which makes a 
causal relationship improbable, and  
b. In which other drugs, chemicals or underlying disease provide plausible explanations. 
Definitely Not.  An event, including laboratory test abnormality, which is known to be 
associated with the subject’s clinical condition, or with other medication taken by the subject. 

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 Adverse Event Collection Period 
All AEs reported from the time that informed consent is obtained until 30 days following the 
last dose of study drug 
will be collected, 
whether elicited or spontaneously reported by the subject.  Adverse events should be collected 
at End of Study and Early Termination visits even if these visits occur more than 30 days after 
last dose of study drug.  Serious adverse events considered related to study drug or procedures 
should be reported even if they occur more than 30 days after the last dose of study drug.   
At every study visit, subjects will be asked a standard question to elicit any medically related 
changes in their well-being.  They will also be asked if they have been hospitalized, had any 
accidents, used any new medications, or changed concomitant medication regimens (both 
prescription and over-the-counter medications). 
 Adverse Event Reporting 
The investigator will monitor each subject for clinical and laboratory evidence of AEs on a 
routine basis throughout the study.  Conditions present at baseline will be documented.  
Deterioration or worsening of conditions present at baseline should be reported as an AE.  All 
AEs reported or observed during the study will be recorded in the AE eCRF.  Information to be 
collected includes the type of event, date of onset, investigator-specified assessment of severity 
and relationship to study drug, date of resolution of the event, and seriousness.  Treatments for 
AEs will be recorded on the concomitant medication eCRF.  AEs resulting from concurrent 
illnesses, reactions to concurrent illnesses, reactions to concurrent medications, or progression 
of disease states must also be reported.  All AEs, whether serious or non-serious, should be 
followed to resolution or until the AE is determined by the investigator not to be clinically 
significant or to be chronic or stable.  Medical Dictionary for Regulatory Activities (MedDRA®) 
will be used to code all AEs. 
 Serious Adverse Event Reporting 
The principal investigator must report to 
Safety (formerly known as 
) any AE 
considered serious by the investigator, or which meets any of the specified criteria in section 
7.1.2.  Refer to each drug-specific appendix for drug-specific AE and SAE reporting.  The initial 
report must be submitted within 24 hours from the time site personnel first learn about the 
event by entry in inform (EDC); in cases where a back-up submission method is needed the site 
must submit SAE documentation to the project mailbox:  
 

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Contact information for 
Safety:  
 SAFETY: 
Toll-free for US sites: 
Phone: 
 
Fax: 
 
For all sites/international:   
 or  
(alternative number) 
Additional contact information is detailed in the Global Manual of Operations. 
The reporting should include completion of the eCRF Adverse Event Form with Serious event 
indicated as Yes, and verification of current data entry in the eCRFs or de-identified source 
documents for the demographics page(s), medical history page(s), AE page(s) and concomitant 
medication page(s).  If the subject is hospitalized because of or during the course of an SAE, 
then a copy of the hospital discharge summary should be faxed to 
Safety as soon as it 
becomes available.  Withdrawal from the study and all therapeutic measures will be at the 
discretion of the investigator unless the event meets a protocol-specified discontinuation 
criterion.  All SAEs will be followed until satisfactory resolution or until the investigator deems 
the event to be chronic or the subject to be stable. 
The sponsor or its designee will be responsible for reporting SAEs to FDA, European Medicines 
Agency (EMA) and other relevant regulatory authorities accordingly to local regulatory 
requirements.  Sites are responsible for reporting to their local ethics committees /IRBs per 
their reporting requirements and/or local laws. 
 Pregnancy Reporting 
Cases of pregnancy that occur during maternal or paternal exposures to study drug or within 16 
weeks following last dose of study drug should be reported.  Data on fetal outcome and breast-
feeding are collected for regulatory reporting and drug safety evaluation.  Sites should report 
pregnancies to 
 Safety in the same manner and timing as for Serious Adverse Events 
specified in section 7.6. 
 Adverse Events of Special Interest 
Refer to the drug-specific appendices for drug-specific reporting for adverse events of special 
interest (AESI).  Sites should report an AESI to 
 Safety in the same manner and timing as 
for Serious Adverse Events specified in section 7.6. 

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 Data Safety Monitoring Board (DSMB) 
Unblinded data from study drug arms on safety-related endpoints (clinical laboratory test 
results, ECGs, MRI findings, cognitive and clinical endpoint results) and SAEs will be reviewed 
quarterly by the DSMB.  Complete details are available in the DSMB charter.   
8 STATISTICAL PLAN 
 
 All statistical analyses described are related to the 
study drug arms that are included in this protocol. 
A detailed statistical analysis plan will be used for interim and final efficacy analyses and for the 
biomarker interim analyses. 
 Descriptive Statistics 
Descriptive statistics will be provided for safety and efficacy variables at each time point 
collected by treatment groups and across combined placebo groups.  Continuous variables 
(e.g., biomarker values) will be summarized using the number of observations, mean, standard 
deviation (SD), minimum, lower quartile, median, upper quartile, and the maximum.  These 
statistics will be provided by PROC UNIVARIATE/SAS (SAS Institute Inc. 2009).  Categorical 
variables (e.g., presence of absence of an APOE ε4 allele) will be summarized using the number 
and percentage in each category. 
 Safety Analysis 
Safety analysis will include all subjects who consent to participate and are randomized to 
receive any study-related drugs or placebo and will be reported to an independent Data Safety 
Monitoring Board (DSMB) for regular reviews.  The following are major safety endpoints that 
will be analyzed: treatment-emergent adverse events (AE), serious treatment-emergent AEs, 
serious drug-related treatment-emergent AEs, treatment-emergent AEs that lead to 
discontinuation of the study, treatment-emergent AEs resulting in death, safety MRIs, 
laboratory parameters, vital signs and physical examinations.  Adverse event reporting will 
include the severity, onset, duration, relief measures, outcome, and relationship to study drug.  
Adverse events will be classified using MedDRA preferred terms.  Adverse events noted on MRI 
scans, including ARIA, will be analyzed as will adverse events noted as significant changes or 
new abnormalities in vital signs, clinical laboratory test values or ECGs. 
 Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification 
Each drug that enters the DIAN-TU platform trial will have biomarker defined interim analyses.  
The goal of the interim analyses is to stop or adjust a treatment that is not demonstrating 

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sufficient efficacy on the target biomarker.  Each study drug arm will have a target biomarker, a 
target biomarker analysis, and a remediation plan should the biomarker analysis demonstrate 
lack of success.  The remediation plan will include dose-adjustment strategies, if appropriate, to 
maximize the efficacy, if the tolerability and safety profile is acceptable.  If no adjustments are 
possible, then failing the biomarker interim will lead to stopping the regimen for futility.  Each 
drug-specific appendix will detail the biomarker interim analysis.  The biomarker interim 
analyses will only be used for dose-adjustment, remediation, or stopping a study drug arm for 
futility and will not be used for any conclusion of success or efficacy on the primary cognitive 
endpoint. 
Interim biomarker analyses will be conducted for each study drug arm to assess whether the 
active study drug is engaging its biological target.  The timing of the interim biomarker analyses 
may vary for each study drug arm.  At each interim, an analysis will be conducted for the 
biomarker endpoints, comparing the active drug to its own (direct) placebo group or to a 
pooled placebo group (mutation positive placebos).  Pre-specified definitions for early 
termination for futility will be drug-specific and based on collection of appropriate biomarker 
assessments following sufficient drug exposure.  Details about the interim biomarker analyses 
are described in each drug-specific appendix. 
 Cognitive Endpoint Statistical Analysis, Power and Sample Size Justification 
8.4.1 Cognitive Analysis Populations and Primary Efficacy Analysis 
The modified intent-to-treat (mITT) population is defined as all subjects who will be 
randomized, treated, and assessed for their primary cognitive outcomes at least once after the 
baseline assessment. 
All efficacy analyses will be conducted on the mITT population and the eligible DIAN-OBS 
subjects. 
The primary efficacy outcome (DIAN-MCE) is defined in section 3.5. The primary efficacy 
hypothesis will be tested by comparing the relative rate of cognitive decline between the active 
drug and the mutation positive placebos and the eligible DIAN-OBS subjects using the MDPM 
developed by the DIAN-TU.  The MDPM includes 2 subject-level random effects to account for 
the between-subject variability and a model of the mean rate of decline as a function of 
expected years from symptom onset (EYO) to estimate a proportional slowing of decline of the 
primary endpoint in active drug compared with the mutation positive placebos and the eligible 
DIAN-OBS subjects.  This model was developed using Data Freeze 13 from the DIAN-OBS study.  
To test the hypothesis of a disease progression benefit we calculate the posterior probability of 
superiority in cognitive slowing and if it is above a pre-specified threshold (which controls the 
experiment wise type I error at 2.5%) then a claim of cognitive slowing will be made.  The pre-
specified threshold may vary from study drug to study drug depending on the drug-specific 
sample size or the interim analysis plan.  All these analyses will be implemented using SAS or 
validated MDPM software. 

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Final analysis will be pre-specified in the SAP and drug-specific SAP appendices. 
8.4.2 Cognitive Endpoint Power Analysis and Sample Size Determination 
The power analysis and sample size determination for each study drug is presented in each 
drug-specific appendix (Appendices 3 and 4) of this protocol, or in the SAP.   
9 DATA HANDLING AND RECORD KEEPING 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol.  The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. 
Electronic Case Report Forms (eCRFs) or appropriate access to the electronic data capture 
(EDC) system by investigator-delegated site personnel.  These forms and system(s) will be 
used to transmit information collected during the study to the sponsor and designee, those in 
collaboration with the sponsor for the study, and regulatory authorities, as applicable.  All data 
should be entered into the EDC system in a timely manner as specified in the Global Manual of 
Operations.  All information entered in the EDC must also be reflected in the subject source 
documents. 
The principal investigator will review the source documentation and eCRFs (EDC) for 
completeness and accuracy and sign/date via electronic signature in the system where 
indicated. 
The investigator will retain all essential documents until at least two years after the last 
approval of a marketing application in an International Conference on Harmonisation (ICH) 
region and until there are no pending or contemplated marketing applications in an ICH region 
or at least two years have elapsed since the formal discontinuation of clinical development of 
the investigational product.  It is the responsibility of the investigator and/or institution to 
notify the sponsor in writing of any change in record retention, i.e., transfer of responsibility in 
the event of relocation, retirement, etc.  It is the responsibility of the sponsor or designee to 
inform the investigator/institution as to when these documents no longer need to be retained. 
10 STUDY MONITORING, AUDITING AND INSPECTING 
The subject data (EDC and source documents) will be reviewed for completeness, legibility and 
acceptability by the sponsor or designee/representatives.  The sponsor and 
designee/representatives will be allowed access to all source documents in order to verify all 
EDC entries.  Source documents are defined as original documents, data and records.  This may 
include hospital records, clinical and office charts, laboratory data/information, subject diaries, 
pharmacy dispensing and other records, recorded data from automated instruments, magnetic 
media, x-rays, etc. 

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The investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s), providing direct access to source data documents.  In the event of 
an audit, the investigator agrees to allow the sponsor, representatives of the sponsor and 
applicable regulatory authorities access to all study records.  The investigator should promptly 
notify the sponsor of any audits scheduled by any regulatory authorities and promptly forward 
copies of any audit reports received to the sponsor. 
All aspects of the study will be carefully monitored, by the sponsor or designee, for compliance 
with applicable government regulations with respect to current GCP and current standard 
operating procedures. 
The monitor will visit the investigator and study facility at periodic intervals, in addition to 
maintaining necessary telephone and letter correspondence contact.  The monitor will maintain 
current personal knowledge of the study through observation, review of study records and 
source documentation, and discussion of the conduct of the study with the investigator and 
staff. 
 Protocol Deviations 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes outlined within the protocol.  The investigator or designee must 
document and explain in the subject’s source documentation any deviation from the IRB/IEC 
approved protocol.  Protocol deviations will also be documented by the clinical monitor 
throughout the course of the monitoring visit.  The site must notify their IRB/IEC of required 
and/or significant protocol deviations in a timely manner in accordance with their policies and 
any local regulations. 
 Study Reporting Requirements 
By participating in this study, the investigator agrees to submit reports of Serious Adverse 
Events according to the timeline and method outlined in the protocol.  In addition, the 
investigator agrees to submit annual reports to his/her IRB/IEC as appropriate.  The investigator 
also agrees to provide the sponsor with an adequate report shortly after completion of the 
investigator’s participation in the study. 
 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH Guidance E6 8.2 
and Title 21 of the Code of Federal Regulations (CFR) by providing the following essential 
documents, including but not limited to: 
• An original investigator-signed Investigator’s Statement of Agreement page of the 
protocol. 

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• An IRB/IEC-approved ICF, samples of site advertisements for recruitment for this study, 
and any other written information regarding this study that is to be provided to the 
subject/legal guardian/representative. 
• IRB/IEC approval. 
• Form FDA 1572, fully executed, and all updates on a new fully executed Form FDA 1572 
for all US sites.  These may be required for non-US sites at the discretion of the sponsor 
or designee. 
• Curriculum vitae (CV) for the principal investigator and each sub-investigator listed on 
Form FDA 1572.  Current licensure must be noted on the CV and/or included.  CVs 
should be signed and dated by the principal investigators and sub-investigators at study 
start-up, indicating that they are accurate and current. 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under Part 54 of Title 21 of the CFR.  In 
addition, the investigators must provide to the sponsor a commitment to promptly 
update this information if any relevant changes occur during the course of the 
investigation and for one year following the completion of the study. 
11 ETHICAL CONSIDERATIONS 
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 parts 50, 54, 56, and 312 and International Conference on Harmonization 
guidelines), applicable government regulations and Institutional research policies and 
procedures.  At each participating DIAN-TU site, the principal investigator will submit this 
protocol and any amendments, Investigator’s Brochure, informed consent, recruitment 
materials, etc., to the properly constituted IRB or IEC, in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the IEC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor or its designee before commencement of this study.  Each 
DIAN-TU site will be responsible for obtaining appropriate approvals for satellite sites and other 
providers (e.g., home health nurses, infusion sites) used by their subjects for study activities, as 
applicable. 
Any amendments to the protocol and informed consent will require IRB/IEC approval prior to 
implementation of any changes made to the study design. 
The investigator agrees that the study will be conducted according to the principles of the 
ICH E6 Guideline on GCP and the World Medical Association Declaration of Helsinki.  The 
investigator will conduct all aspects of this study in accordance with all national, state, and local 
laws or regulations. 
The written consent documents will embody the elements of informed consent as described in 
the Declaration of Helsinki, 21 CFR Part 50.25, ICH GCP, and in accordance with any local 
regulations.  The ICF must be approved by the clinical site’s IRB/IEC and be acceptable to 
Washington University in St. Louis. 

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12 STUDY FINANCES 
Investigators are required to provide financial disclosure information to allow the sponsor or 
designee to submit the complete and accurate certification or disclosure statements required 
under Part 54 of Title 21 of the CFR.  In addition, the investigator must provide to the sponsor a 
commitment to promptly update this information if any relevant changes occur during the 
course of the investigation and for one year following the completion of the study.   
The sponsor is not financially responsible for further testing/treatment of any medical condition 
that may be detected during the baseline process.  In addition, in the absence of specified 
arrangements, the sponsor is not financially responsible for further treatment of the subject’s 
disease. 
13 PUBLICATION PLAN  
The DIAN-TU committee on data sharing and publications will establish policies and guidelines 
for DIAN-TU data sharing and oversight of publications using DIAN-TU data.  Pharma partners 
will be consulted when issues specific to their study compounds arise, but Washington 
University in Saint Louis retains the right to publish the results of this trial consistent with the 
policies of the University and any regional regulatory requirements. 

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14 REFERENCES 
Aisen , P.S., Cummings J.L., Sperling RA. (2016). “TPC-PAD: Using Run-In Data for Screen Failure 
Reduction.” Alzheimer's & Dementia 12(7):P372. 
Bateman, R.J., C. Xiong, et al. (2012).  "Clinical and Biomarker Changes in Dominantly Inherited 
Alzheimer's Disease." N Engl J Med 367(9): 795-804. 
Bayer-Carter, J. L., P. S.  Green, et al.  (2011).  "Diet intervention and cerebrospinal fluid 
biomarkers in amnestic mild cognitive impairment." Arch Neurol 68(6): 743-752. 
Benzinger, T. L., T. Blazey, et al.  (2013).  "Regional variability of imaging biomarkers in 
autosomal dominant Alzheimer's disease." Proc Natl Acad Sci U S A 110(47): E4502-4509. 
Blom, E. S., V. Giedraitis, et al.  (2009).  "Rapid progression from mild cognitive impairment to 
Alzheimer's disease in subjects with elevated levels of tau in cerebrospinal fluid and the APOE 
epsilon4/epsilon4 genotype." Dement Geriatr Cogn Disord 27(5): 458-464. 
Braak, H. and E. Braak (1995).  "Staging of Alzheimer's disease-related neurofibrillary changes." 
Neurobiol Aging 16(3): 271-278; discussion 278-284. 
Brier, Matthew R., et al.  "Tau and Aβ imaging, CSF measures, and cognition in Alzheimer’s 
disease." Science translational medicine 8.338 (2016): 338ra66-338ra66. 
Buchhave, P., L. Minthon, et al.  (2012).  "Cerebrospinal fluid levels of beta-amyloid 1-42, but 
not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia." 
Arch Gen Psychiatry 69(1): 98-106. 
Buerger, K., M. Ewers, et al.  (2006).  "CSF phosphorylated tau protein correlates with 
neocortical neurofibrillary pathology in Alzheimer's disease." Brain 129(Pt 11): 3035-3041. 
Chang WP, Huang X, Downs D, Cirrito JR, Koelsch G, Holtzman DM, Ghosh AK, Tang J.  Beta-
secretase inhibitor GRL-8234 rescues age-related cognitive decline in APP transgenic mice.  
FASEB J.  2011;25(2):775-84. 
Chetelat, G., V. L. Villemagne, et al. (2012).  "Accelerated cortical atrophy in cognitively normal 
elderly with high beta-amyloid deposition." Neurology 78(7): 477-484. 
Craft, S., L. D. Baker, et al. (2012).  "Intranasal insulin therapy for Alzheimer disease and 
amnestic mild cognitive impairment: a pilot clinical trial." Arch Neurol 69(1): 29-38. 
Craig-Schapiro, R., R. J. Perrin, et al.  (2010).  "YKL-40: a novel prognostic fluid biomarker for 
preclinical Alzheimer's disease." Biol Psychiatry 68(10): 903-912. 
 
 
DeMattos R, May P, Racke M, Hole J, Tzaferis J, Liu F, DeLong C, Day T, Yang Z, Boggs L, Monk S, 
Mergott D, Tang Y, Lu J, Hutton M, Nordstedt C, Anderson W, Iverson Pp.  Combination therapy 

Washington University in St. Louis 
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CONFIDENTIAL 
Version: Amendment 10
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Page 104 of 265 
with a plaque-specific ABeta antibody and Bace inhibitor results in dramatic plaque lowering in 
aged PDAPP transgenic mice.  Alzheimer's & Dementia.  2014;10(4):149. 
Derby, C. A., L. C. Burns, et al.  (2013).  "Screening for predementia AD: time-dependent 
operating characteristics of episodic memory tests." Neurology 80(14): 1307-1314. 
Donohue, M. C., R. A. Sperling, et al.  (2014).  "The preclinical Alzheimer cognitive composite: 
measuring amyloid-related decline." JAMA Neurol 71(8): 961-970. 
Doraiswamy, P. M., R. A. Sperling, et al.  (2012).  "Amyloid-beta assessed by florbetapir F 18 PET 
and 18-month cognitive decline: A multicenter study." Neurology 79: 1633-1644. 
Duyckaerts, C., J. P. Brion, et al.  (1987).  "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 
Neuropathol 73(2): 167-170. 
Fagan, A. M., D. Head, et al.  (2009).  "Decreased cerebrospinal fluid Abeta(42) correlates with 
brain atrophy in cognitively normal elderly." Ann Neurol 65(2): 176-183. 
Fagan, A. M., C. M. Roe, et al.  (2007).  "Cerebrospinal fluid tau/beta-amyloid(42) ratio as a 
prediction of cognitive decline in nondemented older adults." Arch Neurol 64(3): 343-349. 
Fagan, A. M., C. Xiong, et al.  (2014).  "Longitudinal change in CSF biomarkers in autosomal-
dominant Alzheimer's disease." Sci Transl Med 6(226): 226ra230. 
Frost C, Kenward MG, Fox NC. (2008). "Optimizing the design of clinical trials where the 
outcome is a rate. Can estimating a baseline rate in a run‐in period increase efficiency?"  
Statistics in Medicine 27(19):3717-3731. 
Gaetani L., Blennow K., et al. (2019). "Neurofilament light chain as a biomarker in neurological 
disorders." J Neurol Neurosurg Psychiatry 90(8): 870-881.  
Gordon, Brian A., et al.  "The relationship between cerebrospinal fluid markers of Alzheimer 
pathology and positron emission tomography tau imaging." Brain (2016): aww139. 
Grober, E., C. Hall, et al.  (2008).  "Neuropsychological strategies for detecting early dementia." 
J Int Neuropsychol Soc 14(1): 130-142. 
Hansson, O., H. Zetterberg, et al.  (2006).  "Association between CSF biomarkers and incipient 
Alzheimer's disease in patients with mild cognitive impairment: a follow-up study." Lancet 
Neurol 5(3): 228-234. 
Hassenstab, J. et al.  (2015). "Absence of practice effects in preclinical Alzheimer’s disease."  
Neuropsychology 29: 940–948. 
Hesse, C, L. Rosengren, et al.  (2000).  "Cerebrospinal fluid markers for Alzheimer's disease 
evaluated after acute ischemic stroke." J Alzheimers Dis 2(3-4): 199-206. 
Hostetler, E. D., A. M. Walji, Z. Zeng, P. Miller, I. Bennacef, C. Salinas, B. Connolly, L. Gantert, H. 
Haley, M. Holahan, M. Purcell, K. Riffel, T. G. Lohith, P. Coleman, A. Soriano, A. Ogawa, S. Xu, X. 

Washington University in St. Louis 
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Page 105 of 265 
Zhang, E. Joshi, J. Della Rocca, D. Hesk, D. J. Schenk and J. L. Evelhoch (2016). "Preclinical 
Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human 
Neurofibrillary Tangles." J Nucl Med 57(10): 1599-1606. 
Ivnik R, Smith G, Petersen R, Boeve B, Kokmen E, Tangalos E.  (2000)  "Diagnostic accuracy of 
four approaches to interpreting neuropsychological test data."  Neuropsychology.  14(2):163-
177. 
Jacobsen H., L. Ozmen et al.  (2014). "Combined treatment with a BACE inhibitor and anti-Abeta 
antibody gantenerumab enhances amyloid reduction in APPLondon mice."  J Neurosci.  34(35): 
11621-30. 
Johnson, D. K., M. Storandt, et al.  (2008).  "Cognitive profiles in dementia: Alzheimer disease vs 
healthy brain aging." Neurology 71(22): 1783-1789. 
Landau, S. M., D. Harvey, et al.  (2010).  "Comparing predictors of conversion and decline in 
mild cognitive impairment." Neurology 75(3): 230-238. 
Langbaum, J. B., S. B.  Hendrix, et al.  (2014).  "An empirically derived composite cognitive test 
score with improved power to track and evaluate treatments for preclinical Alzheimer's 
disease." Alzheimers Dement 10(6): 666-674. 
Li, G., I. Sokal, et al.  (2007).  "CSF tau/Aβ42 ratio for increased risk of mild cognitive 
impairment: a follow-up study." Neurology 69(7): 631-639. 
Lohith, T., I. Bennacef, C. Sur, R. Declercq, K. Serdons, G. Bormans, E. Hostetler, K. Van Laere, R. 
Vandenberghe and A. Struyk (2017). "Quantification of [18F] MK-6240, a new PET tracer 
targeting human neurofibrillary tangles (NFTs) in brain of healthy elderly and subjects with 
Alzheimer’s disease." Journal of Nuclear Medicine 58(supplement 1): 277-277. 
Lohith, T., I. Bennacef, Z. Zeng, M. Holahan, M. Koole, K. Van Laere, C. Sur, A. Struyk, A. Walji 
and E. Hostetler (2016). "Preclinical evaluation and first-in-human dosimetry of [18F] MK-6240, 
a new PET tracer for in vivo quantification of human neurofibrillary tangles." Journal of Nuclear 
Medicine 57(supplement 2): 125-125. 
Marquié, Marta, et al.  "Validating novel tau positron emission tomography tracer [F‐18]‐AV‐
1451 (T807) on postmortem brain tissue." Annals of neurology 78.5 (2015): 787-800. 
McKhann, G. M., D. S. Knopman, et al.  (2011).  "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 7(3): 263-
269. 
Mintun, M. A., G. N. Larossa, et al.  (2006).  "[11C]PIB in a nondemented population: potential 
antecedent marker of Alzheimer disease." Neurology 67(3): 446-452. 
Moonis, M., J. M. Swearer, et al.  (2005).  "Familial Alzheimer disease: decreases in CSF Abeta42 
levels precede cognitive decline." Neurology 65(2): 323-325. 

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Morris, J. C., C. M. Roe, et al.  (2009).  "Pittsburgh Compound B Imaging and Prediction of 
Progression From Cognitive Normality to Symptomatic Alzheimer Disease." Archives of 
Neurology 66(12): 1469-1475. 
Neelamegam, R., D. L. Yokell, P. A. Rice, S. Furumoto, Y. Kudo, N. Okamura and G. El Fakhri 
(2017). "A report of the automated radiosynthesis of the tau positron emission tomography 
radiopharmaceutical,[18F]‐THK‐5351." Journal of Labelled Compounds and 
Radiopharmaceuticals 60(2): 140-146. 
Nelson, P. T., I. Alafuzoff, et al.  (2012).  "Correlation of Alzheimer disease neuropathologic 
changes with cognitive status: a review of the literature." J Neuropathol Exp Neurol 71(5): 362-
381. 
Ost, M., K. Nylen, et al.  (2006).  "Initial CSF total tau correlates with 1-year outcome in patients 
with traumatic brain injury." Neurology 67(9): 1600-1604. 
Ostrowitzki, S., D. Deptula, et al.  (2012).  "Mechanism of amyloid removal in patients with 
Alzheimer disease treated with gantenerumab." Arch Neurol 69(2): 198-207. 
Pablos-Méndez A, Barr RG, Shea S. (1998). "Run-in periods in randomized trials: implications for 
the application of results in clinical practice." JAMA 279(3):222-225. 
Pontecorvo, M, et al. (2015). "Relationships between 18F-AV-1451 (aka 18F-T807) PET Tau 
Binding and Amyloid Burden in Cognitively Normal Subjects and Patients with Cognitive 
Impairments Suspected of Alzheimer’s Disease." Journal of Nuclear Medicine 56(supplement 3): 
245-245. 
Portelius, E., J. Fortea, et al.  (2012).  "The amyloid-beta isoform pattern in cerebrospinal fluid in 
familial PSEN1 M139T- and L286P-associated Alzheimer's disease." Mol Med Report 5(4): 1111-
1115. 
Preische, O, Schultz S, et al. (2019).  “Serum Neurofilament Dynamics Predicts 
Neurodegeneration and Clinical Progression in Presymptomatic Alzheimer’s Disease.” Nature 
Medicine 25: 277–283. 
Price, J. L., D. W. McKeel, Jr., et al.  (2009).  "Neuropathology of nondemented aging: 
presumptive evidence for preclinical Alzheimer disease." Neurobiol Aging 30(7): 1026-1036. 
Price, J. L.  and J. C. Morris (1999).  "Tangles and plaques in nondemented aging and 
"preclinical" Alzheimer's disease." Ann Neurol 45(3): 358-368. 
Ringman, J. M., G. Coppola, et al.  (2012).  "Cerebrospinal Fluid Biomarkers and Proximity to 
Diagnosis in Preclinical Familial Alzheimer's Disease." Dement Geriatr Cogn Disord 33(1): 1-5. 
Ringman, J. M., S. G.  Younkin, et al.  (2008).  "Biochemical markers in persons with preclinical 
familial Alzheimer disease." Neurology 71(2): 85-92. 
Ryman, D. C., N. Acosta-Baena, et al.  (2014).  "Symptom onset in autosomal dominant 
Alzheimer disease: a systematic review and meta-analysis." Neurology 83(3): 253-260. 

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Salloway, S., R. Sperling, et al.  (2011).  "A phase 2 randomized trial of ELND005, scyllo-inositol, 
in mild to moderate Alzheimer disease." Neurology 77(13): 1253-1262. 
Schechtman K.B., Gordon M.E. (1993).  "A comprehensive algorithm for determining whether a 
run‐in strategy will be a cost‐effective design modification in a randomized clinical trial." 
Statistics in Medicine 12(2):111-128. 
Schwarz, Adam J., et al.  "Regional profiles of the candidate tau PET ligand 18F-AV-1451 
recapitulate key features of Braak histopathological stages." Brain 139.5 (2016): 1539-1550. 
Siemers, E. R., S. Friedrich, et al.  (2010).  "Safety and changes in plasma and cerebrospinal fluid 
amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects 
with Alzheimer disease." Clin Neuropharmacol 33(2): 67-73. 
Snider, B. J., A. M. Fagan, et al.  (2009).  "Cerebrospinal fluid biomarkers and rate of cognitive 
decline in very mild dementia of the Alzheimer's type." Archives of Neurology 66(5): 638-645. 
Sperling, R., S. Salloway, et al.  (2012).  "Amyloid-related imaging abnormalities in patients with 
Alzheimer's disease treated with bapineuzumab: a retrospective analysis." Lancet Neurol 11(3): 
241-149. 
Sperling, R. A., K. A.  Johnson, et al.  (2012).  "Amyloid deposition detected with florbetapir F 18 
((18)F-AV-45) is related to lower episodic memory performance in clinically normal older 
individuals." Neurobiol Aging. 
Storandt, M., D. A. Balota, et al.  (2014).  "Clinical and psychological characteristics of the initial 
cohort of the Dominantly Inherited Alzheimer Network (DIAN)." Neuropsychology 28(1): 19-29. 
Strobel G.  Aducanumab, Solanezumab, Gantenerumab data lift Crenezumab, as well.  Series: 
Alzheimer's Association International Conference 2015, part 4 of 15.  AlzForum [Internet].  
2015.  Available from: http://www.alzforum.org/news/conference-coverage/aducanumab-
solanezumab-gantenerumab-data-lift-crenezumab-well. 
Tarawneh, R., G. D'Angelo, et al.  (2011).  "Visinin-like protein-1: diagnostic and prognostic 
biomarker in Alzheimer disease." Ann Neurol 70(2): 274-285. 
Varhaug K., Torkildsen Q, et al. (2019). "Neurofilament Light Chain as a Biomarker in Multiple 
Sclerosis." Front. Neurol 10:338 
Vos, S. J., C. Xiong, et al.  (2013).  "Preclinical Alzheimer's disease and its outcome: a 
longitudinal cohort study." Lancet Neurol 12(10): 957-965. 
Walji, A. M., E. D. Hostetler, H. Selnick, Z. Zeng, P. Miller, I. Bennacef, C. Salinas, B. Connolly, L. 
Gantert and M. Holahan (2016). "Discovery of 6-(Fluoro-18 F)-3-(1 H-pyrrolo [2, 3-c] pyridin-1-
yl) isoquinolin-5-amine ([18F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent 
for Quantification of Neurofibrillary Tangles (NFTs)." Journal of medicinal chemistry 59(10): 
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Wang, L., A. M. Fagan, et al.  (2011).  "Cerebrospinal Fluid Proteins Predict Longitudinal 
Hippocampal Degeneration in Early-stage Dementia of the Alzheimer Type." Alzheimer Dis 
Assoc Disord 26(4): 314-321. 
Wang, Liang, et al.  "Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing 
Interactions Between β-Amyloid and Tauopathy." JAMA neurology 73.9 (2016): 1070-1077. 
Woodcock J, LaVange LM. (2017). "Master Protocols to Study Multiple Therapies, Multiple 
Diseases, or Both." N Engl J Med 377:62-70. 
 

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or in cognitive testing. 
•
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 2: SCHEDULE OF VISITS: SCREENING AND BASELINE 
MAIN PROTOCOL SCHEDULE OF VISITS: SCREENING AND BASELINE 
 
PROCEDURES 
VISIT SITE 
Home (H)1 
DIAN-TU 
Visit No 
V1 (screen) 
V2 (baseline) 
Timing (weeks)2  
-8 to -2 
0 
Informed Consent3 
X 
X4 
Family History/Age at Onset Assessment5 
X 
 
Demographics/Study Partner Information5 
X 
 
Medical/Treatment History6 
X 
X 
Concomitant Medications 
 
X 
Adverse Event Assessment 
X 
X7 
Genetic Testing/APOE8 
X 
X9 
Hematology, Chemistry, Urinalysis 10 
X 
 
Pregnancy Testing11 
X 
X 
Drug-specific Labs 
 
X12, 13 
Stored Plasma and/or Serum and DNA14 
 
X 
C-SSRS 
X 
X 
Vital Signs15 
X 
X 
Physical/Neurological Exam 
 
X 
Clinical Assessment16  
 
X 
12-Lead ECG 
 
X 
Cognitive Testing17 
X 
X 
Annual/Volumetric MRI 
 
X 
Lumbar Puncture (CSF)18 
 
X 
PET Imaging 
 
X19 
3T Safety and Volumetric MRI 
 
X 
Randomization 
 
X20 
Study Drug Administration  
 
X 
Footnotes: 
1. Visits (designated as occurring at home[H]) may occur at the DIAN-TU site or, for subjects who live at a distance from 
the DIAN-TU site, these visits may be conducted by a home health nurse at the subject’s home or other trial-identified 
location.  These visits may include phone calls from the host DIAN-TU site staff. 
2. The specific date during the baseline visit (V2) when the first dose of study drug is administered should be used to 
determine timing of subsequent visits and for calculating time between screening visit (V1) and baseline visit (V2). 
3. Informed consent may be obtained in two steps if more than one drug is enrolling concurrently.  Subjects will have the 
opportunity to review the main informed consent form (ICF) and, if applicable, the supplemental drug-specific ICF and 
to discuss with DIAN-TU site study staff on the phone or in-person.  They can sign the main ICF at home or at the DIAN-
TU site.  The main ICF must be signed before any study procedures are performed.  After screening labs are obtained 
and the subject is randomized to a specific study drug arm at V2, the subject will review and sign a supplemental study 
drug-specific consent that details specific risks/benefits and procedures for the study drug arm to which they were 
assigned, when applicable.  If only one study drug arm is enrolling, one consent may be used in the same fashion as the 

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‘main consent’ is referenced within. 
4. If applicable, study drug-specific supplemental consent should be reviewed and signed after randomization. 
5. Family history/age at onset and demographic information for subject and study partner will be collected during the 
screening period and confirmed at the baseline visit, 
.  
This information will not be collected at subsequent visits unless the subject or study partner becomes aware of new 
information or the study partner changes during the study. 
6. Home health nurses will have specific scripts or forms to prompt assessment and collection of medical treatment 
history, health changes or complaints (for assessment of adverse events by the site) and concomitant medications.  
 
7. Preexisting conditions will be documented at screening visit and reviewed at baseline visit (V2) prior to study drug 
administration. 
 
 
9. Provenance testing to confirm specimen identity will be performed at baseline visit only (V2), 
 
 
10. Includes TSH, B12, hemoglobin A1c, PT, PTT, and INR are drawn at Visit 1 only 
11. Serum pregnancy testing will be performed at screening (V1).  Urine pregnancy testing will be performed at V2.  
Pregnancy tests must be confirmed as negative prior to dosing with study drug.  Urine pregnancy test must be 
completed and confirmed as negative either the day of or the day prior to any PET scan; if PET scans occur on more 
than 2 consecutive days during annual visits more than one urine pregnancy test will be required.  Women who have 
undergone tubal ligation are required to have pregnancy tests performed.  Alternate tests may be used if urine 
collection is not feasible but must be approved by the sponsor in advance. 
12. Pharmacokinetic (PK) blood samples will be obtained before study drug administration.  Time of collection and timing 
of drug administration will be recorded. 
13. See each drug-specific appendix for additional details. 
14. For future studies, including future regulatory inquiries or additional monitoring of anti-drug antibodies or other drug-
specific tests.  See main protocol section 6.1.12. 
15. Blood pressure, heart rate, respiratory rate, and body temperature will be collected at all visits.  Height will be 
measured at baseline.  Weight will be collected at baseline (V2). 
16. Clinical assessments: DIAN-TU clinical assessment battery includes: study partner interview and administration of 
Clinical Dementia Rating (CDR) and supplemental CDR; clinician assessment of symptoms and diagnosis; Geriatric 
Depression Scale (GDS), Functional Assessment Scale (FAS), Neuropsychiatric Inventory (NPI-Q), and Mini Mental State 
Evaluation (MMSE). 
17. The Cognitive testing battery will include both iPad administered and conventional psychometric (pen/paper) cognitive 
testing.  See section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core Procedures Manual for additional 
information.  The full battery will be administered at baseline (V2) and at annual visits.  A subset of the full battery (see 
section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core Procedures Manual) will be administered by the 
home health nurse in the home, if applicable, as a practice battery at the screening visit (V1), 
 
.  Cognitive testing should be completed before study drug infusion or injection. 
18. Lumbar puncture (LP) should be performed after magnetic resonance imaging (MRI), if on the same date.  Lumbar 
punctures should be performed at approximately 8 am local time under fasting conditions (water is allowed and 
encouraged).  Cerebrospinal fluid (CSF) will be sent to a local laboratory for cell count and differential, glucose and 
protein as well as to central lab for sample management, including Washington University Biomarker Core lab and 
designated research/referral labs for biomarker and drug-specific analyses.  Site staff should contact the subject 24-48 
hours after the LP to assess for adverse effects of the LP. 
19. See details in each drug-specific appendix. 
20. Prior to randomization, verify that all inclusion/exclusion criteria are met, including ARIA findings on baseline MRI. 
 

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APPENDIX 3: GANTENERUMAB 
 
DRUG-SPECIFIC INFORMATION: 
Gantenerumab (RO4909832) 
 
DIAN-TU-001:  A Phase II/III Randomized, Double-Blind, Placebo-
Controlled, Cognitive Endpoint, Multicenter Study of Potential Disease 
Modifying Therapies in Individuals at Risk for and with Dominantly 
Inherited Alzheimer’s Disease 
 
Regulatory Sponsor: 
Washington University in St. Louis 
Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) 
Department of Neurology 
Campus Box 8111, 660 S. Euclid 
Saint Louis, MO 63110 
 
Study Product: 
Gantenerumab (RO4909832) 
Protocol Number: 
DIAN-TU-001 
Protocol Version: 
Amendment 10 
Version Date: 
20 Dec 2019 
IND Number: 
115,652 
 
 

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TABLE OF CONTENTS 
APPENDIX 3: GANTENERUMAB ........................................................................................... 123 
TABLE OF CONTENTS .......................................................................................................... 124 
LIST OF TABLES ................................................................................................................... 127 
LIST OF FIGURES ................................................................................................................. 128 
1 
DRUG-SPECIFIC INTRODUCTION ............................................................................... 129 
 
Background ......................................................................................................... 129 
 
Study Drug ........................................................................................................... 129 
 
Preclinical Data ................................................................................................... 129 
 
Clinical Data ........................................................................................................ 130 
 
Dose Selection/Rationale in Double-Blind Period .............................................. 137 
 
Risks/Benefits ...................................................................................................... 141 
 
Drug-specific Study Design ................................................................................. 142 
 
Rationale for Biomarker Endpoint ...................................................................... 142 
 
Primary Study Endpoint ...................................................................................... 142 
 
Additional Study Endpoints and Biomarker Endpoint for Interim Analyses ...... 142 
 
Primary Safety Endpoints .................................................................................... 143 
 
Drug-specific Tests .............................................................................................. 143 
1.12.1 
Pharmacokinetics (PK) ...................................................................... 143 
1.12.2 
Anti-drug-antibodies (ADA) .............................................................. 144 
 
Drug-specific Safety Concerns ............................................................................ 145 
1.13.1 
Amyloid related imaging abnormalities (ARIA) ................................ 145 
1.13.2 
Injection site reactions ...................................................................... 146 
 
ARIA-Related Interventions Including Dose Changes and Discontinuation ....... 146 
 
Drug-specific Discontinuations or Withdrawal ................................................... 149 
2 
STUDY DRUG ........................................................................................................... 149 
 
Double-blind Period ............................................................................................ 149 
2.1.1 
Drug Description ............................................................................... 149 
2.1.2 
Drug Treatment Regimen ................................................................. 150 
2.1.3 
Packaging, Preparation and Administration of Study Drug .............. 151 

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2.1.4 
Blinding of Study Drug ...................................................................... 152 
2.1.5 
Dispensing of Study Drug .................................................................. 152 
2.1.6 
Assessing Compliance with Study Drug ............................................ 153 
 
Open-label Extension Period .............................................................................. 153 
2.2.1 
Drug Description ............................................................................... 153 
2.2.2 
Drug Treatment Regimen ................................................................. 154 
2.2.3 
Packaging, Preparation and Administration of Drug Product .......... 156 
2.2.4 
Blinding of Drug Product ................................................................... 157 
2.2.5 
Dispensing of Drug Product .............................................................. 157 
2.2.6 
Assessing Compliance with Drug Product......................................... 158 
3 
STUDY PROCEDURES ............................................................................................... 158 
 
Enrollment .......................................................................................................... 158 
 
Randomization .................................................................................................... 158 
 
Specific Study Visits – Double-blind Treatment Period ...................................... 159 
3.3.1 
Visit 1 (screening visit) ...................................................................... 160 
3.3.2 
Visit 2 (baseline/first dose) ............................................................... 161 
3.3.3 
Visit 3 ................................................................................................. 163 
3.3.4 
Visits 4, 6, 7, 9, 10, 12-14, 16, 17, 19, 20, 22, 23, 25-27, 29-33, 35-
40, 42-46, 48-53, 55-59, 61-66, 68-72, 74-79, 81-85, and 87-92...... 163 
3.3.5 
Visits 5, 11, 18, and 24 ...................................................................... 164 
3.3.6 
Visit 8 ................................................................................................. 165 
3.3.7 
VISIT 15: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 166 
3.3.8 
Visit 21 ............................................................................................... 167 
3.3.9 
VISIT 28: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 167 
3.3.10 
Visits 34 and 47 ................................................................................. 169 
3.3.11 
VISIT 41: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 169 
3.3.12 
VISIT 54: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 170 
3.3.13 
VISITS 60, 73, and 86 ......................................................................... 171 
3.3.14 
VISITS 67, 80, and 93: ANNUAL VISITS AT HOST DIAN-TU SITE/END 
OF DOUBLE-BLIND TREATMENT ....................................................... 172 

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3.3.15 
End of Study Visit .............................................................................. 173 
3.3.16 
Early Termination/Post-treatment Follow-up .................................. 173 
3.3.17 
Safety Magnetic Resonance Imaging ................................................ 174 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 
DRUG-SPECIFIC ANALYSIS PLAN ............................................................................... 181 
 
DIAN-Multivariate Cognitive Endpoint Power Analysis and Sample Size 
Determination ..................................................................................................... 181 
 
Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification .. 181 
4.2.1 
Biomarker Endpoint Power Analysis ................................................. 181 
4.2.2 
Biomarker Endpoint Sample Size Justification .................................. 182 
4.2.3 
Interim Analysis ................................................................................. 183 
 
Other Drug-Specific Analyses .............................................................................. 184 
 
Changes to the Data Analysis .............................................................................. 184 
5 
DRUG-SPECIFIC ADVERSE EVENTS AND REPORTING ................................................. 184 
REFERENCES ....................................................................................................................... 185 
GANTENERUMAB SCHEDULE OF VISITS:  4 YEAR DOUBLE-BLIND TREATMENT PERIOD ......... 186 
GANTENERUMAB SCHEDULE OF VISITS: TREATMENT BEYOND YEAR 4 ................................. 192 
GANTENERUMAB SCHEDULE OF VISITS: OPEN-LABEL EXTENSION ........................................ 196 
 

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LIST OF TABLES 
Table 1 
Procedures for Asymptomatic ARIA-E ....................................................................... 147 
Table 2 
Procedures for Symptomatic ARIA-E: Any incidence of symptomatic ARIA-E or 
asymptomatic with lesions >2 cm .............................................................................. 148 
Table 3 
Procedures for ARIA-H Microhemorrhage ................................................................. 148 
Table 4 
Procedures for Superficial Siderosis .......................................................................... 149 
Table 5 
DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule .................................... 150 
Table 6 
Gantenerumab High-concentration Liquid Formulation Dosing Table ..................... 153 
 
 
Table 8 
Gantenerumab - Q4Wk Formulation Dosing Table ................................................... 157 
Table 9 
The effect size with 80% power in comparison to the reported effect size in a 
prior study and the corresponding power with proposed sample sizes ................... 183 
Table 10 Power to detect the planned differences after dose titration by 52 subjects on 
active drug (42 after 5% annual attrition) and 34 subjects on placebo (27 after 
5% annual attrition) ................................................................................................... 183 
 

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LIST OF FIGURES 
Figure 1 Mean (SD) SUVR reduction by treatment group over time (mean cerebellum 
grey reference) ........................................................................................................... 139 
Figure 2 Randomization Scheme:  All Subjects in Gantenerumab and Solanezumab Arms ... 159 
Figure 3 Randomization Scheme: Gantenerumab and Solanezumab Mutation Positive 
Subjects Only .............................................................................................................. 159 
 

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1 
DRUG-SPECIFIC INTRODUCTION 
 Background 
Both active and passive immunization strategies directed against amyloid beta peptides are 
currently under investigation.  The first preclinical studies demonstrating reduction in amyloid 
burden were performed in APPV717F (“PDAPP”) transgenic mice over 12 years ago (Schenk et al., 
1999; Bard et al., 2000).  The PDAPP mouse and all other genetic mouse models of AD are 
based on the mutations in APP, PSEN1 and PSEN2 that underlie the dominantly inherited forms 
of AD represented in the DIAN cohort.  The preclinical studies in these mouse models are even 
more relevant to these individuals than to those with sporadic AD. 
 Study Drug 
Gantenerumab is a fully human IgG1 antibody which binds specifically to aggregated forms of 
Aβ (including oligomers, fibrils, and plaques) and targets the amyloid pathology associated with 
AD. Because Aβ accumulation is believed to begin well before the onset of AD dementia, early 
intervention is expected to provide the greatest benefit to patients. 
 Preclinical Data 
Gantenerumab is a recombinant, completely human, monoclonal antibody of the IgG1 subclass 
directed against the Aβ peptide.  It is a novel type of antibody that recognizes a conformational 
epitope of Aβ and binds to both major types of Aβ (Aβ40/42).  Binding characteristics for 
gantenerumab were engineered to achieve specific and highly sensitive recognition of 
aggregated Aβ, like the fibrillar assembly structure of the human Aβ peptide, which is the 
predominant component in Aβ plaques.  Gantenerumab recognizes aggregated Aβ with high 
affinity 
 as determined in vitro.  Specificity was demonstrated for native human Aβ 
plaques on brain sections.  
 
In functional assays gantenerumab induced cellular phagocytosis of human amyloid-β deposits 
in AD brain slices when co-cultured with primary human macrophages and neutralized 
oligomeric Aβ42-mediated inhibitory effects on long-term potentiation in rat brain.  In 
APP751swedishxPS2N141I transgenic mice, gantenerumab showed sustained binding to 
cerebral Aβ and, upon chronic treatment, significantly reduced small Aβ plaques by recruiting 
microglia and prevented new plaque formation.  Unlike other Aβ antibodies, gantenerumab did 
not alter plasma Aβ suggesting undisturbed systemic clearance of soluble Aβ.  Overall, 
gantenerumab preferentially interacts with aggregated Aβ in the brain and lowers Aβ by 
eliciting effector cell-mediated clearance (Bohrmann et al., 2012; Ostrowitzki et al., 2012). 
Effective brain penetration and binding to Aβ plaques was demonstrated in a double-transgene 
mouse model expressing AD-related mutations that display a pronounced amyloidosis 

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phenotype.  Gantenerumab showed significant Aβ plaque binding up to nine weeks, indicating 
that there is no requirement for continuous high peripheral levels to achieve a sustained 
binding of gantenerumab to amyloid plaques. 
 Clinical Data  
Gantenerumab has been investigated in seven completed Phase 1 clinical trials.  A brief 
summary of the results of these studies follows.  For a more thorough description, refer to the 
IB. 
BN18726 
A total of 30 patients (16 males, 14 females) diagnosed with mild to moderate probable AD 
participated in a single ascending dose (SAD) study (BN18726) which was completed in August 
2008.  Patients received a single IV (intravenous) dose of gantenerumab (doses ranging from 
6 mg to 400 mg) or placebo.  All patients completed the SAD study and gantenerumab was well 
tolerated. 
WP22461 
WP22461 was a bioavailability study conducted in 42 healthy male subjects. The study 
evaluated safety, tolerability, and pharmacokinetics of gantenerumab following a single IV 
infusion or subcutaneous (SC) injection.  In this study, subjects received a single dose of 
gantenerumab at the following doses and routes: 60 mg by IV infusion, 75 mg SC injection, or 
150 mg SC injection.  Gantenerumab was generally well tolerated when administered SC. 
JP22474 
Study JP22474 was a Phase I SAD study designed to investigate safety, tolerability, PK and PD 
after IV infusion of gantenerumab in Japanese AD patients.  The results showed that single IV 
doses of up to 200 mg gantenerumab were well tolerated. 
NN19866 
In the multiple ascending dose (MAD) study (NN19866), a total of 60 patients (34 males and 
26 females) diagnosed with mild to moderate probable AD received multiple IV doses of 
gantenerumab (doses of 6 mg, 20 mg, 60 mg, and 200 mg) or placebo on an every 4-week 
(q-4-wk) schedule for up to 7 months.  Due to findings of “vasogenic edema” and “microbleeds” 
on brain magnetic resonance imaging (MRI) scans (amyloid-related imaging abnormalities or 
ARIA) which occurred in some patients in cohort 4 (gantenerumab 200 mg or placebo), it was 
decided to terminate dosing for all patients on June 9, 2008.  At that time, 16 patients were 
receiving 200 mg of gantenerumab, and 4 patients were receiving placebo.  These patients had 
received between 2 to 5 doses each.  When the patients were then genotyped for APOE, APOE4 
carrier status emerged as a risk factor for the occurrence of these MRI findings, as has been 

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reported for bapineuzumab.  The MRI findings are described further below.  Otherwise, 
gantenerumab was well tolerated in NN19866. 
NN19866 Pharmacodynamics 
In a substudy of NN19866 (NN19866-PET), the protocol was amended in order to evaluate the 
effect of gantenerumab on amyloid load in the brain (defined as standardized uptake value 
ratio of a cortical composite volume of interest over cerebellar cortex and using [11C]PiB-PET) in 
18 patients (4 in the placebo group, 8 in the 60-mg dose group and 6 in the 200-mg dose 
group).  A median decrease from baseline 
 was seen in the gantenerumab 200 mg dose 
group while an increase was seen in the placebo group 
 and relative stability 
compared to baseline in the 60-mg group
 
NN19866 Magnetic Resonance Imaging  
The multiple ascending dose (MAD) study NN19866 was prematurely terminated (after patients 
in the 200-mg group had received 2 to 5 doses) due to ARIA-E seen after 2 to 4 doses of 
gantenerumab 200 mg.  Notably, the findings, best seen on the Fluid Attenuated Inversion 
Recovery (FLAIR) sequences, were only reported in carriers of APOE-4 and seemed more 
prominent in patients who were homozygous for APOE-4 (E4/E4).  Concomitant ARIA-H 
microbleeds were only observed in the two carrier patients homozygous for APOE4 (E4/E4).  No 
patient required treatment and the ARIA-E findings spontaneously resolved 1-4 months after 
discontinuation of gantenerumab. 
JP22431 
In a MAD study (JP22431), a total of 29 patients diagnosed with mild to moderate probable AD 
received multiple SC doses of gantenerumab (doses of 75 mg, 105 mg, and 225 mg) or placebo 
on q-4-wk schedule for up to 7 months.  Gantenerumab was generally well tolerated when 
administered SC. 
WP27951 
A study comparing lyophilized (Lyo-F) and high-concentration liquid formulations (HCLF) 
included a total of 120 healthy subjects.  Subjects were randomized to receive single SC doses 
of either 105 or 225 mg of the Lyo-F formulation or 105, 225, or 300 mg of the HCLF 
formulation.  Gantenerumab was generally well tolerated when administered SC. 
BP29113 
A study comparing Lyo-F and HCLF formulations included a total of 48 healthy subjects.  
Subjects were randomized to receive single SC dose of 225 mg in a pre-filled syringe or as a 
lyophilized formulation.  Gantenerumab was generally well tolerated when administered SC. 

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BP30042 
A study assessing the safety and tolerability of single ascending doses of SC gantenerumab 
included a total of 38 healthy male subjects (32 on gantenerumab and 6 on placebo). Subjects 
were randomized to receive single doses of 450 mg, 900 mg or 1500 mg. Gantenerumab was 
generally well tolerated up to the highest tested dose when administered SC. 
WP39322 
A study comparing pain of a single dose of gantenerumab administered SC in the abdomen 
included a total of 50 subjects. Subjects were randomized to receive a single dose of 300 mg in 
the abdomen in 5 or 15 seconds followed by 2 SC administrations of a placebo solution (one in 
abdomen and one in the thigh). Gantenerumab was generally well tolerated. 
WP40052 
A study comparing the relative bioavailability, safety and tolerability following single dose SC 
administration of 600 mg of gantenerumab produced with the G3 (Reference) or G4 (Test) 
process included a total of 114 healthy subjects.  The plasma exposure in terms of AUCInf was 
approximately 1.18 fold higher after SC administration of 600 mg gantenerumab G4 compared 
to 600 mg gantenerumab G3, whereas Cmax were similar. Gantenerumab produced with either 
process was generally well tolerated. 
Clinical Pharmacokinetics 
The PK of gantenerumab after intravenous administration were investigated in Caucasian 
patients with mild to moderate AD after single (Study BN18726) and multiple doses (Study 
NN19866), after single dose in Japanese patients with mild to moderate AD (Study JP22474), 
and after single dose in healthy volunteers (Study WP22461). 
 
 Plasma concentrations of 
gantenerumab appeared to increase dose-proportionally after intravenous dosing. 
 
 
The PK of gantenerumab following a single SC dose was assessed in 6 studies in healthy 
volunteers (WP22461, WP27951, BP29113, BP30042, WP39322 and WP40052). 
 
 
 

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In general, gantenerumab exposures increased dose proportionally.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phase III Studies 
Global Phase III studies investigating the effect of SC gantenerumab on cognition and function 
include two multicenter, double-blind, randomized, placebo-controlled Phase III studies, 
WN29922 (Graduate 1) and WN39658 (Graduate 2), in patients with early (prodromal to mild) 
AD, the ongoing open-label extension of Study WN25203 in subjects with prodromal AD, and 
ongoing open-label extension of Study WN28745 in subjects with mild AD. 
The double-blind phase of ongoing Study WN28745 was unblinded to selected Roche personnel 
as of 3 March 2016.  Upon review of the unblinded data, the Independent Data Monitoring 
Committee (IDMC) recommended the continued implementation of the open-label extension.  
Further details from each study are summarized below. 
WN29922 and WN39658 
WN29922 (Graduate 1) and WN39658 (Graduate 2), in patients with early (prodromal to mild) 
AD are identical in design, and meet health authority expectations for two confirmatory Phase 
III studies that are conducted independently, yield consistent results, and ensure an adequate 
safety database. The study drug target dose in WN29922 and WN39658 (510 mg SC every 2 

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weeks [Q2W], which is equivalent to 1020 mg SC Q4W) has been adjusted to account for the 
difference in bioavailability between the newly-developed gantenerumab drug substance (G4) 
and the drug substance used in Studies WN25203 and WN28745 (G3). 
WN25203 
WN25203 is a Phase III study investigating the effect of SC gantenerumab on cognition and 
function in prodromal AD with futility analysis conducted when 50% of the subjects completed 
treatments for 2 years.  The doses in the study were 105 mg and 225 mg SC every 4 weeks for 
4 years (including a 2-year double blind placebo-controlled extension).  Because ARIA findings 
seemed to be more frequent in carriers of APOE ε4 in the earlier MAD study, subjects who were 
homozygous for this gene initially did not receive the dose of 225 mg SC in Study WN25203 but 
an amendment later allowed for full dose regardless of APOE ε4.  This futility analysis took 
place in December 2014 and led to the study being declared futile and suspension of dosing.  
No safety issues were identified in the futility analysis.  Subsequently, the trial has continued as 
an open-label extension utilizing doses of up to 1200 mg. 
WN25203-PET 
Study WN25203 includes a substudy, WN25203-PET, designed to assess changes in amyloid 
load over time in a subset of patients with prodromal AD by PET imaging using the amyloid 
tracer Florbetapir 18F (18F-AV-45; AMYViD). Results from amyloid PET assessments show clear 
dose- and time-dependent reductions in cortical to cerebellum standard uptake value ratios 
(SUVr), with greater reduction over longer periods of exposure to gantenerumab. This 
reduction was present regardless of the reference region utilized for the analysis. Patients in 
the 225 mg gantenerumab arm showed consistent and potentially cumulative SUVr reduction 
of 5 to 10% over a period of 2 to 3 years. In an analysis of the concentration dependence of the 
SUVr reductions, patients with greater concentrations of gantenerumab experienced greater 
reductions in SUVr. 
WN28745 
Study WN28745 was initially designed as a 2-year, double-blind, placebo-controlled, efficacy 
and safety study of gantenerumab in approximately 1000 patients with mild AD, and was 
initiated in the first quarter of 2014.  Patients with probable mild AD were identified based on 
established NINCDS/ADRDA clinical criteria, low CSF Aβ42, and cognitive decline.  The 
co-primary efficacy endpoints included measures of cognition (Alzheimer's Disease Assessment 
Scale - Cognitive Subscale [ADAS-Cog]) and function (Alzheimer's Disease Co-operative Study - 
Activities of Daily Living Inventory [ADCS-ADL]).  Based on the initial design of WN28745, all 
patients were to follow a slow titration scheme independent of the ApoE ε4 genotype, starting 
gantenerumab at 105 mg SC Q4W (every 4 weeks) for seven doses, with progression to 225 mg, 
based on acceptable MRI findings.  The study enrolled 389 patients.  Analysis of the WN25203 
results, and data from other AD studies, indicated that efficacy would likely be apparent at 
much higher doses than originally tested in the Phase III Studies.  As a result, enrollment in the 

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double-blind phase of the WN28745 study was halted in November 2015.  The study was 
amended into an open-label extension evaluating the safety and tolerability of gantenerumab 
at higher doses (up to 1200 mg) using different titration schemes. 
Dosing of Gantenerumab up to 1200 mg Q4W: Open-label Extension of WN25203 and Study 
WN28745 
Both protocols for Studies WN25203 and WN28745 were amended to convert the studies into 
open label extensions to evaluate SC dosing of gantenerumab up to target dose of 1200 mg 
Q4W.  Enrollment into the WN25203 OLE was closed on 30 June 2017; overall 154 of the 799 
patients originally randomized into the study entered the OLE.  Enrollment into the WN28745 
OLE was closed on 31 July 2017; overall, 230 of 389 patients originally randomized into the 
study entered the OLE. 
Eighty-nine patients were initially enrolled in the OLE PET substudies, of whom 67 patients 
received follow-up scans at OLE week 52, 40 received scans at OLE week 104, and 23 received 
scans at OLE week 156 by the cutoff date of 31 May 2019.  Patients were divided into three 
analysis cohorts due to heterogeneous baseline characteristics, time off-dose before OLE 
dosing, and OLE titration schedules: 1) MR-DBP: patients in the placebo arm of WN28745 
Marguerite RoAD, 2) MR-DBA: patients in the active treatment arms of WN28745, and 3) SR: a 
combined cohort of all patients from the WN25203 Scarlet RoAD study.  SR patients were 
combined into a single cohort since all patients were off dose for 16-19 months prior to OLE 
dosing. 
 
  Amyloid reductions are consistently seen in 
nearly all patients of the three analyzed subgroups. 
The study showed higher reductions of amyloid plaque over a shorter time period with the 
1200 mg dosing regimen of gantenerumab compared to 105 or 225 mg dosing.  
 
 
Study WN25203 includes a substudy, WN25203-PET, designed to assess changes in amyloid 
load over time in a subset of patients with prodromal AD by PET imaging using the amyloid 
tracer Florbetapir 18F (18F-AV-45; AMYViD).  Results from amyloid PET assessments show clear 
dose- and time-dependent reductions in cortical to cerebellum standard uptake value ratios 
(SUVr), with greater reduction over longer periods of exposure to gantenerumab.  This 
reduction was present regardless of the reference region utilized for the analysis.  Patients in 
the 225 mg gantenerumab arm showed consistent and potentially cumulative SUVr reduction 
of 5 to 10% over a period of 2 to 3 years.  In an analysis of the concentration dependence of the 
SUVr reductions, patients with greater concentrations of gantenerumab experienced greater 
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In the OLE period of Study WN25203 up to 1 May 2019, all 154 patients dosed with 
gantenerumab had a post-baseline MRI scan;
 
 The majority of ARIA-E findings were asymptomatic, 
 
  The CNS AEs were mostly mild to 
moderate in intensity, non-serious, did not require permanent cessation of study treatment, 
and resolved with protocol-defined ARIA management rules. 
 
In the OLE period of Study WN25203 up to 13 February 2018, all 154 patients dosed with 
gantenerumab had a post-baseline MRI scan;
 The majority of ARIA-E findings were asymptomatic, 
 
The CNS AEs were mostly mild to 
moderate in intensity, non-serious, did not require permanent cessation of study treatment, 
and resolved with protocol defined ARIA management rules
 
  
In the OLE period of Study WN28745, 219 of 225 patients dosed with gantenerumab had a post-
baseline MRI scan;
 
  The majority of ARIA-E events were 
asymptomatic, 
  The CNS 
AEs were mostly mild to moderate in intensity, non-serious, did not require permanent 
cessation of study treatment, and resolved spontaneously with protocol-defined ARIA 
management rules.  
 
 
 
Immunogenicity and Safety 
 
 
 
 
 

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of 100.  Beyond ARIA events, injection site reactions were the most common event occurring 
more frequently with gantenerumab than with placebo; these events were also mild, non-
serious, 
  No drug-effect on 
white blood cells or neutrophils was observed. 
Summary 
Early evidence with anti-amyloid monoclonal antibodies revealed dose-dependent ARIA, small 
effects on clinical outcomes, and a mixed impact on biomarkers, namely, an association 
between clinical and biomarker (PET) outcomes with solanezumab but no such association with 
bapineuzumab (Salloway et al.  2014, Sperling et al.  2012, and Doody et al.  2014).  Evidence 
from two clinical trials with highly similar antibodies against aggregated Aβ including plaques 
(i.e., gantenerumab and aducanumab) provide new insights into the biological mechanism of 
aggregated amyloid removal, and the doses required to potentially achieve a therapeutic effect. 
This new evidence also indicates that ARIAs are predictable and manageable events, and that 
higher dosing for gantenerumab may be needed to achieve clinical efficacy.  New 
gantenerumab data also suggest that beneficial impact on target and downstream biomarkers 
effects are measurable and reproducible (gantenerumab WN25203 positron emission 
tomography [PET] and cerebrospinal fluid [CSF] data). 
ARIAs and injection site reactions are the dominating safety events that have emerged as of 
today, under the treatment of gantenerumab.  Overall, gantenerumab up-titration reduces the 
risk of ARIA-E; ARIA-E incidence observed in the open-label extensions has been in the expected 
range and in alignment with the ARIA-E PK-PD model.  ARIAs are clinically manageable by 
protocol-defined MRI monitoring and dose intervention algorithms. 
A dedicated risk management for ARIA has been implemented.  It appears that appropriate MRI 
monitoring associated with drop-out criteria provides a sufficient risk minimization.   
No other clinical safety liabilities of major relevance have emerged. 
 Dose Selection/Rationale in Double-Blind Period 
The initial dose in the DIAN-TU-001 study is 225 mg gantenerumab, administered 
subcutaneously (SC), every 4 weeks. 
This dosing regimen was investigated in heterozygous and non-carriers of ApoE4 in the 
WN25203 trial with an apparently acceptable safety profile.  In this study (WN25203), the dose 
administered to homozygous ApoE4 carriers is 105 mg Q4W SC. 
The starting dose of 225 mg in the DIAN-TU-001 study, including in subjects homozygous for the 
ApoE4 allele is justified based on the following considerations: 
• The DIAN-TU-001 study will apply a similar MRI monitoring scheme to WN25203 and 
WN28745 with a predefined ARIA related intervention algorithm  

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• All new ARIA findings will be reviewed by the Project Arm Leader (PAL) who will advise 
the site on whether a more conservative approach should be considered than defined in 
the ARIA related intervention algorithm (see section 1.14) 
• Subjects recruited into the trial are generally at an early stage of the disease, i.e., at an 
earlier clinical stage or a similar stage as requested for prodromal and mild (sporadic) 
AD patients in the ongoing WN25203 and WN28745 trials 
• The dominantly inherited mutation carrier status (rather than APOE genotype) is the 
predominant risk for AD and for amyloid deposition in the DIAN-TU population 
• Given the PET data obtained in the MAD study where decreases in the amyloid plaque 
burden were observed, the dosage selected based on systemic overall exposure is 
expected to reduce the plaque burden relative to placebo 
Following the approval of Amendment 5, all subjects will initiate up titration.  The proposed 
dose escalation in the DIAN-TU-001 study will begin at 450 mg, administered subcutaneously 
(SC) 
, every 4 weeks.  The titration 
schedule is provided in Table 5. 
Escalation of the initial dose of 225 mg in the DIAN-TU-001 study is justified based on the 
following considerations: 
1) The futility Analyses of trial WN25203 which revealed: 
a) Patient Disposition: Participant attrition rates were not associated with higher doses 
and were nearly identical in the three doses under investigation (placebo, 105 mg, 
and 225 mg), 
 
 
b) Safety: Gantenerumab was safe and well tolerated by patients in this study.  
 
 
 
 
 
 
 The majority of 
ARIA events were asymptomatic. 
c) Biomarker outcome: Results from [AV-45] amyloid PET assessments showed clear 
time-dependent reductions in SUVR, with greater reduction over longer periods of 
exposure to gantenerumab 
 
Overall, these analyses indicated a signal of serum concentration-dependent clinical 
activity and clear evidence of dose-dependent biological activity, suggesting under-
dosing as a potential explanation for the negative outcome of WN25203.  With this 

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conclusion of the need to expand the dose range of gantenerumab, uncertainty 
remained around which ‘higher’ dose to target to achieve clinical efficacy. 
2) The safety reviews of the ongoing DIAN-TU-001 study indicated no clear imaging-related 
serious adverse events and further verified the dose of 225 mg was well tolerated.  In 
the blinded gantenerumab arm of the trial, there were 4 cases of mild symptoms 
associated with ARIA.  Further, the rate of incident microhemorrhage is consistent with 
the current rates in the DIAN observational (DIAN-OBS) study indicating no clear 
differences from the natural history in those exposed to gantenerumab.  Compared to 
the WN25203 ARIA rates reported, the DIAN-TU-001 study has far fewer events.  The 
reason for these differences could in part be due to less vascular risks in the younger 
DIAN-TU population, as well as lower prevalence of APOE ε4 in the DIAN-TU population.  
Together, the excellent safety of gantenerumab 225 mg in the DIAN-TU-001 and the 
need for a higher pharmacodynamics effect strongly supports the decision of increasing 
the dose of gantenerumab. 
 
 
 
 
 
 

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 Risks/Benefits 
Plaque removal effect was demonstrated in the prodromal study WN25203 with the higher 
225 mg dose showing a stronger effect of removal.  These results for the first time showed the 
effect of immunotherapies against Aβ in early (prodromal) AD.  In dominantly inherited 
Alzheimer’s disease (DIAD), amyloid deposition is present at early stages of the disease when 
no memory impairment is present (Bateman et al., 2012).  Thus, the current dose and the 
higher doses to be administered are expected to be effective in DIAD. 
The mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) 
that are associated with DIAD and which subjects in this study who receive active study drug 
will have tested positive for, have very high penetrance (near 100%).  AD is a progressive and 
ultimately fatal disease and no disease modifying treatment is available to date. 
Besides injection site reactions which, however appear of mild intensity in most subjects and 
not limiting the maintenance of subjects in the long-term treatment trial, ARIAs represent a 
side effect of concern in the development of immune-therapeutics targeting Aβ in the brain  
(Sperling et al., 2012).  These changes may include micro-hemorrhage, vasogenic 
edema/effusion and infarction; they are most often asymptomatic, but symptoms have been 
reported in some cases. 

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Therefore, dedicated monitoring and action plans for ARIAs are implemented in respective 
multiple dose clinical trials of gantenerumab including the DIAN-TU-001 study.  Given the 
experiences made with gantenerumab thus far, the proposed risk minimization plan including 
frequent MRI monitoring and reads by independent experts together with an ARIA based dose 
intervention algorithm appears to be effective in preventing clinical sequelae to the subjects 
treated with gantenerumab. 
 Drug-specific Study Design 
Drug-specific study design features include the use of [11C]PiB-PET as the biomarker endpoint.  
In addition, there is an increased frequency of safety MRI scans during the dose escalation 
period, and then every 3 to 6 months thereafter, based on available clinical safety data from 
treatment trials with gantenerumab.  Specific action plans that include dose modification 
should ARIA occur are provided (for details, see section 1.14). 
 Rationale for Biomarker Endpoint  
Rationale for change in amyloid load as measured by [11C]PiB-PET composite standardized 
uptake value (C-SUVR) as biomarker endpoint for DIAN-TU Gantenerumab Arm 
Preliminary studies show that mutation carriers eligible for enrollment in this study are likely to 
have abnormal levels of brain amyloid as measured by [11C]PiB binding (Bateman et al., 2012).  
Statistically significant reductions in [11C]PiB binding were observed in patients treated with 
gantenerumab as compared to controls in a recently completed multiple ascending dose study 
of gantenerumab in which patients with mild to moderate (sporadic) Alzheimer’s disease 
received up to 7 monthly doses (Ostrowitzki et al., 2012). 
 Primary Study Endpoint  
A multivariate disease progression model (MDPM) for repeated measures with a proportional 
treatment effect will be used to assess statistical differences in the rate of decline, relative to 
the expected years from symptom onset, of the DIAN-MCE between the active drug and the 
mutation positive placebos and eligible DIAN-OBS subjects.  See section 3.5 of the main 
protocol for more details. 
 Additional Study Endpoints and Biomarker Endpoint for Interim Analyses 
Additional study endpoints are described in the main study protocol and will be specified as 
secondary and/or exploratory in the gantenerumab-specific SAP.  Refer to the final SAP for 
drug-specific differentiation of endpoint classification based on the respective drug’s target and 
mechanism of action. 

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The following will be used as the biomarker endpoint for interim analysis as well as an 
additional endpoint for the gantenerumab drug arm as specified in the gantenerumab-specific 
SAP appendix: 
Cerebral amyloid imaging using [11C]PiB-PET: Change in the amount of fibrillar amyloid 
deposition as measured by [11C]PiB-PET scans is the biomarker endpoint for gantenerumab.  
Most mutation carriers who are in the range of -15 to + 10 years of dementia onset have 
increased [11C]PiB-PET signal in some brain regions (Figure 1 in main protocol and Bateman et 
al., 2012).  The composite PiB standardized uptake value ratio (C-SUVR, the composite SUVR of 
precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex and 
temporal cortex) is used as the biomarker endpoint. 
 Primary Safety Endpoints  
This study will assess safety and tolerability of treatment with gantenerumab in individuals at 
risk for and with DIAD.  The primary safety endpoints are identical for all study compounds and 
are listed in the main study protocol. 
Particular safety focus in the gantenerumab arm will be given to ARIA and injection site 
reactions.  However, given the still limited data base available today, safety monitoring includes 
all general safety monitoring parameters, including those for vital signs and ECGs, clinical 
chemistry and hematology, urinalysis and any AEs. 
 Drug-specific Tests 
 
 
 
 
 
 
 
 
 
 

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 Drug-specific Safety Concerns 
1.13.1 Amyloid related imaging abnormalities (ARIA) 
As outlined above (section 1.4), ARIAs are a special safety endpoint in studies of Alzheimer’s 
immunotherapies, including both active and passive immunization.  This study includes 
frequent MRI scans to assess for ARIA changes.  ARIA can occur as either cerebral 
edema/effusion (ARIA-E) or as hemorrhages (ARIA-H), typically microhemorrhages, but possibly 
larger hemorrhages or infarction (Sperling et al., 2012). 
Time points for Safety MRI at the 225 mg dose level were originally scheduled for: before the 
first dose (baseline scan for safety reads done at V2) and then about 1 week after dose 2; dose 
4; dose 6; dose 9; dose 17 and dose 22.  Additional safety MRIs were scheduled as part of the 
volumetric MRI at the annual assessments before dose 14 (V15, week 52), dose 27 (V28, week 
104), dose 40 (V41, week 156), and V54 (week 208). 
Following the approval of Amendment 5, all subjects will sign the new ICF and initiate up 
titration starting at the 450 mg dose level.  Subjects may be at different time points in the 
schedule of visits when initiating titration, therefore safety MRIs will be scheduled based on the 
DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule (Table 5).  A safety MRI will be 
scheduled 1 week after the second dose of each titration step, unless otherwise indicated by 
the ARIA-E and ARIA-H management algorithms (section 1.15).  If an annual visit follows the 
second dose of a titration step, the annual MRI assessment can fulfill this requirement as long 
as the MRI reading is reviewed prior to dosing at that visit.  Although the titration schema was 
designed to reach the target dose of 1200 mg administered every 4 weeks, the target dose may 
not be achieved as otherwise dictated by the ARIA-related intervention algorithms or more 
conservative action by the site/sponsor.  The stable dose is defined as the maximum dose the 
subject will remain at for the duration of the trial based on safety.  Once a subject reaches their 
stable dose, safety MRIs will be scheduled to follow every third dose (or approximately every 
3 months).  Additional safety MRIs are done as part of the volumetric MRI at the annual 
assessments: Visit 15 (week 52), Visit 28 (week 104), Visit 41 (week 156), Visit 54 (week 208), 
Visit 67 (week 260), Visit 80 (week 312), and Visit 93 (week 364). 
Amendment 8 includes a revised safety MRI schedule.  A safety MRI will be scheduled 1 week (± 
4 days) after the second dose of each titration step (225 mg, 450 mg, 675 mg, 900 mg), unless 
otherwise indicated by the ARIA-E and ARIA-H management algorithms (section 1.14).  Subjects 

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may be at different titration steps and time points in the schedule of visits at the time of this 
amendment and should be scheduled based upon their current titration step/stable dose at the 
time of the amendment.  For titration step #4, the final titration step (1200 mg), safety MRIs 
will be scheduled 1 week (± 4 days) after every third dose (or approximately every 3 months) 
for the next 6 doses unless otherwise indicated by the algorithm ARIA-E and ARIA-H 
management algorithms.  Although the titration schema was designed to reach the target dose 
of 1200 mg administered every 4 weeks, the target dose may not be achieved as otherwise 
dictated by the ARIA-related management algorithms or more conservative action by the site 
principal investigator/sponsor.  The stable dose is defined as the maximum dose the subject will 
remain at for the duration of the trial based on safety.  Once a subject reaches their stable 
dose, safety MRIs will be scheduled after every 6 doses (or approximately every 6 months) for 
the remainder of the trial unless otherwise indicated by the algorithm (i.e., 6 doses, MRI, 6 
doses, MRI, etc.).  The annual MRI assessment can fulfill these requirements as long as the MRI 
reading is reviewed prior to dosing at that visit; however, the safety MRIs following every sixth 
dose of 1200 mg must occur regardless of when the annual MRI is scheduled. 
Safety MRIs will be performed at the same field strength throughout the study, and if possible 
on the same scanner.  All MRIs will be centrally read. 
The MRI schedule may be changed according to the ARIA-related dosing intervention algorithm 
(see tables in section 1.14) or per individual request by the site principal investigator or 
delegated sub-investigator, Project Arm Leader (PAL), or Medical Director or designee. 
1.13.2 Injection site reactions 
Injection site reactions after subcutaneous administration have been observed in up to one-
third of subjects.  These reactions are mainly characterized as injection site erythema and rash.  
It is likely that the injection site reactions may be at least partly related to the injection volume.  
The large majority of events have been mild. 
 ARIA-Related Interventions Including Dose Changes and Discontinuation 
See main protocol sections 1.2, 3.8, 6.1.15 and 6.1.16 for details of MRI reading and reporting.  
The Mayo-ADIR Clinic will review MRIs and provide a report on ARIA-E and ARIA-H.  This report 
will include both definite and possible findings.  A report of new definite ARIA changes in a 
subject will trigger a review by the Medical Director or designee, Project Arm Leader (PAL), and 
site principal investigator or delegated sub-investigator.  The site principal investigator or 
designated sub-investigator, in conjunction with the appropriate PAL and the DIAN-TU Medical 
Director or designee, will review new ARIA findings and apply the intervention algorithms 
below using best clinical judgment to weigh the data available to decide whether changes in 
drug treatment are indicated. 

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ARIA-related intervention algorithm 
The tables below detail the ARIA-E linked intervention algorithm based on these scores (Table 1 
and Table 2) and the intervention algorithm for ARIA-H microhemorrhage (Table 3) and 
superficial siderosis (Table 4).  Algorithms are based on definite ARIA findings only.  For ARIA-E, 
the algorithm relies on measures of the largest diameter of any ARIA-E.  For ARIA-H, areas of 
microhemorrhage are counted and larger areas of hemorrhage (macrohemorrhage) are noted.  
Should both, ARIA-E and ARIA-H be present in the same subject, the more conservative 
procedure should be followed. 
For ARIA cases where there are symptoms that are possibly related to the ARIA findings, more 
stringent procedures should be considered (e.g., withhold treatment for symptomatic cases 
even if the procedures in the table would not require it). 
Table 1 
Procedures for Asymptomatic ARIA-E 
Number of New 
Occurrences1  
Dose Adjustment 
MRI Monitoring 
Any new individual 
lesions ≤ 2 cm  
Continue current dose; do NOT titrate up 
If stable or decreased on subsequent MRI, continue 
study drug at the same dose but do NOT titrate up 
Once resolved, up titration may resume.  An 
appropriate dosage may be resumed based on 
discussion between the site PI or designated sub-
investigator, Project Arm Leader, and Medical 
Director or designee, at minimum 
Every 4 weeks until 
resolved 
 
 
Any new individual 
lesions > 2 cm  
Follow the Symptomatic ARIA-E guidance 
Follow the Symptomatic 
ARIA-E guidance 
1 Based on new definite ARIA findings (excluding baseline incidences) 

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Table 2 
Procedures for Symptomatic ARIA-E: Any incidence of symptomatic ARIA-E or 
asymptomatic with lesions >2 cm 
Step-wise Response 
Dose Adjustment 
MRI Monitoring 
Initial action 
Suspend/hold dosing. 
Every 4 weeks until 
resolved 
Once symptoms and 
ARIA-E resolve 
Restart study drug at an appropriate dosage 
based on discussion between the site PI or 
designated sub-investigator, Project Arm 
Leader, and Medical Director or designee, at 
minimum 
4 weeks after dosing 
restart  
If no new MRI findings 
after dosing restart and 
MRI 
Resume up titration per protocol.  An 
appropriate dosage may be resumed based on 
discussion between the site PI or designated 
sub-investigator, Project Arm Leader, and 
Medical Director or designee, at minimum 
Resume MRI monitoring 
per protocol 
Note: Asymptomatic lesions > 2 cm are based on measurements of new definite ARIA findings 
 
Table 3 
Procedures for ARIA-H Microhemorrhage 
Number of New 
Occurrences1  
Dose Adjustment 
MRI Monitoring 
5-9 new, 
cumulative 
occurrences2 
Continue current dose and titration schedule 
MRI 4 weeks later then 
continue MRI monitoring 
per protocol 
10-15 new, 
cumulative 
occurrences 
Suspend/hold dosing until stable upon MRI.   
An appropriate dosage may be resumed based on 
discussion between the site PI or designated sub-
investigator, Project Arm Leader, and Medical 
Director or designee, at minimum 
Every 4 weeks until 
stable 
>15 new, 
cumulative 
occurrences 
A dosing and safety monitoring plan for the subject 
to be developed by the Site PI, Project Arm Leader, 
and Medical Director or their designees based on a 
thorough safety review. If dosing is discontinued, 
the subject will be encouraged to complete other 
assessments and visits per protocol 
MRI 4 weeks later with 
further MRI monitoring 
based on the safety 
monitoring plan 
developed for the subject 
1 Based on new definite ARIA findings (excluding baseline incidences) 
2 MRI 4 weeks after each new occurrence between 2-4 microhemorrhages, i.e., 2, 2 to 3, 3 to 4. 
 

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Table 4 
Procedures for Superficial Siderosis 
Number of New 
Occurrences1  
Dose Adjustment 
MRI Monitoring 
1 new occurrence 
of superficial 
siderosis 
Continue dosing at the subject’s current dose; do 
NOT titrate up. 
MRI 4 weeks later then 
continue MRI monitoring 
per protocol 
2-3 new 
occurrences of 
superficial siderosis 
Stop/hold dosing until MRI 4 weeks later.   
If additional MRI shows no new lesions, an 
appropriate dosage and MRI monitoring frequency 
may be resumed based on discussion between site 
PI or designated sub-investigator, Project Arm 
Leader, and Medical Director or designee, at 
minimum 
MRI 4 weeks later then 
continue MRI monitoring 
per protocol 
> 3 new 
occurrences of 
superficial siderosis 
Consider discontinuation of dosing for the 
remainder of the trial but continue participation 
and completion of other assessments and visits per 
protocol 
MRI 4 weeks later with 
further MRI monitoring 
per the safety monitoring 
plan developed for the 
subject 
1 Based on new definite ARIA findings (excluding baseline incidences) 
 Drug-specific Discontinuations or Withdrawal 
Following the approval of Amendment 5, all subjects will initiate dose titration.  Refusal to dose 
escalate will be considered as withdrawal of consent and the subject will be discontinued from 
the study. 
2 STUDY DRUG 
 Double-blind Period 
2.1.1 Drug Description 
Gantenerumab (RO4909832) is a recombinant human anti-Aβ monoclonal antibody of the 
immunoglobulin subclass G1 (IgG1) that binds specifically to aggregated Aβ.  
 
  
Following the approval of Amendment 5, study drug is provided as sterile, preservative-free 
high-concentration liquid formulation 
 
  

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2.1.2 Drug Treatment Regimen 
All subjects start at a dose of 225 mg of study drug administered SC approximately every 
4 weeks. 
Following the approval of Protocol Amendment 5, all subjects will sign the new ICF and initiate 
up titration starting at the 450 mg dose level.  Subjects should receive at least two doses at 
each titration step, 4 weeks (± 4 days) apart, before proceeding to the next titration step.  
Advancement to the next titration step is guided by the ARIA related intervention algorithm for 
dose titration (see tables in section 1.14).  The dose titration and safety MRI schedule is 
provided in Table 5. 
Subjects will continue dosing up to a minimum of 204 weeks and a maximum of 360 weeks 
based upon when the subject was randomized into the study. 
Table 5 
DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule  
 
a 
Up through Amendment 4, safety MRIs will be scheduled before the first dose (baseline scan for safety reads done at V2) 
and then about 1 week (± 4 days) after dose 2; dose 4; dose 6; dose 9; dose 17 and dose 22.  Additional safety MRIs are 
done as part of the volumetric MRI at the annual assessments before dose 14 (V15, week 52), dose 27 (V28, week 104), 
dose 40 (V41, week 156), and V54 (week 208).  This schedule will be followed until up titration is initiated. 
b 
Amendment 8 includes a revised safety MRI schedule.  A safety MRI will be scheduled 1 week (± 4 days) after the second 
dose of each titration step (225 mg, 450 mg, 675 mg, 900 mg), unless otherwise indicated by the ARIA-E and ARIA-H 
management algorithms (section 1.15).  Subjects may be at different titration steps and time points in the schedule of 
visits at the time of this amendment and should be scheduled based upon their current titration step/stable dose at the 
time of the amendment.  If an annual visit follows the second dose of a titration step, the annual MRI assessment can 
fulfill this requirement as long as the MRI reading is reviewed prior to dosing at that visit. 
c 
For the titration step #4, the final titration step (1200 mg), safety MRIs will be scheduled 1 week (± 4 days) after every 
third dose (or approximately every 3 months) for the next 6 doses unless otherwise indicated by the ARIA-E and ARIA-H 
management algorithms (section 1.15).  If an annual visit follows the third dose, the annual MRI assessment can fulfill 
this requirement as long as the MRI reading is reviewed prior to dosing at that visit. 
d 
The titration schema was designed to reach the target dose of 1200 mg administered every 4 weeks; however, the target 
dose may not be achieved as otherwise dictated by ARIA-E and ARIA-H management algorithms (section 1.15) or more 
conservative action by the site principal investigator/sponsor.  Once a subject reaches their stable dose (defined as the 
maximum dose the subject will remain at for the duration of the trial) safety MRIs will follow every 6 doses (or 
approximately every 6 months) unless otherwise indicated by the algorithm.  The safety MRIs following every sixth dose 
of 1200 mg must occur regardless of when the annual MRI is scheduled. 
INITIAL                  
DOSE
•225 mg every 
4 weeks until 
up titration 
initiated
•MRI 
Frequencya,b
TITRATION              
STEP #1
• Dose 1: 450 mg
• Dose 2: 450 mg
• Safety MRI:          
1 week after 2nd
450 mg dose, 
before increase  
to 675 mgb
TITRATION              
STEP #2
•Dose 1: 675 mg
•Dose 2: 675 mg
•Safety MRI:               
1 week after 
2nd 675 mg 
dose, before 
increase to 900 
mgb
TITRATION              
STEP #3
•Dose 1: 900 mg
•Dose 2: 900 mg
•Safety MRI:           
1 week after 
2nd 900 mg 
dose, before 
increase to 
1200 mgb
TITRATION                 
STEP #4
•Dose 1: 1200 mg
•Dose 2: 1200 mg
•Dose 3: 1200 mg
•Safety MRI:           
1 week after 3rd
1200 mg dose
•Dose 4: 1200 mg
•Dose 5: 1200 mg
•Dose 6: 1200 mg
•Safety MRIc
STABLE               
DOSE
•1200 mg dose 
every 4 weeks
•Safety MRI: 1 
week after every 
6th dose; safety 
MRI must occur 
regardless of 
when annual 
MRI is 
scheduledd

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NOTE: The annual MRI assessment can fulfill the safety MRI assessment as long as the MRI 
reading is reviewed prior to dosing at that visit; however, the safety MRIs following every sixth 
dose of 1200 mg must occur regardless of when the annual MRI is scheduled. 
Study drug arms that demonstrate a potential clinical benefit may have an open-label extension 
period.  Eligible subjects may be offered the opportunity to receive active drug for up to 2 years 
in an open-label extension (OLE).  
 
 
2.1.3 Packaging, Preparation and Administration of Study Drug 
Supplies are designated with the following information, as applicable:  
 
     
 
     
 
 
   
 
 
   
 
   
  
   
 
 
Upon approval of Amendment 5, the drug product formulation for doses of 225 mg and above, 
consists of a sterile, preservative-free, solution for subcutaneous injection 
 
 
 The placebo products contain the 
same excipients without the active substance.  
 
 
 
 
 
 
The investigator or designee is responsible for administering the study drug to the subject, 
verifying that instructions are followed properly, maintaining accurate records of study drug 

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dispensing and administration, and returning all unused or used study drug supplies to the trial 
sponsor’s designee or destroyed locally with sponsor approval.  Drug reconciliation must be 
completed and documented prior to destruction.  Refer to the Pharmacy Manual and Global 
Manual of Operations for additional details. 
 
 
   
Clinical study materials will be labeled according to the country’s regulatory requirements. 
Site staff preparing and administering the study drug should contact the trial sponsor or 
designee as soon as possible if he or she has a complaint or problem with the study drug so that 
the situation can be assessed. 
2.1.4 Blinding of Study Drug 
Subjects will be randomized to receive gantenerumab or placebo by the IWRS in order to 
maintain blinding.  All treatment kits will be supplied in numbered kits.  The subject, study 
nurses, and DIAN-TU site staff will be blinded as to treatment assignment (active or placebo) 
but not study drug arm. 
In the double-blind period of the study, personnel involved in preparing and filling syringes with 
study drug must not be involved with subject care in the study nor communicate any 
observations made during the study drug preparation to any personnel involved in the care of 
the subject.  Personnel who reconstitute and/or fill syringes may also give the injections but 
must observe the rules above for those involved in study drug preparation. 
The study drug administered for subjects that may enter OLE will not be blinded. 
2.1.5 Dispensing of Study Drug 
Upon approval of Amendment 5, the study drug for doses of 225 mg and above will be 
administered subcutaneously (SC) 
 
 The amount of 
the dose will be dependent on where the subject is at in the dose titration schedule (Table 5). 
 
 
 
 
 
 
 

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Note that all cognitive scales are to be administered before administration of study drug. 
2.1.6 Assessing Compliance with Study Drug  
Strict adherence to the planned dose regimen is required.  However, a single missed dose may 
not automatically result in study withdrawal.  Site staff or designee will document completion 
of injection on study documents.  Because all dosing is supervised by trained healthcare 
providers, subjects who successfully receive at least 70% of a dose (e.g., complete dose not 
administered due to technical complications) are automatically compliant with treatment. 
 
 
 
 
 
 
 
 
 
 
 
 

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3 STUDY PROCEDURES 
 Enrollment 
See details in section 3.4 of the main protocol.   
 Randomization 
From the perspective of the subjects and site study staff, subjects were randomized to one of 
two study drug arms (gantenerumab or solanezumab).  Within each study drug arm, subjects 
were further divided into those who receive active drug or placebo (Figure 2).   
Subject randomization was performed separately for mutation positive and mutation negative 
subjects.  Mutation positive subjects were randomized using a minimization strategy.  Groups 
were balanced as to the predetermined number of asymptomatic (Clinical Dementia Rating 
[CDR]=0) and symptomatic (CDR>0) subjects based on power calculations for the primary 
outcome of each individual study drug arm in the DIAN-TU platform.  Other factors such as 
Clinical Dementia Rating Sum of Boxes (CDR-SB), years to estimated age at onset, and the 
presence or absence an apolipoprotein E (APOE) ε4 allele were included as minimization factors 
designed to ensure optimal balance between arms on potentially important characteristics.  
The minimization strategy did not differentiate between those who have one (heterozygous) or 
two (homozygous) APOE ε4 alleles.  APOE ε4 was included in the minimization strategy because 
preliminary data suggests the presence of an APOE ε4 allele increases the risk of amyloid-
related imaging abnormalities (ARIA) in sporadic DAT.  It is not known whether the presence of 
an APOE ε4 allele affects the risk of ARIA in the DIAD population.   
Mutation positive subjects (mc+) were randomized to active drug or placebo in a 3:1 ratio 
(Figure 3) while subjects who did not carry a mutation linked to DIAD (mc-) were assigned to 
placebo.  Subjects and site study staff continue to be blinded as to subject’s genetic status (mc+ 
or mc-), unless the subject is aware of their genetic status and chooses to disclose it.   
Mutation negative subjects participate in all study procedures and assessments to maintain 
blinding as to genetic status for those who do not wish to know their genetic status.  Mutation 
negative subjects will not be included in the primary efficacy or futility analyses, as they will not 

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be exposed to study drug; safety data will be reported separately for mutation positive and 
negative subjects. 
Figure 2 
Randomization Scheme:  All Subjects in Gantenerumab and Solanezumab Arms 
 
 
 
Figure 3 
Randomization Scheme: Gantenerumab and Solanezumab Mutation Positive 
Subjects Only  
 
 Specific Study Visits – Double-blind Treatment Period 
The procedures to take place at each study visit during the double-blind treatment period are 
listed below.  All information on timing of visits refers to calendar days.  The specific date 
during the baseline visit (V2) when the first dose of study drug is administered should be used 
to determine timing of subsequent visits and for determining time between the screening and 
baseline visits. 

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The schedule of visits, including drug-specific tests, is provided in the schedule of visits tables at 
the end of this appendix: 
• Gantenerumab Schedule of Visits: 4 Year Double-Blind Treatment Period 
• Gantenerumab Schedule of Visits: Double-Blind Treatment Beyond Year 4 
The frequency for safety MRIs is provided in Table 5. 
3.3.1 Visit 1 (screening visit) 
Location: Visit 1 procedures may be accomplished at the DIAN-TU site or at the subject’s home 
or other trial-identified location with the trial-designated home health nurse.  This visit also 
includes telephone calls with the DIAN-TU site staff.  The subject is contacted by their host 
DIAN-TU site by telephone or during a regular DIAN observational (DIAN-OBS) study visit.  The 
subject is given the opportunity to review the main and drug-specific supplemental ICFs, ask 
questions and obtain answers, and sign the main ICF. 
Time:  Informed consent must be obtained before any other study procedures.  Informed 
consent, family history, demographic information and medical and treatment history may be 
obtained before the 8-week screening period begins.  Informed consent should be obtained 
from both subject and study partner.  Unless otherwise specified, all other Visit 1 procedures 
may occur throughout the screening period (2-8 weeks before V2).  IMPORTANT: Results from 
screening clinical laboratory tests and genetic testing must be available before V2; blood draw 
for genetic testing must be completed at least 6 weeks before V2 to ensure genetic results are 
available for baseline randomization.  The screening visit in the home ensures subject eligibility 
before travel (if applicable) to the DIAN-TU site for baseline testing and randomization. 
Procedures (all can be performed by DIAN-TU site staff or trial-designated and trained home 
health nurse or other staff except as noted-see Global Manual of Operations and DIAN Trials 
Unit Cognition Core Procedures Manual for additional details on order and timing of 
procedures): 
• Obtain informed consent (DIAN-TU site staff should be available to answer questions) 
• Obtain or confirm family history and determine parental estimated age at onset or 
subject’s actual age at onset (DIAN-TU site staff).  Estimated age at onset should be 
determined as outlined in the Global Manual of Operations   
• Verify documentation of subject’s trial eligible mutation status OR confirm via family 
pedigree and mutation documentation (proband) that the subject is at 50% risk for a 
trial-eligible mutation 
• Collect demographic information and study partner information 
• Obtain medical and treatment history 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature).  Weight is 
not required at this visit but subject’s self-reported weight may be noted if required for 
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• Blood draw: 
o Genetic testing (NOTE: genetic testing blood sample must be obtained at least 
6 weeks prior to Visit 2) 
o Clinical laboratory tests, including TSH, B12, hemoglobin A1c, PT, PTT, and INR 
o Serum pregnancy test for women of childbearing potential 
• Urine collection for urinalysis  
• Administration of Columbia Suicide Severity Rating Scale (C-SSRS) 
• Screening cognitive battery (subset of testing serves as practice test; takes about 
30 minutes).  See section 6.1.14 of main protocol 
A study-specific subject identification number is assigned to the subject by the interactive web 
response system (IWRS).  Visit 2 is not scheduled to occur until the results of clinical laboratory 
test are available and results of genetic testing are entered in IWRS.  Results of genotyping of 
APOE and DIAD-associated genes (APP, PSEN1, and PSEN2) will not be sent to the site to ensure 
genetic blinding is maintained during double-blind treatment periods, but they may be 
provided as specified in section 6.1.9 of the main protocol. 
3.3.2 Visit 2 (baseline/first dose) 
Location: Host DIAN-TU site. 
Time/Timing:  Approximately a 3-4 day visit that is scheduled 2-8 weeks after the screening visit 
and at least 6 weeks after the genetic sample draw.  This visit can only take place after results 
from screening clinical laboratory tests are documented as consistent with inclusion/exclusion 
criteria before Visit 2 occurs.  Genotyping results will need to be confirmed as received and 
having completed analysis but no results will be provided or reviewed by site staff.  The study 
partner participates in some of the procedures at Visit 2 and other annual visits at the DIAN-TU 
site.  If possible, the study partner should accompany the subject to the DIAN-TU site for these 
visits.  If this is not possible, the study partner procedures can be completed via telephone.  The 
sequence and timing of visit procedures is very important.  Requirements and suggested timing 
of visit procedures are detailed in the Global Manual of Operations.  Baseline visit procedures 
may be scheduled over a longer period of up to 2 weeks for subjects who live near the study 
site or in the event that some study procedures (e.g., PET imaging) are done at a different 
DIAN-TU site.   
Note: The date during Visit 2 when the first dose of study drug is administered should be used 
for determining the timing of all subsequent visits. 
Procedures: 
• In-person review of informed consent for subjects who provided consent over the 
telephone 
• Medical/treatment history, including: 
o Concomitant medications 
o Assessment /recording of pre-existing conditions or adverse events 

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• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Blood draw for: 
o 
 
 
o Provenance9 testing (to confirm specimen identity) 
• Urine pregnancy testing for women of childbearing potential 
• Administration of C-SSRS 
• Physical and neurological examination 
• Clinical assessments: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
o 
 
 
 
o Functional Assessment Scale (FAS) 
 
 
OTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• MRI to be performed on 1st day and uploaded immediately to ensure reading obtained 
prior to randomization and dosing.  This MRI includes safety MRI sequences.  ARIA 
findings on this MRI may affect eligibility for the trial.  MRI should be performed before 
lumbar puncture, if on the same date 
 
 
 
• PET imaging: 
o [11C]PiB-PET 
 
 
 
 
 
 
• Final verification that all inclusion and no exclusion are met (including receipt of MRI 
read) 
• Randomization in IWRS system 
                                                     
9 Provenance testing is performed for quality assurance purposes to ensure that blood sample obtained at baseline 
visit is from same individual as sample obtained at screening visit. 

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• Supplemental drug-specific informed consent reviewed and signed 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5  
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 
Randomization and assignment to study drug arm is completed using the IWRS during this visit.  
Randomization cannot occur until results of CDR are entered into the IWRS system.  After 
randomization, the subject and legally acceptable representative (if the subject is cognitively 
impaired) should review and sign the supplemental drug-specific consent form, if applicable; 
study staff should be available to answer all questions regarding the study.  Study drug should 
not be administered until MRI is read to confirm eligibility, pregnancy test is confirmed 
negative, and any other drug-specific inclusion/exclusion criteria are met.  All study procedures 
must be completed prior to administration of the first dose of study drug. 
3.3.3 Visit 3 
Location: DIAN-TU site, subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing: 4 weeks +/- 4 days from Visit 2 (calculated from day of first dose). 
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) 
• Clinical laboratory tests 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Phone Call:  Either during the visit or within the next two weeks, the DIAN-TU site 
coordinator calls subject and addresses any concerns, discusses scheduling of safety MRI 
and next visits and encourages compliance 
3.3.4 Visits 4, 6, 7, 9, 10, 12-14, 16, 17, 19, 20, 22, 23, 25-27, 29-33, 35-40, 42-46, 48-53, 55-
59, 61-66, 68-72, 74-79, 81-85, and 87-92 
Location: DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 

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Timing:  Visits as listed below (calculated from day of first dose), with a visit window of +/- 4 
days. 
Visit No. 
4 
6 
7 
9 
10 
12 
13 
14 
16 
17 
19 
20 
Week 
8 
16 
20 
28 
32 
40 
44 
48 
56 
60 
68 
72 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit No. 
22 
23 
25 
26 
27 
29 
30 
31 
32 
33 
35 
36 
Week 
80 
84 
92 
96 
100 
108 
112 
116 
120 
124 
132 
136 
 
Visit No. 
37 
38 
39 
40 
42 
43 
44 
45 
46 
48 
49 
50 
Week 
140 
144 
148 
152 
160 
164 
168 
172 
176 
184 
188 
192 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit No. 
51 
52 
53 
55 
56 
57 
58 
59 
61 
62 
63 
64 
Week 
196 
200 
204 
212 
216 
220 
224 
228 
236 
240 
244 
248 
 
Visit No. 
65 
66 
68 
69 
70 
71 
72 
74 
75 
76 
77 
78 
Week 
252 
256 
264 
268 
272 
276 
280 
288 
292 
296 
300 
304 
 
Visit No. 
79 
81 
82 
83 
84 
85 
87 
88 
89 
90 
91 
92 
Week 
308 
316 
320 
324 
328 
332 
340 
344 
348 
352 
356 
360 
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing as specified in section 2.1.5 
• Phone call (required after Visit 4; not required at all other home/off-site visits but direct 
site-subject contact should occur at least once every 3 months throughout the study): 
the DIAN-TU site coordinator calls subject and addresses any concerns, discusses 
scheduling of safety MRI and next visits, and encourages compliance 
3.3.5 Visits 5, 11, 18, and 24 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 

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Timing:  Visits as listed below (calculated from day of first dose), with a visit window of 
+/- 4 days. 
Visit No. 
5 
11 
18 
24 
Week 
12 
36 
64 
88 
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• C-SSRS administration 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Phone call (required after Visit 5; not required at all other home/off-site visits but direct 
site-subject contact should occur at least once every 3 months throughout the study): 
the DIAN-TU site coordinator calls subject and addresses any concerns, discusses 
scheduling of safety MRI and next visits, and encourages compliance 
3.3.6 Visit 8 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  24 weeks +/- 4 days from Visit 2 (calculated from day of first dose)  
Procedures: 
• Cognitive battery subset (per section 6.1.14 of main protocol) 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• 12-lead ECG 
• C-SSRS administration 
• Blood draw for: 
o Clinical laboratory tests 
 
 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Phone call (not required at all home/off-site visits but direct site-subject contact should 
occur at least once every 3 months throughout the study): the DIAN-TU site coordinator 

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calls subject and addresses any concerns, discusses scheduling of safety MRI and next 
visits, and encourages compliance 
3.3.7 VISIT 15: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing:  52 weeks +/- 7 days from Visit 2 (calculated from day of first dose); approximately a 
3-4 day visit.  The sequence and timing of visit procedures is very important.  Requirements and 
suggested timing of study procedures are detailed in the Global Manual of Operations.  For 
subjects who live near the study site, these visit procedures may be scheduled over a longer 
time period of up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Blood draw for: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
 
 
• Urine pregnancy testing for women of childbearing potential  
• Physical and neurological examination 
• Clinical assessments: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
 
  
 
 
 
 
o Functional Assessment Scale (FAS) 
 
 
OTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences.  MRI should 
be performed before lumbar puncture, if on the same date 

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• PET imaging: 
o [11C]PiB-PET 
 
  
 
 
 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 
3.3.8 Visit 21 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing 76 weeks +/- 4 days from Visit 2 (calculated from day of first dose)  
Procedures: 
• Cognitive battery subset (per section 6.1.14 of main protocol) 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• 12-lead ECG 
• C-SSRS administration 
• Clinical laboratory tests (hematology, chemistry, urinalysis) 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Phone call (not required at all home/off-site visits but direct site-subject contact should 
occur at least once every 3 months throughout the study): the DIAN-TU site coordinator 
calls subject and addresses any concerns, discusses scheduling of safety MRI and next 
visits, and encourages compliance 
3.3.9 VISIT 28: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing: 104 weeks +/- 7 days from Visit 2 (calculated from day of first dose); approximately a 
3-4 day visit.  The sequence and timing of visit procedures is very important.  Requirements and 
suggested timing of study procedures are detailed in the Global Manual of Operations.  For 
subjects who live near the study site, these visit procedures may be scheduled over a longer 
time period of up to 2 weeks. 

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Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Blood draw for: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
 
 
• Urine pregnancy testing for women of childbearing potential 
• Physical and neurological examination 
• Clinical assessments: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms 
 
 
 
 
o Functional Assessment Scale (FAS) 
 
 
OTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences.  MRI should 
be performed before lumbar puncture, if on the same date 
 
 
• PET imaging: 
o [11C]PiB-PET 
 
 
 
 
 
 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 

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3.3.10 Visits 34 and 47 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing: 128 and 180 weeks +/- 4 days from Visit 2 (calculated from day of first dose).   
Procedures: 
• Cognitive battery subset (per section 6.1.14 of main protocol) 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• 12-lead ECG 
• C-SSRS administration 
• Clinical laboratory tests (hematology, chemistry, urinalysis) 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Phone call (not required at all home/off-site visits but direct site-subject contact should 
occur at least once every 3 months throughout the study): the DIAN-TU site coordinator 
calls subject and addresses any concerns, discusses scheduling of next visits, and 
encourages compliance 
3.3.11 VISIT 41: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing:  156 weeks +/- 7 days from Visit 2 (calculated from day of first dose); approximately a 
2-3 day visit.  The sequence and timing of visit procedures is very important.  Requirements and 
suggested timing of events are detailed in the Global Manual of Operations.  For subjects who 
live near the study site, these visit procedures may be scheduled over a longer time period of 
up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Clinical laboratory tests 
• Urine pregnancy testing for women of childbearing potential  
• Physical and neurological examination 

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• Clinical assessments: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
 
 
 
 
o Functional Assessment Scale (FAS) 
 
 
OTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
3.3.12 VISIT 54: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing:  208 weeks +/- 7 days from Visit 2 (calculated from day of first dose); approximately a 
3-4 day visit.  The sequence and timing of visit procedures is very important.  Requirements and 
suggested timing of events are detailed in the Global Manual of Operations.  For subjects who 
live near the study site, these visit procedures may be scheduled over a longer time period of 
up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Blood draw for: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
 
o Serum pregnancy testing for women of childbearing potential, if applicable 
• Physical and neurological examination 
• Clinical assessments: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 

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o Assessment of clinical diagnosis and clinician judgment of symptoms  
 
 
 
 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences.  MRI should 
be performed before lumbar puncture, if on the same date 
 
 
 
• PET imaging: 
o [11C]PiB-PET 
o FDG-PET (subject should be fasting for 4 hours prior to FDG-PET) 
 
 
 
 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 
3.3.13 VISITS 60, 73, and 86 
Location: Host DIAN-TU site 
Timing:  232, 284, and 336 weeks +/- 7 days from Visit 2 (calculated from day of first dose); 
approximately a 3-4 day visit.   
Visits No. 
60 
73 
86 
Week 
232 
284 
336 
Procedures: 
• Cognitive battery subset (per section 6.1.14 of main protocol) 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.1.5 

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• Phone call (not required at all home/off-site visits but direct site-subject contact should 
occur at least once every 3 months throughout the study): the DIAN-TU site coordinator 
calls subject and addresses any concerns, discusses scheduling of safety MRI and next 
visits, and encourages compliance 
3.3.14 VISITS 67, 80, and 93: ANNUAL VISITS AT HOST DIAN-TU SITE/END OF DOUBLE-BLIND 
TREATMENT 
Location: Host DIAN-TU site 
Timing:  260, 312, and 364 weeks +/- 7 days from Visit 2 (calculated from day of first dose); 
approximately a 3-4 day visit.  The sequence and timing of visit procedures is very important.  
Requirements and suggested timing of events are detailed in the Global Manual of Operations.  
For subjects who live near the study site, these visit procedures may be scheduled over a longer 
time period of up to 2 weeks. 
Visits No. 
67 
80 
93 
Week  
260 
312 
364 
 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• 12-lead ECG 
• Administration of C-SSRS 
• Clinical laboratory tests (hematology, chemistry, urinalysis)  
• Urine pregnancy testing for women of childbearing potential at Visits 67 and 80; serum 
pregnancy testing at Visit 93 
• Physical and neurological examination 
• Clinical assessments:   
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
 
 
 
 
o Functional Assessment Scale (FAS) 
 
  
OTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 

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• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences 
• V67 and V80:  Study drug dosing and post-dose monitoring/evaluation as specified in 
section 2.1.5.  Note: dose will not be administered at Visit 93 
3.3.15 End of Study Visit 
Location: DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  The end of study safety follow-up visit should be performed 12 weeks (+/- 7 days) after 
the last dose of double-blind treatment. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol)  
• Clinical laboratory tests 
• Serum pregnancy testing for women of childbearing potential 
3.3.16 Early Termination/Post-treatment Follow-up  
If a subject withdraws, is terminated from the study prior to completion, or is in a study drug 
arm that is stopped prior to the end of the double-blind treatment period, every effort should 
be made to schedule an early termination visit that will include all procedures done at Visit 54 
for those not yet having completed that visit, or Visit 93 for those beyond V54.  Drug-specific 
testing should also be obtained at early termination visit only if prior to completion of V54, 
week 208 (see section 1.12).  PET imaging studies may be omitted if early termination occurs 
less than 6 months after the previous PET imaging or if precluded by local 
regulations/dosimetry limits.  Other procedures may also be eliminated on a case-by-case basis, 
as determined by the sponsor. 
Per the main protocol section 6.3.7, any subject meeting study drug discontinuation criteria per 
main protocol section 4.4.1 due to safety reasons, inability to continue treatment 
administration/dosing, or perform study procedures, will be encouraged to continue 
participation in any of the scheduled clinical, cognitive, and/or biomarker assessments that they 
are able to perform, even though dosing has concluded.  The determination of which 
assessments are to be attempted/completed will be decided by the site principal investigator 
and sponsor and will be based on the subject’s capabilities, the benefit to the study, and the 
risk associated with continued participation at the time of study drug discontinuation.  The level 
of continued participation may change if/as the subject’s status changes. 

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3.3.17 Safety Magnetic Resonance Imaging 
Safety MRI visits will be scheduled over the entire course of the study. 
Location: Safety MRIs may be done at the host DIAN-TU site or, for subjects who live at a 
distance from the host DIAN-TU site, safety MRIs may be performed at an ADNI/ADCS site if 
possible or at a 3T scanner near the subject’s home. 
Timing:  See section 1.13.1.  Sites must ensure that study visits are scheduled so that MRIs are 
uploaded and available for central read at least 10 working days before next administration of 
study drug for parenterally administered drugs. 
Procedures:  Safety MRIs on 3T scanners will be done primarily to monitor for ARIA.  See 
section 1.13.1 and section 6.1.16 of the main protocol for more information.  Detailed 
requirements are provided in the MRI Technical Manual. 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 

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• Clinical assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
   
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 

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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
   
 
 
 
 
 
 
 
 

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rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 DRUG-SPECIFIC ANALYSIS PLAN 
 DIAN-Multivariate Cognitive Endpoint Power Analysis and Sample Size 
Determination 
The power was estimated based on the multivariate disease progression model (MDPM) and 
the DIAN-MCE primary endpoint with four arms: the gantenerumab active drug arm, the 
solanezumab active drug arm, the mutation positive placebos, and the eligible DIAN-OBS 
subjects.  For details, refer to the SAP and gantenerumab-specific SAP appendix. 
 Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification 
4.2.1 Biomarker Endpoint Power Analysis 
Power analysis for the biomarker endpoints suggests 42 mutation positive subjects in the 
gantenerumab arm along with 27 mutation carriers in the pooled placebo group will provide 

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over 99% power to detect the projected effect size for changes in [11C]PiB-PET.  Recruitment 
goal is for 69 mutation positive subjects; 52 on gantenerumab and 17 on placebo, for a total of 
34 in the pooled placebo group.  These recruitment goals will allow for 5% annual attrition rate. 
4.2.2 Biomarker Endpoint Sample Size Justification 
Table 9 summarizes the power analysis by presenting the estimated SD from the DIAN cohort 
and the effect size on the annual rate of change for [11C]PiB-PET C-SUVR that can be detected 
by 42 subjects in the active drug group (52 subjects enrolled, assumes 5% annual dropout rate 
during the trial) and 27 subjects in the pooled placebo group (34 subjects enrolled; assumes a 
5% annual dropout) with at least 80% power.  For comparison, Table 9 also lists the effect size 
on the rate of change for the same biomarkers reported by recently published clinical trials.  
The projected effect size is smaller than all reported effect size for C-SUVR, demonstrating that 
the proposed sample size provides adequate statistical power to detect reasonable effect sizes.  
In fact, for the biomarker endpoint used at the interim analysis, the proposed sample size (i.e., 
52 in the active drug group and 34 in the pooled placebo group) provides more than 99% 
statistical power to detect two-thirds of the reported effect size in the literature or through 
personal communications and at least 80% power even for some other additional endpoints.  
Also provided are the estimated powers for 12 months of exposure of 675 mg, 900 mg, and 
1200 mg (Table 10). 
In summary, recruitment of 52 mutation positive subjects to the active drug group (at least 
42 completers assuming 5% annual attrition during the study period) and 34 mutation positive 
subjects to the pooled placebo group (at least 27 completers assuming 5% annual attrition 
during the study period) would provide statistical power to test the biomarker engagement 
hypotheses. 

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Table 9 
The effect size with 80% power in comparison to the reported effect size in a 
prior study and the corresponding power with proposed sample sizes 
Active Drug 
Efficacy 
outcome 
SD for the 
rate of 
change/year 
among 
untreated 
carriers 
(estimated 
from DIAN 
data) 
Effect size 
that can be 
detected 
with n=42 
(active 
drug) vs. 27 
(placebo) 
completers 
Reported 
effect size 
(p=p-value, 
n= sample 
size of the 
reported 
trial) 
Estimated 
power with 
n=42 
(treatment)
and n=27 
(placebo) 
for the 
reported 
effect size 
Estimated 
power with 
n=42 
(treatment) 
and n=27 
(placebo) to 
detect 2/3 
of the 
reported 
effect size 
Authors of 
the reported 
trials (year) 
Gantenerumab 
(RO4909832) 
Stable Dose: 
4501 
PiB   
C-SUVR 
(Primary) 
 
0.137 
0.096 
0.50 in less 
than 1 year 
(n=4 vs. 6 
for 200 mg) 
>99% 
>99% 
(Ostrowitzki 
et al., 2012) 
Effect Size = difference between active drug and placebo on the annual rate of change for the corresponding efficacy 
endpoint that can be detected by 52 subjects in the active drug group (42 after 5% annual attrition) and 34 subjects in the 
mutation positive (pooled) placebo group (27 after 5% annual attrition)  
1 Taking a conservative manner, the planned reduction in PiB C-SUVR for dose 450 mg is assumed to be 0.096/year, which is 
the same as the planned reduction for the current dose 225 mg. 
 
Table 10 
Power to detect the planned differences after dose titration by 52 subjects on 
active drug (42 after 5% annual attrition) and 34 subjects on placebo (27 after 
5% annual attrition) 
Stable Dose 
Effect size (SD) that can be detected with n=42 (active drug) vs. 
27 (placebo) completers1 
Power for 12 months on 
the stable dose 
675 mg 
0.144 (0.137) 
98.7% 
900 mg 
0.192 (0.137) 
>99% 
1200 mg 
0.256 (0.137) 
>99% 
1 Assuming that the reduction in PiB C-SUVR for dose 450 mg is 0.096/year, the change/year for dose 675 is 0.144 
(= 675/450*0.096), for dose 900 mg is 0.192 (= 900/450*0.096), and for 1200 mg is 0.256 (= 1200/450*0.096).  A 
linear relationship between change/year and dose as well as a consistent standard deviation (SD) is assumed. 
4.2.3 Interim Analysis 
As a result of including dose titration in the study design, subjects will be starting titration at 
different times in relation to their initial enrollment and the titration itself may occur at a 
different rate for each subject.  Therefore, the three interim analyses previously scheduled will 
not be conducted.  Instead, a single biomarker interim analysis will be done when 100% of the 
active subjects have completed 2 years of randomized treatment (Visit 28). 

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At this interim analysis, the pre-specified biomarker endpoint will be examined.  If the drug 
does not meet any of the pre-specified criteria for stopping or modification (as detailed in the 
DSMB Charter or as defined in the gantenerumab-specific SAP appendix), the DIAN-TU 
Coordinating Center and/or DSMB may recommend that the study drug arm continue until the 
pre-planned trial duration is completed. 
 Other Drug-Specific Analyses 
With the dose escalation in the trial, the primary outcome will be analyzed based on the 
randomized population of active vs. mutation carrier placebo and eligible DIAN-OBS subjects, as 
specified in section 8.4 of the main protocol, and the SAP. 
 Changes to the Data Analysis 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be 
described in the final SAP and clinical study report (CSR).  Additional analyses of the data will be 
conducted as deemed appropriate. 
5 DRUG-SPECIFIC ADVERSE EVENTS AND REPORTING 
No adverse events of special interest are defined. 
ARIAs may be reported as an AE per MedDRA-preferred term based upon investigator’s 
discretion upon review of the MRI finding, assessment of clinical symptoms, and adverse event 
definitions as outlined in section 7.1.1. 

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REFERENCES 
Bard F et al.  (2000) Peripherally administered antibodies against amyloid beta-peptide enter 
the central nervous system and reduce pathology in a mouse model of Alzheimer disease.  Nat 
Med 6:916-919. 
Bateman RJ et al.  (2012) Clinical and biomarker changes in dominantly inherited Alzheimer's 
disease.  N Engl J Med 367:795-804. 
Bohrmann B et al.  (2012) Gantenerumab: a novel human anti-Abeta antibody demonstrates 
sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-
beta.  J Alzheimers Dis 28:49-69. 
Doody RS, Thomas RG, Farlow M et al.  Phase 3 trials of solanezumab for mild-to-moderate 
Alzheimer's disease.  N Engl J Med.  2014; 370:311-321. 
Hutmacher M, Hu C, Guenzler-Pukall V, et al.  Pharmacokinetic-pharmacodynamic modeling of 
amyloid-related imaging abnormalities of edema following administration of bapineuzumab to 
subjects with mild to moderate Alzheimer’s disease.  American Conference on 
Pharmacometrics.  2013. 
Ostrowitzki S et al.  (2012) Mechanism of amyloid removal in patients with Alzheimer disease 
treated with gantenerumab.  Arch Neurol 69:198-207. 
Salloway S, Sperling R, Fox NC et al.  Two phase 3 trials of bapineuzumab in mild-to-moderate 
Alzheimer's disease.  N Engl J Med.  2014; 370:322-33. 
Schenk D et al.  (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like 
pathology in the PDAPP mouse.  Nature 400:173-177. 
Sevigny JJ.  Randomized, double‐blind, placebo‐controlled, Phase Ib study of aducanumab 
(BIIB037), an anti‐ab monoclonal antibody, in patients with prodromal or mild Alzheimer’s 
disease: interim results by disease stage and APOE ε4 status.  Abstract published in 
Neurodegener.  Dis.  2015;15(suppl 1):311. 
Sperling R et al.  (2012) Amyloid-related imaging abnormalities in patients with Alzheimer's 
disease treated with bapineuzumab: a retrospective analysis.  Lancet Neurol 11:241-249. 
 

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GANTENERUMAB SCHEDULE OF VISITS:  4 YEAR DOUBLE-BLIND TREATMENT PERIOD 
Gantenerumab Schedule of Visits: 4 Year Double-blind Treatment Period – Page 1 of 4 
PROCEDURE 
VISIT SITE1,2 
Home (H)31F 
DIAN-TU 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
Visit No. 
V1 (screen) 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
Timing (week)3 
-8 to -2 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Informed Consent4 
X 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
Family History/Age at Onset Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Study Partner Information6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment History7 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic Testing/APOE 
X 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry, Urinalysis 
X10 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
Pregnancy Testing11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Vital Signs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment16  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Cognitive Testing17 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Annual/Volumetric MRI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[11C]PiB-PET 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3T Safety/Titration MRI20 
 
       X ---------- Titration Safety MRI - See Table 5 DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule ---------- X 
Randomization21 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call22 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

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Gantenerumab Schedule of Visits: 4 Year Double-blind Treatment Period - Page 2 of 4 
PROCEDURE: 
VISIT SITE1,2 
DIAN-TU 
H 
H 
H 
H 
H 
H  
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No. 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
V28 
Timing (week)3 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
104   
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic Testing/APOE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry, Urinalysis 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pregnancy Testing11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
Vital Signs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment16  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Cognitive Testing17 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Volumetric MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[11C]PiB-PET 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3T Safety/Titration MRI20 
X 
X------Titration Safety MRI - See Table 5 DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule-----X 
X 
Randomization  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call22 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Gantenerumab Schedule of Visits: 4 Year Double-blind Treatment Period - Page 3 of 4 
PROCEDURES: 
Visit Site1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No. 
V29 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
Timing (week)3 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
156 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pregnancy Testing11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment16  
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Cognitive Testing17 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[11C]PiB-PET   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
For sites approved for participation in 
the Tau Addendum: [18F]AV-145119 
 
 
 
 
 
 
 
 
 
 
 
 
 
3T Safety/Titration MRI20 
        X ------------------- Titration Safety MRI - See Table 5 DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule --------------------------- X 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

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Gantenerumab Schedule of Visits: 4 Year Double-blind Treatment Period - Page 4 of 4 
PROCEDURES 
Visit Site1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No. 
V42 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
V53 
V54/ET23 
Timing (week)3 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pregnancy testing11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug-specific Tests: PK 
 
 
 
 
 
 
 
 
 
 
 
 
X24 
Drug-specific Tests: ADA 
 
 
 
 
 
 
 
 
 
 
 
 
X24 
Stored Plasma and Serum14 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C-SSRS 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital signs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment16 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-lead ECG 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Cognitive Testing17 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Lumbar Puncture (CSF) 18 
 
 
 
 
 
 
 
 
 
 
 
 
X 
[11C]PiB-PET 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FDG-PET  
 
 
 
 
 
 
 
 
 
 
 
 
X 
Florbetapir 18F PET  
 
 
 
 
 
 
 
 
 
 
 
 
X 
For sites approved for participation in 
the Tau Addendum: [18F]AV-145119 
 
 
 
 
 
 
 
 
 
 
 
 
X 
3T Safety/Titration MRI20 
      X-----------------------Titration Safety MRI - See Table 5 DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule ------------------------  X 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X25 
Coordinator Phone Call22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ET = Early Termination 
Footnotes: 
1. Annual visits will be conducted at the host DIAN-TU site (DIAN-TU).  For subjects who live at a distance from the DIAN-TU site, other visits may be conducted at a site 
nearer to their home (H); safety magnetic resonance imaging (MRI) may be performed at a study-approved facility nearer to their home.  See next two footnotes for 
additional detail. 
2. Infusions/injections and safety visits (designated as occurring at home[H]) may occur at the DIAN-TU site or, for subjects who live at a distance from the DIAN-TU site, 
these visits may be conducted by a trial-designated home health nurse at the subject’s home or other trial-identified location.  These visits may include phone calls from 
the host DIAN-TU site staff. 
3. The specific date during the baseline visit (V2) when the first dose of study drug is administered should be used to determine timing of all subsequent visits. 
4. Informed consent will be obtained in two steps.  Subjects will have the opportunity to review the main informed consent form (ICF) and the supplemental drug-specific 
ICFs and to discuss with DIAN-TU site study staff on the phone or in-person.  They can sign the main ICF at home or at the DIAN-TU site.  The main ICF must be signed 
before any study procedures are performed.  After screening labs are obtained and the subject is randomized to a specific study drug arm at baseline visit (V2), subject 
will review and sign a supplemental study drug-specific consent that details specific risks/benefits and procedures for the study drug arm to which they were assigned. 

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5. Study drug-specific supplemental consent should be reviewed and signed after randomization prior to first dose. 
6. Family history/age at onset and demographic information for subject and study partner will be collected during the screening period and confirmed at the baseline visit 
(V2).  This information will not be collected at subsequent visits unless the subject or study partner becomes aware of new information or the study partner changes 
during the study. 
7. Home health nurses will have specific scripts or forms to prompt assessment and collection of medical treatment history, health changes or complaints (for assessment 
of adverse events by the site) and concomitant medications. 
8. Preexisting conditions will be documented at screening visit (V1) and reviewed at baseline visit (V2) prior to study drug administration. 
9. Provenance testing to confirm specimen identity will be performed at baseline visit only (V2). 
10. Includes TSH, B12, Hemoglobin A1c, PT, PTT, and INR at Screening Visit (V1) only. 
11. Serum pregnancy testing will be performed at screening visit (V1), V54 and V93 and at the End-of-Study (EOS) visit.  Urine pregnancy testing will be performed at all 
other visits.  Pregnancy tests will be confirmed as negative prior to dosing with study drug.  Urine pregnancy test must be completed and confirmed as negative either 
the day of or the day prior to any PET scan; if PET scans occur on more than 2 consecutive days during annual visits more than one urine pregnancy test will be required.  
Women who have undergone tubal ligation are also required to have pregnancy tests performed.  Alternate tests may be used if urine collection is not feasible but must 
be approved by the sponsor in advance. 
12. Pharmacokinetic (PK) blood samples should be obtained before study drug administration at the indicated visits.  Time of collection and timing of drug administration 
should be recorded. 
13. Anti-drug antibody (ADA) samples should be obtained at the indicated visits.  These should be drawn before study drug administration.  Time of collection and timing of 
drug administration should be recorded. 
14. For future studies, including future regulatory inquiries or additional monitoring of anti-drug antibodies or other drug-specific tests.  See main protocol section 6.1.12. 
15. Blood pressure, heart rate, respiratory rate, and body temperature will be collected at all visits.  Height will be measured at baseline (V2) and annual visits only; weight 
will be measured approximately every 3 months. 
16. Clinical assessments: DIAN-TU clinical assessment battery includes: study partner interview and administration of clinical dementia rating (CDR) and supplemental CDR; 
clinician assessment of symptoms and diagnosis; Geriatric Depression Scale (GDS), Functional Assessment Scale (FAS), Neuropsychiatric Inventory (NPI-Q) and Mini-
Mental State Examination (MMSE). 
17. The Cognitive testing battery will include both computer-administered and conventional testing.  See section 6.1.14 of the main protocol and DIAN Trials Unit Cognition 
Core Procedures Manual for additional information.  The full battery will be administered at baseline visit (V2) and at annual visits.  A subset of the full battery (see 
section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core Procedures Manual will be administered by the home health nurse in the home as a practice 
battery at the screening visit (V1) and at the 6-month visits, for visits not occurring at the DIAN-TU site.  Cognitive testing should be completed as early in the day as 
possible, and before study drug infusion or injection. 
18. Lumbar puncture (LP) should be performed after MRI, if on the same date.  LPs should be conducted as close to the baseline (V2) collection time as possible at each 
subsequent visit and under fasting conditions (water is allowed and encouraged).  Cerebrospinal fluid (CSF) will be sent to a local laboratory for cell count and 
differential, glucose and protein as well as to central lab for sample management, including Washington University Biomarker Core lab and designated research/referral 
labs for biomarker and drug-specific analysis.  Site staff should contact the subject with a follow-up phone call or brief visit within 24 hours after LP, and no longer than 
48 hours later, to review any adverse events. 
19. Only for subjects participating in the tau PET imaging addendum.  Participating subjects may have no more than three (3) scans at any of the indicated visits (refer to the 
tau protocol addendum). 
20. Safety MRIs (SM) visits will be done at the DIAN-TU site or a qualified imaging center in reasonable proximity to the subject’s home for subjects not close to their DIAN-
TU site.  When possible, these will be done at an ADNI and/or ADCS site qualified imaging center.   
21. Prior to randomization, verify that all inclusion/exclusion criteria are met, including ARIA findings on baseline (V2) MRI. 
22. Site study coordinators should call subjects either during or within two weeks after V3, V4 and V5.  For V6 and subsequent home visits, coordinator calls can be made 
with less frequency at the discretion of the principal investigator or designee, and/or coordinator, and subject, but should occur at least every 3 months. 
23. PET imaging studies may be omitted if early termination (ET) occurs less than 6 months after the previous PET imaging or if precluded by local regulations/dosimetry 
limits.  Other procedures may also be eliminated on a case-by-case basis, as determined by the sponsor. 

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24. See section 1.12 for details of drug-specific samples at early termination (ET) visit. 
25. Study drug administration only if subject is continuing double-blind treatment beyond year 4.   

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GANTENERUMAB SCHEDULE OF VISITS: TREATMENT BEYOND YEAR 4   
Gantenerumab Schedule of Visits:  Double-blind Treatment Beyond Year 4 - Year 5, if applicable 
PROCEDURES: 
VISIT SITE1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No. 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
V65 
V66 
V67 
Timing (weeks)3 
212 
216 
220 
224 
228 
232 
236 
240 
244 
248 
252 
256 
260 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testing4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/neurological exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Testing7 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
3T Safety/Titration MRI8 
      X------------------- Titration Safety MRI - See Table 5 DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule -----------------------X 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol #: DIAN-TU-001
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Gantenerumab Schedule of Visits:  Double-blind Treatment Beyond Year 4 - Year 6, if applicable 
PROCEDURES: 
VISIT SITE1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No. 
V68 
V69 
V70 
V71 
V72 
V73 
V74 
V75 
V76 
V77 
V78 
V79 
V80 
Timing (weeks)3 
264 
268 
272 
276 
280 
284 
288 
292 
296 
300 
304 
308 
312 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testing4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/neurological exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Testing7 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
3T Safety/Titration MRI8 
      X--------------------Titration Safety MRI - See Table 5 DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule--------------------X 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

Washington University in St. Louis 
Protocol #: DIAN-TU-001
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Gantenerumab Schedule of Visits:  Double-blind Treatment Beyond Year 4 - Year 7, if applicable 
PROCEDURES: 
VISIT SITE1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
H 
Visit No. 
V81 
V82 
V83 
V84 
V85 
V86 
V87 
V88 
V89 
V90 
V91 
V92 
V93/ET 
End of 
Study Visit10 
Timing (weeks)3 
316 
320 
324 
328 
332 
336 
340 
344 
348 
352 
356 
360 
364 
12 weeks 
post last 
dose 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Testing4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/neurological exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Assessment6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cognitive Testing7 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Annual/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
3T Safety/Titration MRI8 
    X -------- Titration Safety MRI - See Table 5 DIAN-TU-001 Gantenerumab Titration Safety MRI Schedule -------X 
 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Coordinator Phone Call9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ET = Early Termination 
Footnotes: 
1. Annual visits will be conducted at the host DIAN-TU site (DIAN-TU).  For subjects who live at a distance from the DIAN-TU site, other visits may be conducted at a site 
nearer to their home (H); safety magnetic resonance imaging (MRI) may be performed at a study-approved facility nearer to their home.  See next two footnotes for 
additional detail. 
2. Infusions/injections and safety visits (designated as occurring at home[H]) may occur at the DIAN-TU site or, for subjects who live at a distance from the DIAN-TU site, 
these visits may be conducted by a trial-designated home health nurse at the subject’s home or other trial-identified location.  These visits may include phone calls from 
the host DIAN-TU site staff. 
3. The specific date during the baseline visit (V2) when the first dose of study drug is administered should be used to determine timing of all subsequent visits. 
4. Serum pregnancy testing will be performed at screening visit (V1), V54 and V93 and at the End of Study visit.  Urine pregnancy testing will be performed at all other visits.  
Pregnancy tests will be confirmed as negative prior to dosing with study drug.  Urine pregnancy test must be completed and confirmed as negative either the day of or 
the day prior to any PET scan; if PET scans occur on more than 2 consecutive days during annual visits more than one urine pregnancy test will be required.  Women who 
have undergone tubal ligation are also required to have pregnancy tests performed.  Alternate tests may be used if urine collection is not feasible but must be approved 
by the sponsor in advance. 

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5. Blood pressure, heart rate, respiratory rate, and body temperature will be collected at all visits.  Height will be measured at baseline (V2) and annual visits only; weight 
will be measured approximately every 3 months. 
6. Clinical assessments: DIAN-TU clinical assessment battery includes: study partner interview and administration of clinical dementia rating (CDR) and supplemental CDR; 
clinician assessment of symptoms and diagnosis; Geriatric Depression Scale (GDS), Functional Assessment Scale (FAS), Neuropsychiatric Inventory (NPI-Q) and Mini-
Mental State Examination (MMSE). 
7. The Cognitive testing battery will include both computer-administered and conventional testing.  See section 6.1.14 of the main protocol and DIAN Trials Unit Cognition 
Core Procedures Manual for additional information.  The full battery will be administered at baseline visit (V2) and at annual visits.  A subset of the full battery (see 
section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core Procedures Manual will be administered by the home health nurse in the home as a practice 
battery at the screening visit (V1) and at the 6-month visits, for visits not occurring at the DIAN-TU site.  Cognitive testing should be completed as early in the day as 
possible, and before study drug infusion or injection. 
8. Safety MRIs (SM) visits will be done at the DIAN-TU site or a qualified imaging center in reasonable proximity to the subject’s home for those not close to their DIAN-TU 
site.  When possible, these will be done at an ADNI and/or ADCS site qualified imaging center. 
9. Site study coordinators should call subjects either during or within two weeks after V3, V4 and V5.  For V6 and subsequent home visits, coordinator calls can be made 
with less frequency at the discretion of the PI or designee, and/or coordinator, and subject, but should occur at least every 3 months. 
10. The End of Study visit should be performed 12 weeks after the last dose of double-blind treatment.  The double-blind treatment period for each subject may vary based 
on when the subject was enrolled and may last from 4 (208 weeks [V54]) up to 7 years (364 weeks [V93]) or until early termination, whichever is sooner.  Any procedures 
done after the last dose, but before the safety follow-up visit, do not need to be repeated. 
 
 
 

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3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 

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APPENDIX 4: SOLANEZUMAB 
 
DRUG-SPECIFIC INFORMATION: 
Solanezumab (LY2062430)  
 
DIAN-TU-001:  A Phase II/III Randomized, Double-Blind, Placebo-
Controlled, Cognitive Endpoint, Multicenter Study of Potential Disease 
Modifying Therapies in Individuals at Risk for and with Dominantly 
Inherited Alzheimer’s Disease 
 
Regulatory Sponsor: 
Washington University in St. Louis 
Dominantly Inherited Alzheimer’s Network Trials Unit (DIAN-TU) 
Department of Neurology,  
Campus Box 8111, 660 S. Euclid 
Saint Louis, MO 63110 
 
Study Product: 
Solanezumab (LY2062430) 
Protocol Number: 
DIAN-TU-001 
Protocol Version: 
Amendment 10 
Version Date: 
20 Dec 2019 
IND Number: 
115,652 
 

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TABLE OF CONTENTS 
APPENDIX 4: SOLANEZUMAB .............................................................................................. 201 
TABLE OF CONTENTS .......................................................................................................... 202 
LIST OF TABLES ................................................................................................................... 205 
LIST OF FIGURES ................................................................................................................. 206 
1 
DRUG-SPECIFIC INTRODUCTION ............................................................................... 207 
 
Background ......................................................................................................... 207 
 
Study Drug ........................................................................................................... 207 
 
Preclinical Data ................................................................................................... 207 
 
Clinical Data ........................................................................................................ 208 
 
Dose Selection/Rationale .................................................................................... 208 
 
Risks/Benefits ...................................................................................................... 208 
 
Drug-specific Study Design ................................................................................. 210 
 
Rationale for Biomarker Endpoint ...................................................................... 210 
 
Primary Study Endpoint ...................................................................................... 211 
 
Additional Study Endpoints and Biomarker Endpoint for Interim Analyses ...... 212 
 
Primary Safety Endpoints .................................................................................... 212 
 
Drug-specific Tests .............................................................................................. 212 
1.12.1 
Plasma and CSF Samples for Assessment of Aβ, Solanezumab, and 
Serum Samples for Assessment of Anti-solanezumab Antibodies ... 212 
1.12.2 
Plasma and Serum Collection and Retention Procedures ................ 213 
1.12.3 
Technique Used for Evaluation of Plasma ........................................ 213 
1.12.4 
Technique Used for Evaluation of Cerebrospinal Fluid .................... 214 
1.12.5 
Pharmacokinetic Analysis of Plasma Solanezumab .......................... 214 
 
Drug-specific Safety Concerns ............................................................................ 214 
1.13.1 
Amyloid-related Imaging Abnormalities (ARIA) ................................ 214 
1.13.2 
Other Drug-specific Safety Concerns ................................................ 215 
 
ARIA-related Interventions Including Dose Changes and Discontinuation ........ 216 
 
Drug-specific Discontinuations or Withdrawal ................................................... 218 
2 
STUDY DRUG ........................................................................................................... 219 

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Drug Description ................................................................................................. 219 
 
Drug Treatment Regimen ................................................................................... 219 
 
Packaging, Preparation and Administration of Study Drug ................................ 222 
 
Blinding of Study Drug ........................................................................................ 223 
 
Dispensing of Study Drug .................................................................................... 223 
 
Assessing Compliance with Study Drug .............................................................. 224 
3 
STUDY PROCEDURES ............................................................................................... 224 
 
Enrollment .......................................................................................................... 224 
 
Randomization .................................................................................................... 224 
 
Specific Study Visits – Double-blind Treatment Period ...................................... 226 
3.3.1 
Visit 1 (screening visit) ...................................................................... 227 
3.3.2 
Visit 2 (baseline/first dose) ............................................................... 228 
3.3.3 
Visit 3 ................................................................................................. 230 
3.3.4 
Visits 4, 6, 7, 10, 12-14, 16, 17, 19, 20, 23, 25-27, 29-33, 35-40, 42-
46, 48-53, 55-59, 61-66, 68-72, 74-79, 81-85, and 87-92 ................. 230 
3.3.5 
Visit 5 ................................................................................................. 231 
3.3.6 
Visits 8 and 21 ................................................................................... 232 
3.3.7 
Visits 9 and 22 ................................................................................... 233 
3.3.8 
Visits 11, 18, and 24 .......................................................................... 233 
3.3.9 
VISIT 15: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 234 
3.3.10 
VISIT 28: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 235 
3.3.11 
Visits 34 and 47 ................................................................................. 236 
3.3.12 
VISIT 41: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 237 
3.3.13 
VISIT 54: ANNUAL VISIT AT HOST DIAN-TU SITE ............................... 238 
3.3.14 
Visits 60, 73, and 86 .......................................................................... 239 
3.3.15 
Visits 67, 80, and 93: ANNUAL VISIT AT HOST DIAN-TU SITE ........... 239 
3.3.16 
End-of-Treatment Safety Follow-up Visit ......................................... 240 
3.3.17 
Early Termination Visit/Post-treatment Follow-up .......................... 241 
3.3.18 
Safety Magnetic Resonance Imaging (MRI) ...................................... 242 
 
Specific Study Visits – Open-label Extension Period ........................................... 242 

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3.4.1 
OLE Visit 1 (baseline/first dose) ........................................................ 243 
3.4.2 
OLE Visits 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 21, 
22, 23, 24, 25, and 26 ........................................................................ 244 
3.4.3 
OLE Visits 7 and 20 ............................................................................ 245 
3.4.4 
OLE VISIT 14: ANNUAL VISIT AT HOST DIAN-TU SITE ........................ 245 
3.4.5 
OLE VISIT 27: ANNUAL VISIT AT HOST DIAN-TU SITE ........................ 247 
3.4.6 
Early Termination Visit ...................................................................... 248 
3.4.7 
Safety Magnetic Resonance Imaging MRI ........................................ 248 
4 
DRUG-SPECIFIC ANALYSIS PLAN ............................................................................... 248 
 
Cognitive Endpoint (DIAN-MCE) Power Analysis and Sample Size 
Determination ..................................................................................................... 248 
 
Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification .. 248 
4.2.1 
Biomarker Endpoint Power Analysis ................................................. 248 
4.2.2 
Biomarker Endpoint Sample Size Justification .................................. 249 
4.2.3 
Interim Analysis ................................................................................. 249 
 
Other Drug-specific Analyses .............................................................................. 250 
 
Changes to the Data Analysis .............................................................................. 250 
5 
DRUG-SPECIFIC ADVERSE EVENTS AND REPORTING ................................................. 251 
REFERENCES ....................................................................................................................... 252 
SOLANEZUMAB SCHEDULE OF VISITS: 4 YEAR DOUBLE-BLIND TREATMENT PERIOD ............. 253 
SOLANEZUMAB SCHEDULE OF VISITS: DOUBLE-BLIND TREATMENT BEYOND YEAR 4 ........... 259 
SOLANEZUMAB SCHEDULE OF VISITS: OPEN-LABEL EXTENSION ........................................... 263 
 

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LIST OF TABLES 
Table 1  
Procedures for Asymptomatic ARIA-E ....................................................................... 217 
Table 2 
Procedures for Symptomatic ARIA-E: Any incidence of symptomatic ARIA-E or 
asymptomatic with lesions >2 cm .............................................................................. 217 
Table 3  
Procedures for ARIA-H Microhemorrhage ................................................................. 218 
Table 4 
Procedures for Superficial Siderosis .......................................................................... 218 
Table 5 
DIAN-TU-001 Solanezumab Schedule of Visits: Dose Escalation Period (At least 
20 Subjects for Each Dose Level) ............................................................................... 220 
Table 6 
DIAN-TU-001 Solanezumab Schedule of Visits: Dose Escalation Period 
(Remaining Subjects for Each Dose Level After Safety Evaluation and Clearance) ... 221 
Table 7 
DIAN-TU-001 Solanezumab Schedule of Visits: Dose Escalation Period in the 
Open-label Extension Period ...................................................................................... 222 
Table 8 
The effect size with 80% power in comparison to the reported effect size in a 
prior study and the corresponding power with the proposed sample size .............. 249 
 

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LIST OF FIGURES 
Figure 1  Box plots of change from baseline in cerebrospinal fluid Aβ concentrations. .......... 211 
Figure 2 Randomization Scheme:  All Subjects in Gantenerumab and Solanezumab Arms ... 225 
Figure 3 Randomization Scheme: Gantenerumab and Solanezumab (Mutation Positive 
Subjects Only)............................................................................................................. 226 
 
 

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1 
DRUG-SPECIFIC INTRODUCTION 
 Background 
Both active and passive immunization strategies directed against amyloid beta peptides are 
currently under investigation.  The first preclinical studies demonstrating reduction in amyloid 
burden were performed in APPV717F (“PDAPP”) transgenic mice over 15 years ago (Schenk et al., 
1999; Bard et al., 2000).  The PDAPP mouse and all other genetic mouse models of AD are 
based on the mutations in APP, PSEN1 and PSEN2 that underlie the autosomal dominant forms 
of AD represented in the DIAN cohort.  The preclinical studies in these mouse models are even 
more relevant to these individuals than to those with sporadic AD. 
 Study Drug 
Solanezumab/LY2062430 is a humanized anti- Aβ peptide immunoglobulin G-1 (IgG1) 
monoclonal antibody that recognizes a mid-domain epitope of the Aβ peptide (amino acid 
residues 13-28).  Preclinical data (see below) suggest that solanezumab binds to soluble but not 
aggregated Aβ peptides.  Approximately 0.1% of solanezumab crosses the blood–brain barrier 
and binds selectively to soluble monomeric Aβ in the central compartment.  This binding may 
alter equilibria between soluble monomers and other aggregated forms of Aβ.  Nonclinical 
evidence in transgenic mice suggests that the altered equilibria may slow plaque accrual. 
 Preclinical Data 
The first passive immunization studies used antibodies targeted to the N-terminal region of the 
Aβ peptide (e.g., Bard et al., 2000); this region of the peptide is accessible in both aggregated 
and soluble forms of Aβ.  Antibodies that bind to the mid-domain of Aβ such as m266.2 also 
slowed accumulation of amyloid plaque burden in APPV717F (“PDAPP”) mice (DeMattos et al., 
2001) and increased plasma Aβ levels proportionally to the brain amyloid burden (DeMattos et 
al., 2002).  Subsequent studies in PDAPP mice demonstrated that treatment with m266.2 
reversed the cholinergic and cognitive deficits in these mice (Dodart et al., 2002; Bales et al., 
2006). 
In APPV717F transgenic mice, a dosing regimen of 360 µg/week of m266.2 was found to result in 
a significant slowing of amyloid plaque deposition.  Using a mechanistic pharmacokinetic and 
pharmacodynamic (PK/PD) model that used equilibrium binding equations to account for the 
binding between solanezumab and Aβ in the plasma compartment, this dose regimen in mice 
was estimated to produce a time-averaged reduction of unbound plasma Aβ of 67% at steady 
state.  Using the same mechanistic PK/PD model and preliminary solanezumab and Aβ data 
from clinical Study H8A-MC-LZAJ, a simulation was performed to project the time-averaged 
reduction of unbound plasma Aβ for the clinical dose regimen of 400 mg intravenously given 
every 4 weeks.  This regimen was estimated to produce a time-averaged reduction of 93% at 
steady state.  Reductions in unbound plasma Aβ42 are expected to be similar.  This reduction in 
unbound plasma Aβ is greater than the 67% reduction that was associated with biochemical 

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efficacy in APPV717F mice and was in part used to justify the dose regimen to explore in Phase 3 
clinical trials. 
 Clinical Data 
Lilly is conducting 1 ongoing solanezumab clinical trial, in addition to DIAN-TU 001, with 3 
concluded Phase 3 trials. 
As of 13 October 2016, there were 9 solanezumab studies completed or with interim database 
locks (Studies LZAH, LZAI, LZAJ, LZAK, LZAM, LZAN, LZAO, LZAT, and LZAX).  One or more 
infusions of solanezumab were administered to approximately 3725 subjects.  See most current 
Investigator’s Brochure. 
 Dose Selection/Rationale 
The DIAN-TU study was initiated with solanezumab 400 mg administered intravenously every 
4 weeks (400 mg Q4W).  Selection of the 400 mg Q4W dose was based largely, but not entirely, 
on the peripheral sink hypothesis, which held that maximizing peripheral target engagement 
would change Aβ equilibria, resulting in altered amyloid deposition in the central compartment, 
ultimately leading to a slowing of disease progression.  The 400 mg Q4W dose was selected to 
lower free plasma Aβ concentrations by at least 90%, a level that exceeded what had been 
associated with slowing of amyloid plaque deposition in transgenic rodent species. 
The negative primary outcome of Study LZAX, which did not demonstrate statistically significant 
slowing of progression in the population of patients treated with solanezumab 400 mg Q4W 
who were amyloid-positive and who had mild dementia due to AD, suggests that the peripheral 
sink hypothesis for target engagement to determine dose selection may not predict clinical 
efficacy in Phase 3 trials.  Thus, central target engagement based on biomarkers may provide 
better predictive value for Phase 3 dose selection. 
Phase 2 solanezumab data suggest that greater central target engagement is likely to be 
achieved with dosing greater than 400 mg Q4W (Figure 1).  Whether such an increase in target 
engagement will result in improved clinical efficacy remains unknown.  A dose of 400 mg every 
week (400 mg QW), which is equivalent to 1600 mg over a 4-week period, was assessed in 
Phase 2 Studies LZAJ and LZAK, and showed increased CSF Aβ concentrations and an acceptable 
safety profile. 
Based on the safety profile observed with solanezumab at all doses tested in clinical studies 
(section 1.6), and based on the goal of increasing central target engagement, the dose given in 
the DIAN-TU study was increased to 1600 mg Q4W. 
 Risks/Benefits 
A potential side effect of concern for treatments that target Aβ is the development of amyloid-
related imaging abnormalities (ARIA), as reported in studies of passive immunization therapies 
directed against the N-terminal portion of the Aβ peptide (Sperling et al., 2012).  These changes 

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include microhemorrhage, vasogenic edema and infarction; they are most often asymptomatic, 
but symptoms have been reported. 
The safety profile of solanezumab as observed among patients with mild AD who were 
randomized to and received at least 1 dose of placebo (N=1727) or solanezumab (N=1708) for 
up to 18 months in Phase 3 Studies LZAM, LZAN, and LZAX is described below. 
The frequency of ARIA-E in solanezumab treated patients was greater than in patients treated 
with placebo; however, this AE was seen in only 0.6% of solanezumab treated patients and 
0.3% of placebo treated patients and the difference was not statistically significant.  ARIA-E was 
not clearly related to symptoms in any patient.  More solanezumab- than placebo-treated 
patients had an increase in size of pre-existing ARIA-H or number of ARIA-H (6.1% and 5.2%, 
respectively), although this did not have apparent clinical implications. 
None of the cases of ARIA were accompanied by concurrent symptoms in except for 1 patient 
who displayed symptoms during the open-label period in Study LZAX.  For this patient, 
symptoms of dizziness, balance disorder, transient paresthesia, and hemiparesis of the left arm 
were considered possibly related to a right frontal superficial siderosis (a type of ARIA-H) and 
mild right frontal ARIA-E. 
Infusion site reactions (local reactions) were seen in 2.1% and 2.0% of the solanezumab- and 
placebo-treated patients, respectively. 
Treatment-emergent anti-drug antibodies (ADA) developed in 2.7% of patients exposed to 
solanezumab at any time during the placebo-controlled period (1.7% treatment induced, 
1% treatment boosted, and 0.5% neutralizing).  Among placebo-treated patients, 3.2% 
developed treatment-emergent ADA (2.1% treatment induced, 1.1% treatment boosted, and 
0.8% neutralizing).  No TEAEs appeared to be associated with ADA.  Based on completed 
analyses of Studies LZAM and LZAN, these laboratory findings were generally transient and low 
titer and solanezumab treatment-emergent immunogenicity did not appear to impact the PK of 
solanezumab or the PD response.  Analyses of Study LZAX are ongoing.  Thus, the concluded 
Phase 3 studies demonstrated an acceptable safety profile for solanezumab 400 mg Q4W. 
Solanezumab has also been tested in higher doses than 400 mg QW in prior early phase studies.  
Phase 1 Studies LZAH (N=4) and LZAI (N=4) investigated the safety and tolerability of 
solanezumab in AD patients at single doses up to 10 mg/kg, which is approximately equivalent 
to 700 mg.  Of the 8 subjects receiving 10 mg/kg, 3 had apparent mild and self-limited infusion 
reactions.  Phase 2 Studies LZAJ (12-week treatment duration) and LZAK (8-week treatment 
duration) included doses of 400 mg weekly (N=11 in each study), which is the equivalent of 
1600 mg of solanezumab in each 4-week period.  The first 3 of these studies were conducted 
before ARIA-H and ARIA-E were understood as potential risks for anti-amyloid therapies, and 
thus ARIA-H and ARIA-E were not specifically assessed on MRI.  However, no changes in MRIs 
were observed as safety concerns at any of the doses given.  Study LZAK was the first 
solanezumab study to assess for ARIA and no ARIA-E or ARIA-H were reported in this study at 
any of the doses given.  While limited in sample size, these studies suggested an acceptable 
safety profile for solanezumab at these exposures. 

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 Drug-specific Study Design 
Drug-specific study design features include the use of CSF Aβ42 as the biomarker endpoint for 
target engagement.  In addition, anti-solanezumab antibodies will be assessed.  A dose 
escalation period was added in Amendment 7; additional safety assessments are implemented 
during the dose escalation period, as described in the dose escalation study schedule 
(section 2.2).  Specific action plans that include dose modification should ARIA occur are 
provided in section 1.14. 
 Rationale for Biomarker Endpoint 
Rationale for use of CSF Aβ isoforms as target engagement biomarker for DIAN-TU 
Solanezumab Arm  
Although the precise dynamics of Aβ homeostasis in the brain parenchyma and CSF are not fully 
understood, it is likely that levels of free Aβ species (not bound to solanezumab) in the CSF 
reflect levels in brain interstitial fluid.  Emerging evidence suggests that amyloid plaques are not 
static, but rather that Aβ species in plaques also equilibrate with parenchymal Aβ and ultimately 
with CSF.  Because solanezumab binds to soluble Aβ isoforms, free CSF Aβ may serve indirectly 
as a biomarker of target engagement.  Conversely, solubilization of Aβ in plaque might 
confound the use of free CSF Aβ as a biomarker of target engagement.  Solanezumab treatment 
was variably associated with increased, unchanged, or decreased CSF free Aβ42 in studies LZAJ, 
LZAM, LZAN, and LZAX, respectively.  In each of these analyses, CSF free Aβ40 was nominally 
decreased.  Importantly, in all solanezumab trials, a dose dependent increase in total 
(bound+unbound) Aβ40 and Aβ42 was found, suggesting increased target engagement. 
Eli Lilly & Company (Lilly) first developed methods to measure free CSF Aβ species (not bound to 
solanezumab) prior to study LZAJ and demonstrated a nominal decrease in free CSF Aβ40 in CSF 
in the groups treated with 100 mg QW, 100 mg Q4W, 400 mg Q4W and 100 mg QW relative to 
the placebo-treated group, although this only reached significance (P < 0.01 compared to 
placebo) in the 400 mg QW group.  In contrast to the decrease in unbound CSF Aβ40, there was 
an increase in free (unbound) CSF Aβ42.  While opposing effects on free CSF Aβ42 and free CSF 
Aβ40 occurred in LZAJ, significant increases in both total CSF Aβ42 and total CSF Aβ40 were 
associated with solanezumab treatment.  The dose-dependent increase in total CSF Aβ in study 
LZAJ support the contention of dose-dependent increases in target engagement. 
Concentrations in treated groups as compared to placebo are represented in Figure 1 below.  
This contrasts with preclinical studies (in rats without amyloid plaques) where administration of 
the antibody m266.2 results in decreases in both free CSF Aβ40 and Aβ42.  The patients in the 
LZAJ study, unlike the rats, likely had substantial amyloid plaque burden in the CNS before 
initiating treatment. 

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Figure 1  
Box plots of change from baseline in cerebrospinal fluid Aβ concentrations. 
 
 (A) The total CSF (bound and unbound) Aβ40 and Aβ42 concentrations increased among solanezumab-treated cohorts relative to 
baseline.  No such effect was observed for the placebo-treated cohort.  (B) Among solanezumab (LY)-treated cohorts, the 
increase in total Aβ concentrations was numerically dose dependent.  (C) Measurements of only the unbound Aβ 
concentrations in CSF showed a decrease in Aβ40 among solanezumab-treated cohorts relative to baseline.  (D) In contrast, CSF 
unbound Aβ42 concentrations increased among solanezumab-treated cohorts relative to baseline values (p < 0.001).  Boxes 
represent the interquartile range, line represents median, and whiskers are set to the closest observed value not greater than 
1.5 times the interquartile range.  Lines are used for individual values that fall outside whiskers.  CSF = cerebrospinal fluid; 
LY100 mg Q4W = 100 mg every 4 weeks; LY100 mg QW = 100 mg weekly; LY400 mg Q4W = 400 mg every 4 weeks; LY400 mg 
QW = 400 mg weekly. 
 Primary Study Endpoint 
A multivariate mixed effects cognitive disease progression model (MDPM) for repeated 
measures with a proportional treatment effect will be used to assess statistical differences in 
the rate of decline, relative to the expected years from symptom onset, of the DIAN-MCE scores 
between the active drug and the mutation positive placebos and eligible DIAN-OBS subjects.  
See section 3.5 of the main protocol for more details. 

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 Additional Study Endpoints and Biomarker Endpoint for Interim Analyses 
Additional study endpoints are described in the main study protocol and will be specified as 
secondary or exploratory in the solanezumab-specific SAP appendix.  Refer to the final drug-
specific SAP for differentiation of endpoint classification based on the respective drug’s target 
and mechanism of action. 
Change in total amyloid-beta 1-42 (Aβ42) in CSF will be used as the biomarker of interest for 
interim analysis as well as biomarker endpoint for the solanezumab drug arm as specified in the 
solanezumab-specific SAP appendix.  An increase in total CSF Aβ42 concentrations is consistent 
with target engagement in the central compartment (Siemers et al., 2010). 
 Primary Safety Endpoints 
This study will assess safety and tolerability of treatment with solanezumab in individuals at risk 
for dominantly inherited Alzheimer’s disease.  The primary safety endpoints are identical for all 
study compounds.  Only drug-specific safety endpoints are included here. 
 Drug-specific Tests 
1.12.1 Plasma and CSF Samples for Assessment of Aβ, Solanezumab, and Serum Samples for 
Assessment of Anti-solanezumab Antibodies 
Timing of Plasma and Serum Sampling 
Visits when plasma or serum are sampled and the time of sampling relative to study drug 
dosing are shown in the body and footnotes of the Study Procedures and Schedule of Visits and 
described below.  Samples from placebo-treated subjects will not be assayed for solanezumab.  
Amyloid-β peptide results or drug and antibody concentration measurements that could 
unblind the study will not be reported to investigative sites or other blinded personnel. 
Samples will be collected before dosing (serum for anti-solanezumab antibodies and plasma for 
amyloid beta peptide and solanezumab levels) and 30 minutes or less after completion of 
infusion (plasma for solanezumab level) on: 
• Baseline Visit (V2) 
• Visit 5 (12 weeks after baseline) 
• Visit 9 (28 weeks after baseline) 
• Visit 15 (52 weeks after baseline, annual visit at DIAN-TU site) 
• Visit 22 (80 weeks after baseline) 
• Visit 28 (104 weeks after baseline, annual visit at DIAN-TU site) 
• Visit 54 (208 weeks after baseline, annual visit at DIAN-TU site) 
• End of Treatment Safety Follow-up (4-8 weeks after last dose of double-blind treatment) 
• Early termination (only if prior to completion of V28, week 104):  any time during visit 

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In addition, samples for drug-specific testing will be collected at the following time points 
relative to the beginning of the dose escalation period (that is, the first dose of 800 mg): 
• Dose 1 of 800 mg 
• Dose 2 of 800 mg (4 weeks after dose 1 of 800 mg dose) 
• Dose 1 of 1600 mg (8 weeks after dose 1 of 800 mg dose) 
• Dose 2 of 1600 mg (12 weeks after dose 1 of 800 mg dose)  
• Dose 4 of 1600 mg (20 weeks after dose 1 of 800 mg dose) 
During the dose escalation period, samples for plasma solanezumab levels should be collected 
before infusion and within 30 minutes after completion of infusion for post-dose levels. 
1.12.2 Plasma and Serum Collection and Retention Procedures  
Venous blood will be drawn into sodium ethylene diamine tetra-acetic acid (EDTA) tubes for the 
determination of plasma concentrations of solanezumab and Aβ, at the times indicated in the 
Study Schedule (see above).  Serum will be collected for anti-solanezumab antibody titers.  A 
saline well or heparin lock may be used to facilitate blood collection.  On the dosing day, the 
blood will be collected from the arm that did not receive the infusion of study drug. 
It is critical that the date and time of sample acquisition, and date and time of administration of 
study drug are accurately recorded for each blood sample.  Only samples from subjects dosed 
with solanezumab will be assayed for solanezumab.   
Sample handling and shipment to the central laboratory will occur per instructions given to the 
investigative study site. 
Bioanalytical samples collected to measure study drug concentrations will be retained for a 
maximum of one (1) year following last subject visit. 
Plasma and CSF used for the assessment of Aβ may be stored for a maximum of 15 years 
following last subject visit. 
Samples collected to assess anti-solanezumab titers will be retained for a maximum of 15 years 
following last subject visit for the study. 
1.12.3 Technique Used for Evaluation of Plasma 
Plasma concentrations of solanezumab and Aβ for pharmacodynamic analysis will be 
determined from processed blood samples using validated enzyme-linked immunosorbent 
assay (ELISA) methods.  Accurate plasma Aβs analyses can only be achieved using ELISA 
designed to be tolerant to solanezumab as this anti-Aβ drug candidate produces concentration-
dependent interference in traditional immunoassays for analysis of Aβ isoforms. 
Results of solanezumab and Aβ analyses that could unblind the study will not be provided to 
investigators or other blinded personnel. 

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1.12.4 Technique Used for Evaluation of Cerebrospinal Fluid  
Cerebrospinal fluid (CSF) concentrations of solanezumab and Aβ for pharmacodynamic analysis 
will be determined using validated immunoassay methods.  Accurate CSF Aβ analyses can only 
be achieved using immunoassays designed to be tolerant to solanezumab as described above. 
CSF concentrations of total tau and phosphorylated tau (ptau) will also be determined using 
validated immunoassay methods.  Samples from placebo-treated subjects will not be assayed 
for solanezumab.  Amyloid β peptide, tau, and drug concentration measurements that could 
unblind the study will not be reported to investigative sites or other blinded personnel. 
1.12.5 Pharmacokinetic Analysis of Plasma Solanezumab  
PK data analysis for solanezumab will be conducted by Eli Lilly and Company (Lilly), and will be 
conducted according to an analysis plan currently being developed by Lilly.  In general, the 
planned process used to evaluate the PK data will be as follows: The plasma solanezumab 
concentration data collected in the DIAN-TU study will be graphically compared to predictions 
generated from the population PK model developed with data pooled from previous Phase 3 
trials sponsored by Lilly. 
If it is determined that the population PK model adequately predicts the concentration data 
from DIAN-TU, the model will be used to estimate individual exposure parameters (e.g., AUC) 
for the subjects in the DIAN-TU trial.  If it is determined that the model does not adequately 
predict observed plasma concentrations in the DIAN-TU trial, the model may be updated using 
the data from the DIAN-TU trial.  Specifically, modeling will be conducted using nonlinear mixed 
effects modeling (NONMEM) or other appropriate software.  This model may incorporate 
information from the Phase 3 trials in order to better estimate exposure parameters, as 
warranted.  AUC and Cmax estimates will be generated for both the 400 mg and 1600 mg dose 
levels for each patient.  
Graphical analyses will be conducted to summarize the effect of post hoc AUC and/or Cmax 
estimates on CSF and/or plasma biomarkers using the exposure estimate consistent with the 
dose level administered prior to the collection of the biomarkers.  These exposure estimates 
may be used in correlation analyses with various biomarkers, including plasma Aβ 
concentrations.  A population PK/PD model previously developed by Lilly to estimate time-
averaged reduction in free plasma Aβ40 may be used with these data, if appropriate.  If 
warranted, additional modeling may be performed based on the results of these analyses. 
 Drug-specific Safety Concerns 
1.13.1 Amyloid-related Imaging Abnormalities (ARIA) 
Amyloid-related imaging abnormalities (ARIA) are a special safety endpoint in studies of 
Alzheimer’s immunotherapies, including both active and passive immunization.  Since 
compounds studied in DIAN-TU are investigational, this study includes frequent MRI scans to 
assess for ARIA changes.  ARIA can occur as either cerebral edema (ARIA-E) or as hemorrhages 

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(ARIA-H), typically microhemorrhages, but larger hemorrhages and frank infarction have also 
been reported (Sperling et al., 2012).  The number of microhemorrhages will be monitored at 
entry and throughout the trial. 
The frequency of MRI monitoring will be reduced to annually after the first two years of the 
study.  Results from two large Phase 3 trials in mild-to-moderate AD (LZAM and LZAN) and one 
Phase 3 trial in mild AD (LZAX) have been analyzed and have shown no statistically significant 
differences between solanezumab and placebo on safety MRI parameters.  The reduced 
frequency of MRI monitoring here will closely match extension studies (LZAO and open-label 
extension period of LZAX) with solanezumab. 
Following the approval of Amendment 7, the dose escalation process will begin.  Subjects may 
be at different time points in the schedule of visits when initiating dose escalation, but all must 
have had at least 2 doses at 400 mg.  Prior to escalation to the 800 mg dose level, subjects will 
sign a new ICF. 
With other investigational anti-Aβ antibodies, most cases of dose-related ARIA-E have occurred 
after 2 doses of an increased dose (Sperling et al.  2012).  Therefore, an additional safety MRI 
will be conducted before the first dose of 1600 mg (approximately 1 week after the second 
dose of 800 mg).  The annual MRI assessment can fulfill this requirement.  The safety MRI must 
be reviewed prior to dose escalation to 1600 mg. 
Although the dose escalation schema was designed to reach the target dose of 1600 mg every 
4 weeks, the target dose may not be achieved as otherwise dictated by the ARIA-related 
intervention algorithms or more conservative action to be discussed by the site and the 
sponsor.  The MRI schedule may be changed according to the ARIA related dosing intervention 
algorithm (see tables in section 1.15) or per individual request by the site principal investigator 
or delegated sub-investigator, Project Arm Leader (PAL), or Medical Director or designee. 
Safety MRIs will be performed at the same field strength throughout the study, and if possible 
on the same scanner.  All MRIs will be centrally read. 
If any clinical concern arises, unscheduled MRIs can be conducted at any point during the 
DIAN-TU trial. 
1.13.2 Other Drug-specific Safety Concerns 
In addition to ARIA, acute infusion reactions may occur with any agent that may cause cytokine 
release, including monoclonal antibodies such as solanezumab.  Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 24 hours 
of infusion.  Signs/symptoms may include: allergic reaction/ hypersensitivity (including drug 
fever), arthralgia, bronchospasm, cough, dizziness, dyspnea, fatigue, headache, hypertension, 
hypotension, myalgia, nausea, pruritus, rash, rigors/chills, sweating (diaphoresis), tachycardia, 
urticaria, and vomiting. 

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 ARIA-related Interventions Including Dose Changes and Discontinuation  
See main protocol sections 1.2, 3.8, 6.1.15 and 6.1.16 for details of MRI reading and reporting.  
The Mayo-ADIR Clinic will review MRIs and provide a report on ARIA-E and ARIA-H.  This report 
will include both definite and possible findings.  A report of new definite ARIA-H or ARIA-E 
changes in a subject will trigger a review by the Medical Director or designee, Project Arm 
Leader (PAL), and site principal investigator or delegated sub-investigator.  The site principal 
investigator or designated sub-investigator, in conjunction with the appropriate PAL and the 
DIAN-TU Medical Director or designee, will review new ARIA findings and apply the intervention 
algorithms below using best clinical judgment to weigh the data available to decide whether 
changes in drug treatment are indicated. 
ARIA related intervention algorithm 
The tables below detail the ARIA-E linked intervention algorithm based on these scores (Table 1 
and Table 2) and the intervention algorithm for ARIA-H microhemorrhage (Table 3) and 
superficial siderosis (Table 4).  Algorithms are based on definite ARIA findings only.  For ARIA-E, 
the algorithm relies on measures of the largest diameter of any ARIA-E.  For ARIA-H, areas of 
microhemorrhage are counted and larger areas of hemorrhage (macrohemorrhage) are noted.  
Should both, ARIA-E and ARIA-H be present in the same subject, the more conservative 
procedure should be followed. 
For ARIA cases where there are symptoms that are possibly related to the ARIA findings, more 
stringent procedures should be considered (e.g., withhold treatment for symptomatic cases 
even if the procedures in the table would not require it). 

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Table 1  
Procedures for Asymptomatic ARIA-E 
Number of New 
Occurrences1 
Dose Adjustment 
MRI Monitoring 
Any new individual 
lesions ≤ 2 cm  
Appropriate actions should be discussed among the 
site PI, DIAN-TU Medical Director, and PAL 
Every 4 weeks until 
stable 
Any new individual 
lesions > 2 cm  
Follow the Symptomatic ARIA-E guidance 
Follow the Symptomatic 
ARIA-E guidance 
1. 
Based on new definite ARIA findings (excluding baseline incidences) 
 
Table 2 
Procedures for Symptomatic ARIA-E: Any incidence of symptomatic 
ARIA-E or asymptomatic with lesions >2 cm 
Step-wise Response 
Dose Adjustment 
MRI Monitoring 
Initial action 
Suspend/hold dosing 
Every 4 weeks until 
stable 
Once symptoms and 
ARIA-E deemed 
stable 
Appropriate actions should be discussed among 
the site PI, DIAN-TU Medical Director, and PAL 
Consider additional 
MRI(s) depending on the 
size, and presence of 
symptoms.  Subsequent 
MRI monitoring should 
continue per protocol 
unless agreed otherwise 
by PI, PAL, and Medical 
Director  
If no new MRI 
findings after dosing 
restart and MRI 
Appropriate actions should be discussed among 
the site PI, DIAN-TU Medical Director, and PAL 
Resume MRI monitoring 
per protocol  
Note:  Asymptomatic lesions > 2 cm are based on measurements of new definite ARIA findings 

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Table 3  
Procedures for ARIA-H Microhemorrhage 
Number of New 
Occurrences1 
(Cumulative) 
Dose Adjustment 
MRI Monitoring 
10-15 new, 
cumulative 
occurrences  
Appropriate actions should be 
discussed among the site PI, DIAN-TU 
Medical Director, and Project Arm 
Leader (PAL)  
Consider additional MRI monitoring 
until stable 
> 15 new, 
cumulative 
occurrences  
Appropriate actions should be 
discussed among the site PI, DIAN-TU 
Medical Director, and PAL 
MRI 4 weeks later, consider additional 
MRI monitoring until stable, then 
continue monitoring per protocol 
unless agreed upon otherwise by the 
PI, Medical Director, and PAL  
1. Based on new definite ARIA findings (excluding baseline incidences)  
 
Table 4 
Procedures for Superficial Siderosis 
Number of New 
Occurrences1 
Dose Adjustment 
MRI Monitoring 
≥ 1 new 
occurrence of 
superficial 
siderosis 
Appropriate actions should be 
discussed among the site PI, DIAN-TU 
Medical Director, and Project Arm 
Leader (PAL). 
Consider additional MRI(s) depending 
on the size and presence of symptoms.  
Subsequent MRI monitoring should 
continue per protocol unless agreed 
otherwise by PI, PAL, and Medical 
Director 
1. Based on new definite ARIA findings (excluding baseline incidences) 
 Drug-specific Discontinuations or Withdrawal 
Subjects will be discontinued from the study if they had a prolonged acute infusion reaction 
that was not rapidly responsive to symptomatic medication such as antihistamines, 
nonsteroidal anti-inflammatory drugs, and/or narcotics and/or brief interruption of infusion.  
Mild infusion reactions responding to treatment or requiring pretreatment before subsequent 
infusions would not require discontinuation, unless discontinuation was considered appropriate 
based on medical judgment of the principal investigator or Medical Director. 
Following the approval of Amendment 7, the dose escalation process will begin.  If the 
investigator considers that a subject may not be a candidate for dose escalation for any reason, 
the investigator should contact the sponsor to discuss whether to discontinue the subject. 

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2 STUDY DRUG 
 Drug Description 
The active product or placebo will be supplied in a 20 mL vials for preparation with the 
appropriate diluent for intravenous infusion.  Details for supplies will be provided in the 
Pharmacy Manual. 
 Drug Treatment Regimen 
This study was initiated as a comparison of solanezumab (400 mg administered as an 
intravenous infusion of approximately 70 mL) compared to placebo.  The active drug group was 
given an intravenous infusion of solanezumab 400 mg Q4W.   
The study protocol was amended to increase the dose administered up to 1600 mg Q4W; 
following approval of Amendment 7, the dose-escalation process will begin (which includes 
signing a new ICF).  After receiving at least two doses at the 400 mg level, 4 weeks (± 4 days) 
apart, subjects should receive at least two doses at the 800 mg dose level, 4 weeks (± 4 days) 
apart, before proceeding to the 1600 mg dose level.  Changes in dosage may be made in the 
event of ARIA as described in section 1.14 or for other safety reasons at the investigator’s 
discretion with notification of a Medical Director, PAL, or designee. 
In addition to the Solanezumab Schedule of Visits, additional assessments during the dose 
escalation period are required, as described in the dose escalation study schedule.  The first 
doses of 800 mg will be given at the DIAN-TU site or a medically qualified facility, such as an 
infusion clinic, until blinded safety results are evaluated for the first 20 subjects (active or 
placebo) to receive an 800 mg dose infusion (Table 5); subsequent doses may be given by a 
home health nurse.  After the safety evaluation, first doses of 800 mg for the remaining 
subjects may be given by a home health nurse, if deemed appropriate (Table 6). 
Similarly, the first doses of 1600 mg will be given at the DIAN-TU site or a medically qualified 
facility such as an infusion clinic until blinded safety results are evaluated for the first 20 
subjects (active or placebo) to receive a 1600 mg dose infusion (Table 5).  After this evaluation, 
first doses of 1600 mg for the remaining subjects may be given by a home health nurse, if 
deemed appropriate (Table 6). 
All subjects will have a 1-hour post dose monitoring period after their first 800 mg and first 
1600 mg doses. 
Subjects will continue dosing for up to a minimum of 204 weeks and a maximum of 360 weeks 
based upon when the subject was randomized into the study. 

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Table 5 
DIAN-TU-001 Solanezumab Schedule of Visits: Dose Escalation Period (At least 
20 Subjects for Each Dose Level) 
PROCEDURE: 
Dose (mg) 
800 
800 
sMRI 
1600 
1600 
1600 
1600 
VISIT SITE 
DIAN-TUa 
H 
MRI 
DIAN-TUa  
H  
H 
H 
Dose Escalation Timing (weeks)b 
0 
4 
5 
8 
12 
16 
20 
Informed Consent 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
12-Lead ECG 
 
X 
 
 
X 
 
 
3T Safety MRIc 
 
 
X 
 
 
 
 
Drug-specific Testingd 
X 
X 
 
X 
X 
 
X 
Hematology, Chemistry, Urinalysis 
 
X 
 
 
X 
 
 
Study Drug Administration (800 mg)e 
X 
X 
 
 
 
 
 
Study Drug Administration (1600 mg)f 
 
 
 
X 
X 
X 
Xf 
1-Hour Post-Infusion Monitoring 
X 
 
 
X 
 
 
 
Footnotes: 
a The first dose of 800 mg and the first dose of 1600 mg for each subject will be given at the DIAN-TU site or a medically 
qualified facility such as an infusion clinic until blinded safety results are evaluated for the first 20 subjects (active or 
placebo) to receive escalated dose infusions.  After this evaluation, first doses of 800 mg and 1600 mg may be given by a 
home health nurse, if deemed appropriate. 
b Because subjects will begin dose escalation at different visits, timing indicates weeks relative to the first dose of 800 mg. 
c 
Safety magnetic resonance imaging (MRI) will be done at the DIAN-TU site or at a qualified imaging center in reasonable 
proximity to the subject’s home for those not close to their DIAN-TU site.  When possible, these will be done at an ADNI 
and/or ADCS site qualified imaging center.  Safety MRIs must be conducted at least 5 days before escalating dose to 
1600 mg so results of the central read can be reviewed by the site before the escalation. 
d Drug-specific tests include testing for plasma Aβ and other biomarkers, solanezumab levels and anti-solanezumab 
antibodies.  These labs may be drawn more frequently if treatment emergence of immunogenicity is detected.  Samples 
for plasma solanezumab levels should be collected before infusion and within 30 min after completion of infusion for 
post-dose levels. 
e Infusion occurs after all other procedures at each visit. 
f 
Dosing at 1600 mg every 4 weeks to continue through the duration of the study. 
 

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Table 6 
DIAN-TU-001 Solanezumab Schedule of Visits: Dose Escalation Period 
(Remaining Subjects for Each Dose Level After Safety Evaluation and Clearance) 
PROCEDURE: 
Dose (mg) 
800 
800 
sMRI 
1600 
1600 
1600 
1600 
VISIT SITEa 
H 
H 
MRI 
H 
H 
H 
H 
Dose Escalation Timing (weeks)b 
0 
4 
5 
8 
12 
16 
20 
Informed Consent 
X 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
X 
X 
X 
12-Lead ECG 
 
X 
 
 
X 
 
 
3T Safety MRIc 
 
 
X 
 
 
 
 
Drug-specific Testingd 
X 
X 
 
X 
X 
 
X 
Hematology, Chemistry, Urinalysis 
 
X 
 
 
X 
 
 
Study Drug Administration (800 mg)e 
X 
X 
 
 
 
 
 
Study Drug Administration (1600 mg)f 
 
 
 
X 
X 
X 
Xf 
1-Hour Post-Infusion Monitoring 
X 
 
 
X 
 
 
 
Footnotes: 
a Infusions and safety visits (designated as occurring at home [H]) may occur at the DIAN-TU site or, for subjects who live at 
a distance from the DIAN-TU site, these visits may be conducted by a trial-designated home health nurse at the subject’s 
home or other trial-identified location.  These visits may include phone calls from the host DIAN-TU site staff. 
b Because subjects will begin dose escalation at different visits, timing indicates weeks relative to the first dose of 800 mg. 
c 
Safety magnetic resonance imaging (MRI) will be done at the DIAN-TU site or at a qualified imaging center in reasonable 
proximity to the subject’s home for those not close to their DIAN-TU site.  When possible, these will be done at an ADNI 
and/or ADCS site qualified imaging center.  Safety MRIs must be conducted at least 5 days before escalating dose to 1600 
mg so results of the central read can be reviewed by the site before the escalation. 
d Drug-specific tests include testing for plasma Aβ and other biomarkers, solanezumab levels and anti-solanezumab 
antibodies.  These labs may be drawn more frequently if treatment emergence of immunogenicity is detected.  Samples 
for plasma solanezumab levels should be collected before infusion and within 30 min after completion of infusion for 
post-dose levels. 
e Infusion occurs after all other procedures at each visit. 
f 
Dosing at 1600 mg every 4 weeks to continue through the duration of the study. 
Study drug arms that demonstrate a potential clinical benefit may have an open-label extension 
period.  Eligible subjects may be offered the opportunity to receive active drug for up to 2 years 
in an open-label extension.  During OLE, subjects could receive an intravenous infusion of 
solanezumab 400 mg up to 1600 mg once every 4 weeks. 
All subjects enrolled in the open-label extension for solanezumab will start at the 400 mg dose 
level.  After receiving 400 mg every 4 weeks (± 4 days) for at least 2 infusions, subjects will be 
titrated to the 800 mg dose level.  After receiving 800 mg every 4 weeks (± 4 days) for at least 2 
infusions, subjects will be titrated to the 1600 mg dose level.  After 2 doses at the 1600 mg dose 
level, a safety MRI will be performed.  If MRI findings prior to dosing in the OLE warrant more 
frequent MRIs during the dose escalation period of the open-label extension, the PI may 
request for review and approval by the sponsor medical monitoring team.  Please refer to 
Table 7 for a detailed schedule of dose-titration in OLE. 

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Changes in dosage may be made in the event of ARIA as described in section 1.14 or for other 
safety reasons at the investigator’s discretion with notification of a Medical Director or 
designee. 
Table 7 
DIAN-TU-001 Solanezumab Schedule of Visits: Dose Escalation Period in the 
Open-label Extension Period 
PROCEDURE: 
Dose (mg) 
400 
400 
800 
800 
1600 
1600 
sMRI 
VISIT 
OLE V1 
OLE V2 
OLE V3 
OLE V4 
OLE V5 
OVE V6 
MRI 
Dose Escalation Timing 
(weeks) 
0 
4 
8 
12 
16 
20 
21 
Informed Consent 
X 
 
 
 
 
 
 
Verification of Eligibility for OLE 
X 
 
 
 
 
 
 
3T Safety MRIa 
X 
 
 
 
 
 
X 
Study Drug Administration (400 mg)  
X 
X 
 
 
 
 
 
Study Drug Administration (800 mg) 
 
 
X 
X 
 
 
 
Study Drug Administration (1600 mg)b  
 
 
 
 
X 
X 
 
Footnotes: 
a Safety MRI(s) will be done at the DIAN-TU site or at a qualified imaging center in reasonable proximity to the subject’s home 
(MRI) for those not close to their DIAN-TU site.  When possible, these will be done at an ADNI and/or ADCS site qualified 
imaging center. 
b Dosing at 1600 mg every 4 weeks to continue through the duration of the study. 
 Packaging, Preparation and Administration of Study Drug 
The investigator or designee is responsible for administering the investigational agent to the 
subject, verifying that instructions are followed properly, maintaining accurate records of study 
drug dispensing and collection, and returning all unused study drug to the sponsor’s designee at 
the end of the study. 
Materials and Supplies 
The site or trial-designated home health nurse will be provided vials containing 400 mg/20 mL 
of solanezumab or placebo.  The vials should be stored at 2°C to 8°C (36°F to 46°F).  Normal 
sterile saline solution (0.9% sodium chloride) will be used for dilution and as placebo in the 
control subjects. 
For each 400 mg dose, the content of 1 vial will be diluted with 50 mL sodium chloride 
intravenous infusion (0.9%) for a resulting infusate of 400 mg IP/70 mL. 
For each 800 mg dose, the contents of 2 vials will be diluted with 200 mL sodium chloride 
intravenous infusion (0.9%) for a resulting infusate of 800 mg IP/240 mL. 
For each 1600 mg dose, the contents of 4 vials will be diluted with 200 mL sodium chloride 
intravenous infusion (0.9%) for a resulting infusate of 1600 mg IP/280 mL. 

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Additional details are provided in the Pharmacy Manual. 
Before infusion, the diluted solution should be inspected visually for particulate matter or 
discoloration.  If particulate matter or discoloration are present, the solution should NOT be 
used and new product should be dispensed for use via IWRS.  A product complaint form should 
be completed and submitted to the sponsor and the concerning vial quarantined pending 
further instruction.  Refer to the Pharmacy Manual and Global Manual of Operations for 
procedures for reporting problems with drug preparation and for requesting a replacement 
dose.  After each intravenous bag is prepared, it will be identified as a dose of study drug 
without identification of the drug or dose.  Once prepared, the infusate solution should be 
stored at room temperature for a total of no more than 6 hours. 
Clinical study materials will be labeled according to the country’s regulatory requirements. 
All study staff will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study drug so that the situation can be assessed.  If particulate 
matter is seen in the vial or the prepared solution, a product complaint form needs to be 
completed and submitted to the sponsor or designee within 24 hours.  The investigator or 
his/her designee is responsible for handling the following aspects of the product complaint 
process in accordance with the instructions provided for this study (see the Pharmacy Manual 
or Global Manual of Operations for additional details): 
• Recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose 
• Faxing the completed product complaint form within 24 hours to the sponsor or its 
designee 
• If the investigator is asked to return the product for investigation, he/she will return a 
copy of the product complaint form with the product 
 Blinding of Study Drug 
Study drug will be supplied in numbered vials.  Subject, home health nurses, and DIAN-TU site 
staff will be blinded as to whether the subject has been assigned to active drug or placebo.   
For subjects that may enter the open-label extension (OLE), study drug will not be blinded. 
 Dispensing of Study Drug 
The dose will be dependent on where the subject is in the dose escalation schedule (Table 5 or 
Table 6).  Infusions of 400 mg of study drug should be given by IV over a period of 30 minutes.  
Infusions of 800 mg and 1600 mg of study drug should be given by IV over a period of 
approximately 1 hour which may be adjusted as needed.  Refer to the Pharmacy Manual for full 
dose preparation and administration instructions. 
If a subject demonstrates an infusion reaction to the study drug, the subject may be 
premedicated with antihistamines (such as diphenhydramine HCl, 50 mg orally or 

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intravenously), and the infusion time may be extended for the remaining infusions.  An attempt 
should be made to complete the infusion within 2 hours of when first started. 
For the double-blind period,  the subject should be observed for approximately 1 hour following 
the first infusion of study drug (V2) and after the first dose of each dose escalation step (i.e., 
after first 800 mg dose and after first 1600 mg dose).   
For the OLE period, no post-dose observation period is required.  The dose escalation schedule 
for OLE is outlined in Table 7 DIAN-TU-001 Solanezumab Schedule of Visits: Dose Escalation 
Period in the Open-label Extension Period. 
Note that all cognitive scales are to be administered before infusions. 
 Assessing Compliance with Study Drug 
DIAN-TU site staff or trial-designated home health nurse should document completion of 
infusion on study source documents.  Because dosing occurs at study visits, subjects who attend 
all visits and successfully receive infusions are automatically compliant with treatment.  Any 
infusion at which 75% (approximately 52.5 mL for 400 mg doses, 180 mL for 800 mg doses, and 
210 mL for 1600 mg doses) or more of the infusate is given will be considered a complete 
infusion. 
If a subject attends a visit but does not receive a complete infusion (for example, due to 
technical complications), every effort should be made to reschedule the infusion within 
24 hours if possible.  If less than 75% of the infusate is given, this must be recorded as an 
incomplete infusion in the study source documents. 
Missed infusions should be recorded on the study source documents.  Subjects who miss 
3 consecutive infusions or 7 overall may be discontinued from the study unless infusions are 
intentionally held due to ARIA or other AE. 
3 STUDY PROCEDURES 
 Enrollment 
See details in section 3.4 of the main protocol. 
 Randomization 
From the perspective of the subjects and site study staff, subjects were randomized to one of 
two treatment arms (gantenerumab or solanezumab).  Within each treatment arm, subjects 
were further divided into those who receive active drug or placebo (Figure 2). 
Subject randomization was performed separately for mutation positive and mutation negative 
subjects.  Mutation positive subjects were randomized using a minimization strategy.  Groups 
were balanced as to the predetermined number of asymptomatic (Clinical Dementia Rating 
[CDR] = 0) and symptomatic (CDR>0) subjects based on power calculations for the primary 
outcome of each individual study drug arm in the DIAN-TU platform.  Other factors such as 

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Clinical Dementia Rating Sum of Boxes (CDR-SB), years to estimated age at onset, and the 
presence or absence an apolipoprotein E (APOE) ε4 allele were included as minimization factors 
designed to ensure optimal balance between arms on potentially important characteristics.  
The minimization strategy did not differentiate between those who have one (heterozygous) or 
two (homozygous) APOE ε4 alleles.  APOE ε4 was included in the minimization strategy because 
preliminary data suggests the presence of an APOE ε4 allele increases the risk of amyloid-
related imaging abnormalities (ARIA) in sporadic DAT.  It is not known whether the presence of 
an APOE ε4 allele affects the risk of ARIA in the DIAD population. 
Mutation positive subjects (mc+) were randomized to active drug or placebo in a 3:1 ratio 
(Figure 3) while subjects who did not carry a mutation linked to DIAD (mc-) were assigned to 
placebo.  Subjects and site study staff continue to be blinded as to subject’s genetic status (mc+ 
or mc-, unless the subject is aware of their genetic status and chooses to disclose it) and 
whether they are on active drug or placebo. 
Mutation negative subjects participate in all study procedures and assessments to maintain 
blinding as to genetic status for those who do not wish to know their genetic status.  Mutation 
negative subjects will not be included in the primary efficacy or futility analyses, as they will not 
be exposed to study drug; safety data will be reported separately for mutation positive and 
negative subjects. 
Figure 2 
Randomization Scheme:  All Subjects in Gantenerumab and Solanezumab Arms 
 

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Figure 3 
Randomization Scheme: Gantenerumab and Solanezumab (Mutation Positive 
Subjects Only) 
 
 Specific Study Visits – Double-blind Treatment Period 
The procedures to take place at each study visit during the double-blind treatment period are 
listed below.  All information on timing of visits refers to calendar days.  The specific date 
during the baseline visit (V2) when the first dose of study drug is administered should be used 
to determine timing of subsequent visits and for determining time between the screening and 
baseline visits. 
The schedule of visits, including drug-specific tests and frequency of safety MRIs, is provided in 
the schedule of visit tables at the end of this appendix: 
• Solanezumab Schedule of Visits: 4 Year Double-blind Treatment Period 
• Solanezumab Schedule of visits: Double-blind Treatment Beyond Year 4 
Following the approval of Amendment 7, the dose-escalation process will begin.  During the 
dose escalation period, procedures outlined in section 2.2 should be completed in addition to 
the procedures for the scheduled visit.  These additional safety assessments include vital signs, 
safety laboratory testing (hematology, chemistry, urinalysis), drug-specific monitoring, and 
ECGs (Table 5 and Table 6).  When the additional assessment is part of the regularly scheduled 
visit, it does not need to be repeated. 
Upon completion of the double‐blind treatment period for each study drug arm (i.e., last 
enrolled subject has completed 4 years [208 weeks] of treatment), subjects may be eligible to 
receive active study drug in an open‐label extension period for up to an additional 2 years 
(24 months).  Eligible subjects may start treatment in the open‐label extension period only after 
the final analysis of the double‐blind treatment period has been completed and the study drug 
arm has demonstrated a potential clinical benefit.  See section 3.4 for more details. 
A study drug arm may be stopped early or revised (e.g. dose adjustment or treatment 
duration), based upon the results of the interim analyses or information from other clinical 

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trials for the same drug.  The sponsor may choose at any time to limit treatment duration to 4 
years (208 weeks) for a study drug arm even if some subjects have exceeded this limit at the 
time of the decision. 
3.3.1 Visit 1 (screening visit) 
Location: Visit 1 procedures may be accomplished at the DIAN-TU site or at the subject’s home 
or other trial-identified location with the trial-designated home health nurse.  This visit also 
includes telephone calls with the DIAN-TU site staff.  The subject is contacted by their host 
DIAN-TU site by telephone or during a regular DIAN Observational (DIAN-OBS) study visit.  The 
subject is given the opportunity to review the main and drug-specific supplemental ICFs, ask 
questions and obtain answers, and sign the main ICF. 
Time:  Informed consent must be obtained before any other study procedures.  Informed 
consent, family history, demographic information and medical and treatment history may be 
obtained before the 8-week screening period begins.  Informed consent should be obtained 
from both subject and study partner.  Unless otherwise specified, all other Visit 1 procedures 
may occur throughout the screening period (2-8 weeks before V2).  IMPORTANT: Results from 
screening clinical laboratory tests and genetic testing must be available before V2; blood draw 
for genetic testing must be completed at least 6 weeks before V2 to ensure genetic results are 
available for baseline randomization.  The screening visit in the home ensures subject eligibility 
before travel (if applicable) to the DIAN-TU site for baseline testing and randomization. 
Procedures (all can be performed by DIAN-TU site staff or trial-designated and trained home 
health nurse or other staff except as noted—see Global Manual of Operations and DIAN Trials 
Unit Cognition Core Procedures Manual for additional details on order and timing of 
procedures): 
• Obtain informed consent (DIAN-TU site staff should be available to answer questions) 
• Obtain or confirm family history and determine parental estimated age at onset or 
subject’s actual age at onset (DIAN-TU site staff).  Estimated age at onset should be 
determined as outlined in the Global Manual of Operations   
• Verify documentation of subject’s trial eligible mutation status OR confirm via family 
pedigree and mutation documentation (proband) that the subject is at 50% risk for a 
trial-eligible mutation 
• Collect demographic information and study partner information 
• Obtain medical and treatment history 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature).  Weight is 
not required at this visit but subject’s self-reported weight may be noted if required for 
laboratory tests 
• Screening cognitive battery (subset of testing serves as practice test; takes about 
30 minutes).  See section 6.1.14 of main protocol 

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• Blood draw for:  
o Genetic testing (NOTE: genetic testing blood sample must be obtained at least 
6 weeks prior to Visit 2) 
o Clinical laboratory tests, including TSH, B12, hemoglobin A1c, PT, PTT, and INR 
o Serum pregnancy test for women of childbearing potential 
• Urine collection for urinalysis 
• Administration of Columbia Suicide Severity Rating Scale (C-SSRS) 
A study-specific subject identification number is assigned to the subject by the interactive web 
response system (IWRS).  Visit 2 is not scheduled to occur until the results of clinical laboratory 
tests are available and results of genetic testing are entered in IWRS.  Results of genotyping of 
APOE and DIAD-associated genes (APP, PSEN1, and PSEN2) are not sent to the site to ensure 
genetic blinding is maintained. 
3.3.2 Visit 2 (baseline/first dose) 
Location: Host DIAN-TU site. 
Time/Timing:  Approximately a 3-4 day visit that is scheduled 2-8 weeks after the screening visit 
and at least 6 weeks after the genetic sample draw.  This visit can only take place after results 
from screening clinical laboratory tests are documented as consistent with inclusion/exclusion 
criteria before Visit 2 occurs.  Genotyping results will need to be confirmed as received and 
having completed analysis but no results will be provided or reviewed by site staff.  The study 
partner participates in some of the procedures at Visit 2 and other annual visits at the DIAN-TU 
site.  If possible, the study partner should accompany the subject to the DIAN-TU site for these 
visits.  If this is not possible, the study partner procedures can be completed via telephone.  The 
sequence and timing of visit procedures is very important.  Requirements and suggested timing 
of visit procedures are detailed in the Global Manual of Operations.  Baseline visit procedures 
may be scheduled over a longer time period of up to 2 weeks for subjects who live near the 
study site or in the event that some study procedures (e.g., PET imaging) are done at a different 
DIAN-TU site. 
Note: The date during Visit 2 when the first dose of study drug is administered should be used 
for determining the timing of all subsequent visits. 
Procedures: 
• In-person review of informed consent for subjects who provided consent over the 
telephone 
• Medical/treatment history, including: 
o Concomitant medications 
o Assessment /recording of pre-existing conditions or adverse events 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 

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• Blood draw for: 
o Drug-specific testing (section 1.12): 
- pre-dose serum for anti-solanezumab antibodies; plasma for amyloid beta 
peptide and solanezumab levels; stored plasma and serum, and  
- post-dose plasma for solanezumab level 30 minutes or less after completion 
of infusion  
o Provenance4F10 testing (to confirm specimen identity)  
• Urine pregnancy testing for women of childbearing potential  
• Administration of C-SSRS 
• Physical and neurological examination 
• Clinical assessment: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• MRI to be performed on 1st day and uploaded immediately to ensure reading obtained 
prior to randomization and dosing.  This MRI includes safety MRI sequences.  ARIA 
findings on this MRI may affect eligibility for the trial.  MRI should be performed before 
lumbar puncture, if on the same date 
• Lumbar Puncture (LP) for CSF collection should be performed at approximately 8 am 
local time under fasting conditions (water is allowed and encouraged)   
• Positron emission tomography (PET) imaging: 
o [11C]PiB-PET 
o FDG-PET [subject should be fasting 4 hours prior to FDG-PET] 
o Florbetapir 18F PET amyloid imaging 
o For sites approved for participation in the Tau Addendum: [18F]AV-1451 tau imaging, 
if applicable 
• Final verification that all inclusion and no exclusion are met (including receipt of MRI 
read). 
• Randomization in IWRS system 
                                                     
10 Provenance testing is performed for quality assurance purposes to ensure that blood sample obtained at 
baseline visit is from same individual as sample obtained at screening visit. 

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• Supplemental drug-specific informed consent reviewed and signed 
• Study drug dosing and post-dose monitoring/evaluation as specified in section 2.5 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events. 
Randomization and assignment to study drug arm is completed using the IWRS during this visit.  
Randomization cannot occur until results of CDR are entered into the IWRS system.  After 
randomization, the subject and legally acceptable representative (if the subject is cognitively 
impaired) should review and sign the supplemental drug-specific consent form, if applicable; 
study staff should be available to answer all questions regarding the study.  Study drug should 
not be administered until MRI is read to confirm eligibility, pregnancy test is confirmed 
negative, and any other drug-specific inclusion/exclusion criteria are met.  All study procedures 
must be completed prior to administration of the first dose of study drug. 
3.3.3 Visit 3 
Location: DIAN-TU site, subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing: 4 weeks +/- 4 days from Visit 2 (calculated from day of first dose).   
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) 
• Clinical laboratory tests 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5. 
• Phone Call:  Either during the visit or within the next two weeks, the DIAN-TU site 
coordinator calls subject and addresses any concerns, discusses scheduling of safety MRI 
and/or next visits, and encourages compliance. 
3.3.4 Visits 4, 6, 7, 10, 12-14, 16, 17, 19, 20, 23, 25-27, 29-33, 35-40, 42-46, 48-53, 55-59, 61-
66, 68-72, 74-79, 81-85, and 87-92 
Location: DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 

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Timing:  Visits as listed below (calculated from day of first dose), with a visit window of 
+/- 4 days. 
Visit No. 
4 
6 
7 
10 
12 
13 
14 
16 
17 
19 
20 
23 
Week 
8 
16 
20 
32 
40 
44 
48 
56 
60 
68 
72 
84 
 
Visit No. 
25 
26 
27 
29 
30 
31 
32 
33 
35 
36 
37 
38 
Week 
92 
96 
100 
108 
112 
116 
120 
124 
132 
136 
140 
144 
 
Visit No. 
39 
40 
42 
43 
44 
45 
46 
48 
49 
50 
51 
52 
Week 
148 
152 
160 
164 
168 
172 
176 
184 
188 
192 
196 
200 
 
Visit No. 
53 
55 
56 
57 
58 
59 
61 
62 
63 
64 
65 
66 
Week 
204 
212 
216 
220 
224 
228 
236 
240 
244 
248 
252 
256 
 
Visit No. 
68 
69 
70 
71 
72 
74 
75 
76 
77 
78 
79 
81 
Week 
264 
268 
272 
276 
280 
288 
292 
296 
300 
304 
308 
316 
 
Visit No. 
82 
83 
84 
85 
87 
88 
89 
90 
91 
92 
 
 
Week 
320 
324 
328 
332 
340 
344 
348 
352 
356 
360 
 
 
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of the main protocol) 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5 
• Phone call (required at Visit 4; not required at all other home/off-site visits but direct 
site-subject contact should occur at least once every 3 months throughout the study): 
the DIAN-TU site coordinator calls subject and addresses any concerns, discusses 
scheduling of safety MRI and/or next visits, and encourages compliance   
3.3.5 Visit 5 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  12 weeks +/-4 days from Visit 2 (calculated from day of first dose) 
 

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Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• 12-lead ECG 
• C-SSRS administration 
• Blood draw for drug-specific testing (section 1.12): 
o pre-dose serum for anti-solanezumab antibodies; plasma for amyloid beta peptide 
and solanezumab levels; stored plasma and serum collection, and  
o post-dose plasma for solanezumab level 30 minutes or less after completion of 
infusion 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5 
• Phone Call: Either during the visit or within the next two weeks, the DIAN-TU site 
coordinator calls subject and addresses any concerns, discusses scheduling of safety MRI 
and next visits and encourages compliance 
3.3.6 Visits 8 and 21 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  24 and 76 weeks +/- 4 days from Visit 2 (calculated from day of first dose)  
Procedures: 
• Cognitive battery subset (per section 6.1.14 of main protocol) 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• 12-lead ECG 
• C-SSRS administration 
• Clinical laboratory tests 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5 
• Phone Call (not required at every home/off-site visit but direct site-subject contact 
should occur at least once every 3 months throughout the study): the DIAN-TU site 
coordinator calls subject and addresses any concerns, discusses scheduling of safety MRI 
and/or next visits, and encourages compliance 

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3.3.7 Visits 9 and 22 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  28 and 80 weeks +/- 4 days from Visit 2 (calculated from day of first dose)  
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature) 
• Blood draw for drug-specific testing (section 1.12):  
o pre-dose serum for anti-solanezumab antibodies; plasma for amyloid beta peptide 
and solanezumab levels; stored plasma and serum, and  
o post-dose plasma for solanezumab level 30 minutes or less after completion of 
infusion 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing as specified in section 2.5 
• Phone call (not required at every home/off-site visit, but should be performed at least 
once for every 3 home visits for the remainder of the study):  the DIAN-TU site 
coordinator calls subject and addresses any concerns, discusses scheduling of safety MRI 
and/or next visits, and encourages compliance 
3.3.8 Visits 11, 18, and 24  
Location: DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  36, 64, and 88 weeks +/- 4 days from Visit 2 (calculated from day of first dose)   
Visit No. 
11 
18 
24 
Week 
36 
64 
88 
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight is 
measured approximately every 3 months beginning at V2) 
• C-SSRS administration 
• Urine pregnancy testing for women of childbearing potential 
• Study drug dosing as specified in section 2.5 
• Phone call (not required at every home/off-site visit, but should be performed at least 
once for every 3 home visits for the remainder of the study):  the DIAN-TU site 

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coordinator calls subject and addresses any concerns, discusses scheduling of safety MRI 
and next visits and encourages compliance 
3.3.9 VISIT 15: ANNUAL VISIT AT HOST DIAN-TU SITE   
Location: Host DIAN-TU site 
Timing:  52 weeks +/- 7 days from Visit 2 (calculated from day of first dose).  Approximately a 
3-4 day visit.  The sequence and timing of visit procedures is very important; requirements and 
suggested timing of study procedures are detailed in the Global Manual of Operations.  For 
subjects who live near the study site, these visit procedures may be scheduled over a longer 
time period of up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Blood draw for: 
o Clinical laboratory tests (hematology, chemistry, urinalysis)  
o Drug-specific testing (section 1.12):  
- pre-dose serum for anti-solanezumab antibodies; plasma for amyloid beta 
peptide and solanezumab levels; stored plasma and serum, and  
- post-dose plasma for solanezumab level 30 minutes or less after completion of 
infusion 
• Urine pregnancy testing for women of childbearing potential  
• Physical and neurological examination 
• Clinical assessment: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE)  
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing.   
• Complete cognitive battery (per section 6.1.14 of the main protocol) 

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• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences.  MRI should 
be performed before lumbar puncture, if on the same date 
• Lumbar Puncture (LP) should be conducted as close to the baseline collection time as 
possible under fasting conditions (water is allowed and encouraged).      
• Positron emission tomography (PET) imaging: 
o [11C]PiB-PET 
o FDG-PET [subject should be fasting 4 hours prior to FDG-PET]  
o For sites approved for participation in the Tau Addendum: [18F]AV-1451 tau imaging, 
if applicable  
• Study drug dosing as specified in section 2.5 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 
3.3.10 VISIT 28: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing: 104 weeks +/- 7 days from Visit 2 (calculated from day of first dose).  Approximately a 
3-4 day visit.  The sequence and timing of visit procedures is very important; requirements and 
suggested timing of study procedures are detailed in the Global Manual of Operations.  For 
subjects who live near the study site, these visit procedures may be scheduled over a longer 
time period of up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Blood draw for: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
o Drug-specific testing (section 1.12):  
– pre-dose serum for anti-solanezumab antibodies; plasma for amyloid beta 
peptide and solanezumab levels; stored plasma and serum  
– post-dose plasma for solanezumab level 30 minutes or less after completion of 
infusion 
• Urine pregnancy testing for women of childbearing potential 
• Physical and neurological examination 
• Clinical assessment: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 

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o Assessment of clinical diagnosis and clinician judgment of symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE)  
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences.  MRI should 
be performed before lumbar puncture, if on the same date 
• Lumbar Puncture (LP) should be conducted as close to the baseline collection time as 
possible and under fasting conditions (water is allowed and encouraged).   
• Positron emission tomography (PET) imaging: 
o [11C]PiB-PET 
o FDG-PET (subject should be fasting 4 hours prior to FDG-PET) 
o Florbetapir [18F]PET amyloid imaging 
o For sites approved for participation in the Tau Addendum: [18F]AV-1451 tau imaging, 
if applicable 
• Study drug dosing as specified in section 2.5  
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 
3.3.11 Visits 34 and 47 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse.   
Timing: 128 and 180 weeks +/- 4 days from Visit 2 (calculated from day of first dose).   
Procedures: 
• Cognitive battery subset – Subset (per section 6.1.14 of main protocol) 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• C-SSRS administration 
• Clinical laboratory tests (hematology, chemistry, urinalysis) 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5 

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• Phone Call (not required at every home/off-site visit, but should be performed at least 
once for every 3 home visits for the remainder of the study):  the DIAN-TU site 
coordinator calls subject and addresses any concerns, discusses scheduling of safety MRI 
and/or next visits, and encourages compliance 
3.3.12 VISIT 41: ANNUAL VISIT AT HOST DIAN-TU SITE   
Location: Host DIAN-TU site 
Timing:  156 weeks +/- 7 days from Visit 2 (calculated from day of first dose).  Approximately a 
2-3 day visit.  The sequence and timing of visit procedures is very important.  Requirements and 
suggested timing of events are detailed in the Global Manual of Operations.  For subjects who 
live near the study site, these visit procedures may be scheduled over a longer time period of 
up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG  
• Administration of C-SSRS 
• Clinical laboratory tests (hematology, chemistry, urinalysis) 
• Urine pregnancy testing for women of childbearing potential  
• Physical and neurological examination 
• Clinical assessments: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences 
• Study drug dosing as specified in section 2.5 

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3.3.13 VISIT 54: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing:  208 weeks +/- 7 days from Visit 2(calculated from day of first dose).  Approximately a 
3-4 day visit.  The sequence and timing of visit procedures is very important; requirements and 
suggested timing of events are detailed in the Global Manual of Operations.  For subjects who 
live near the study site, these visit procedures may be scheduled over a longer time period of 
up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Blood draw for: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
o Serum pregnancy testing for women of childbearing potential 
o Drug-specific testing (section 1.12):  
- pre-dose serum for anti-solanezumab antibodies; plasma for amyloid beta 
peptide and solanezumab levels; stored plasma and serum, and  
- post-dose plasma for solanezumab level 30 minutes or less after completion of 
infusion 
• Physical and neurological examination 
• Clinical assessments:   
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences 
• Lumbar Puncture (LP) should be conducted as close to the baseline collection time as 
possible and under fasting conditions (water is allowed and encouraged). 

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• Positron emission tomography (PET) imaging: 
o [11C]PiB-PET 
o FDG-PET (subject should be fasting 4 hours prior to FDG-PET) 
o Florbetapir [18F]PET amyloid imaging 
o For sites approved for participation in the Tau Addendum: [18F]AV-1451 tau imaging, 
if applicable  
• Study drug dosing as specified in section 2.5 (subjects continuing treatment beyond 
year 4) 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 
3.3.14 Visits 60, 73, and 86 
Location: DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  232, 284, and 336 weeks +/- 4 days from Visit 2 (calculated from day of first dose).   
Visit No. 
60 
73 
86 
Week 
232 
284 
336 
Procedures: 
• Cognitive battery subset (per section 6.1.14 of main protocol) 
• Concomitant medication review 
• Adverse event assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, and body temperature; weight 
may be obtained approximately every 3 months per section 6.1.6 of main protocol) 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5 
• Phone call (not required at every home/off-site visit, but should be performed at least 
once for every 3 home visits for the remainder of the study):  the DIAN-TU site 
coordinator calls subject and addresses any concerns, discusses scheduling of next visits, 
and encourages compliance 
3.3.15 Visits 67, 80, and 93: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing:  260, 312, and 364 weeks +/- 7 days from Visit 2 (calculated from day of first dose).  
Approximately a 3-4 day visit.  The sequence and timing of visit procedures is very important; 
requirements and suggested timing of events are detailed in the Global Manual of Operations.  

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For subjects who live near the study site, these visit procedures may be scheduled over a longer 
time period of up to 2 weeks. 
Visit No. 
67 
80 
93 
Week 
260 
312 
364 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight and 
height) 
• 12-lead ECG 
• Administration of C-SSRS 
• Clinical laboratory tests (hematology, chemistry, urinalysis) 
• Urine pregnancy testing for women of childbearing potential at V67 and V80; Serum 
pregnancy testing at V93 
• Clinical assessments:   
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing 
• Physical and neurological examination 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) uploaded immediately to ensure 
reading obtained prior to dosing.  This MRI includes safety MRI sequences. 
• V67 and V80:  Study drug dosing as specified in section 2.5.  Note: dose will not be 
administered at Visit 93 
3.3.16 End-of-Treatment Safety Follow-up Visit  
The double-blind treatment period for each subject may vary based on when the subject was 
enrolled and may last from 4 up to 7 years (364 weeks [V93]) or until early termination, 
whichever is sooner.  Subjects will continue treatment with the assigned study drug until every 
subject randomized to this study drug arm has received a minimum of 4 years (208 weeks) of 
treatment or is withdrawn, at which time study treatment will be discontinued for all subjects 

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in the solanezumab study arm and all subjects should be scheduled for an end-of-treatment 
safety follow-up visit. 
Location: Procedures/contacts may be accomplished at the DIAN-TU site or subject’s home or 
other trial-identified location with the trial-designated home health nurse. 
Timing:  The end-of-treatment safety follow-up visit should be performed 4 to 8 weeks (+/- 7 
days) after the subject’s last dose of double-blind treatment.   
Procedures*: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight)  
• 12-lead ECG 
• Blood draw for: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
o Serum pregnancy testing for women of childbearing potential 
o Drug-specific testing (section 1.12) serum for anti-solanezumab antibodies; plasma 
for amyloid beta peptide and solanezumab levels    
• Urine collection for urinalysis  
*Any procedures done after the last dose, but before the safety follow-up visit, do not need to 
be repeated. 
3.3.17 Early Termination Visit/Post-treatment Follow-up 
If a subject withdraws, is terminated from the study prior to completion, or is in a study drug 
arm that is stopped prior to the end of the double-blind treatment period, every effort should 
be made to schedule an early termination visit that will include all procedures done at Visit 54 
for those not yet having completed that visit, or Visit 93 for those beyond V54.  End of study 
drug-specific tests should also be obtained (see section 1.12).  PET imaging studies may be 
omitted if early termination occurs less than 6 months after the previous PET imaging or if 
precluded by local regulations/dosimetry limits.  Other procedures may also be eliminated on a 
case-by-case basis, as determined by the sponsor. 
Per the main protocol section 6.3.7, any subject meeting study drug discontinuation criteria per 
main protocol section 4.4.1 due to safety reasons, inability to continue treatment 
administration/dosing, or perform study procedures, will be encouraged to continue 
participation in any of the scheduled clinical, cognitive, and/or biomarker assessments that they 
are able to perform, even though dosing has concluded.  The determination of which 
assessments are to be attempted/completed will be decided by the site principal investigator 
and sponsor and will be based on the subject’s capabilities, the benefit to the study, and the 
risk associated with continued participation at the time of study drug discontinuation.  The level 
of continued participation may change if/as the subject’s status changes. 

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3.3.18 Safety Magnetic Resonance Imaging (MRI) 
A series of 6 safety MRI visits will be scheduled over the first 2 years of the double-blind 
treatment period.  Safety MRIs on 3T scanners will be done primarily to monitor for ARIA. 
Location: Safety MRIs may be done at the host DIAN-TU site or, for subjects who live at a 
distance from the host DIAN-TU site, safety MRIs may be performed at an ADNI/ADCS site if 
possible or at a 3T scanner near the subject’s home. 
Timing:  13, 25, 37, 65, 77, and 89 weeks +/- 7 days from Visit 2 (calculated from day of first 
dose).  Sites must ensure that study visits are scheduled so that MRI images are uploaded and 
available for central read at least 10 working days before next administration of study drug for 
parenterally administered drugs. 
Procedures:  Safety MRIs on 3T scanners will be done primarily to monitor for ARIA.  See 
section 6.1.16 of the main protocol for more information.  Detailed requirements are provided 
in the MRI Technical Manual. 
 Specific Study Visits – Open-label Extension Period 
Upon completion of the double‐blind treatment period (i.e., last enrolled subject has 
completed 4 years [208 weeks] of treatment), subjects may be eligible to receive active study 
drug in an open‐label extension period for up to an additional 2 years (24 months).  Eligible 
subjects may start treatment in the open‐label extension (OLE) period only after the final 
analysis of the double‐blind treatment period has been completed and the study drug arm has 
demonstrated potential clinical benefit. 
If/when the OLE period is offered/opened, the procedures to take place at each study visit are 
listed below. All OLE subjects and study sites will be kept blinded to prior drug assignment until 
the end of OLE to protect study integrity. 
Biomarker testing (PET imaging, CSF biomarkers, etc.) and cognitive batteries will be performed 
at the discretion of the sponsor and pharma partner contingent upon the individual biomarker 
or outcome measure demonstrating continued utility in OLE based on the results of the double-
blind period of the study. 
For the OLE period, the specific date during the first visit (OLE V1) when the first dose of open-
label study drug is administered should be used to determine the timing of all subsequent visits.  
The dose and treatment regimen are detailed in section 2.2. 
The schedule of visits for the OLE period is provided in the series of tables “Solanezumab 
Schedule of Visits: Open-label Extension” at the end of this appendix. 
Subjects interested in joining the OLE period may sign consent once a decision regarding OLE 
has been communicated by the sponsor, and an approved OLE ICF is available at the site.  
Subjects are encouraged to proceed with genetic counseling, at a minimum, in preparation for 
genetic testing and disclosure for DIAD mutations, before the end of the double-blind 
treatment period to enable more rapid entry into the OLE. 

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All subjects enrolled in the solanezumab OLE will start at the 400 mg dose level and titrate 
based on safety evaluations to a target dose of 1600 mg as specified in section 2.2 for the OLE 
period. 
3.4.1 OLE Visit 1 (baseline/first dose) 
Location: Host DIAN-TU site. 
Time/Timing:  Approximately a 2-3 day visit that is scheduled after the decision is made to 
continue the drug arm in an open-label extension.  If possible, the study partner should 
accompany the subject to the DIAN-TU site for this visit.  If this is not possible, the study 
partner procedures can be completed via telephone.  The sequence and timing of visit 
procedures is very important.  Detailed requirements and suggested timing of events at 
OLE Visit 1 and at subsequent annual visits (OLE V14, and OLE V27) are detailed in the Global 
Manual of Operations. 
Note: The date during OLE Visit 1 when the first dose of study drug is administered should be 
used for determining timing of all subsequent visits.  If the OLE V1 is scheduled to occur after a 
prior annual visit, the Medical Director or designee may review the timing and waive the 
requirement to complete assessments; results from annual visit may be used. 
Biomarker collection and cognitive batteries will be performed at the discretion of the 
sponsor and pharma partner contingent upon the results of the double-blind period of the 
study. 
 
Procedures: 
• Obtain informed consent.  Subjects who wish to join the OLE may sign informed consent 
once a decision regarding OLE has been communicated by the sponsor and an approved 
OLE ICF is available at the site.  This will enable ample time for review and consideration 
of the consent, and genetic counseling prior to dosing in the OLE period 
• The following must be confirmed for the subject to be eligible for the OLE period:  
(i) participated in the double-blind period,  
(ii) has a confirmed trial-eligible pathogenic DIAD variant,  
(iii) in the opinion of the investigator and sponsor, treatment is not contraindicated for 
safety,  
(iv) is capable of receiving drug and appropriate clinical safety assessments, and 
(v) if the sponsor indicates that [18F]AV-1451 tau PET is to be performed, confirm the 
subject is not taking any medications on the [18F]AV-1451 DIAN-TU Restricted 
Medications List, and does not have a history of hypersensitivity to [18F]AV-1451 or 
any of its excipients 
• Administration of C-SSRS 
• Concomitant medication review 
• Adverse event assessment 
• Serum pregnancy test for women of childbearing potential.  

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• Neurological examination 
• Clinical assessments: 
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms 
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE)  
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI) to be performed on 1st day and 
uploaded immediately to ensure reading obtained prior to dosing.  This MRI includes 
safety MRI sequences.  ARIA findings on this MRI may affect eligibility for the OLE. MRI 
should be performed before LP, if on the same date 
• Blood draw for stored serum and plasma unless the subject had an LP in the prior 6 
months where blood collection was completed 
• PET imaging, unless completed in the preceding 6 months:  
o [11C]PiB-PET   
o FDG-PET (subject should be fasting 4 hours prior to FDG-PET) 
o [18F]AV-1451 tau PET   
• Lumbar puncture (LP) should be conducted as close to the subject’s double-blind Visit 2 
(Baseline) collection time as possible and under fasting conditions (water is allowed and 
encouraged), unless the subject had this procedure done in the preceding 6 months.  LP 
should be performed as specified in the main protocol, section 6.1.17. 
• Study drug dosing as specified in section 2.5.  Vital signs will be assessed per standard of 
care when administering IV product, however the data will not be collected 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 
3.4.2 OLE Visits 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, and 26 
Location: DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  Visits as listed below (calculated from day of first dose at OLE Visit 1), with a visit 
window of +/- 4 days.   

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Visit No. 
2 
3 
4 
5 
6 
8 
9 
10 
11 
12 
13 
Week 
4 
8 
12 
16 
20 
28 
32 
36 
40 
44 
48 
 
 
 
 
Visit No. 
15 
16 
17 
18 
19 
21 
22 
23 
24 
25 
26 
Week 
56 
60 
64 
68 
72 
80 
84 
88 
92 
96 
100 
Procedures: 
• Concomitant medication review 
• Adverse event assessment 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5.  Vital signs will be assessed per standard of 
care when administering IV product, however the data will not be collected 
• Phone call required for OLE visit 2, 3, 4, and 5; For OLE 6 and subsequent home visits 
coordinator calls can be made with less frequency at the discretion of the PI or 
designee, and/or coordinator, and subject, but should occur at least every 3 months 
3.4.3 OLE Visits 7 and 20 
Location:  DIAN-TU site or subject’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  24 weeks and 76 weeks +/- 4 days from day of first dose at OLE Visit 1.   
Procedures: 
• Cognitive battery subset (per section 6.1.14 of main protocol) 
• Mini-Mental State Examination (MMSE) 
• Concomitant medication review 
• Adverse event assessment 
• C-SSRS administration 
• Urine pregnancy testing for women of childbearing potential  
• Study drug dosing as specified in section 2.5.  Vital signs will be assessed per standard of 
care when administering IV product, however the data will not be collected 
• Phone call (coordinator calls) can be made with less frequency at the discretion of the PI 
or designee, and/or coordinator, and subject, but should occur at least every 3 months 
3.4.4 OLE VISIT 14: ANNUAL VISIT AT HOST DIAN-TU SITE   
Location: Host DIAN-TU site 
Timing:  52 weeks +/- 7 days from day of first dose at OLE Visit 1.  Approximately a 2-3 day visit.  
The sequence and timing of visit procedures is very important; requirements and suggested 
timing of study procedures are detailed in the Global Manual of Operations.  For subjects who 

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live near the study site, these visit procedures may be scheduled over a longer time period of 
up to 2 weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Administration of C-SSRS 
• Urine pregnancy testing for women of childbearing potential  
• Neurological examination 
• Clinical assessments:   
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) 
o Assessment of clinical diagnosis and clinician judgment of symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI), to be performed on the 1st day 
and uploaded immediately to ensure reading obtained prior to dosing.  This MRI 
includes safety MRI sequences.  MRI should be performed before LP, if on the same date 
• PET imaging:  
o [11C]PiB-PET scan 
o FDG-PET (subject should be fasting 4 hours prior to FDG-PET) 
o [18F]AV-1451 tau PET scan  
• Blood draw for stored serum and plasma 
• Lumbar Puncture (LP) should be conducted as close to the subject’s double-blind Visit 2 
(Baseline) collection time as possible and under fasting conditions (water is allowed and 
encouraged). LP should be performed as specified in the main protocol, section 6.1.17. 
• Study drug dosing as specified in section 2.5.  Vital signs will be assessed per standard of 
care when administering IV product, however the data will not be collected 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 

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3.4.5 OLE VISIT 27: ANNUAL VISIT AT HOST DIAN-TU SITE 
Location: Host DIAN-TU site 
Timing: 104 weeks +/- 7 days from day of first dose at OLE Visit 1.  Approximately a 2-3 day visit.  
The sequence and timing of visit procedures is very important.  Requirements and suggested 
timing of events are detailed in the Global Manual of Operations.  For subjects who live near 
the study site, these visit procedures may be scheduled over a longer time period of up to 2 
weeks. 
Procedures: 
• Concomitant Medications 
• Adverse Event Assessment 
• Administration of C-SSRS 
• Serum pregnancy test for women of childbearing potential 
• Neurological examination 
• Clinical assessments:   
o Clinical Dementia Rating (CDR) including calculation of Clinical Dementia Rating Sum 
of Boxes (CDR-SB) Assessment of clinical diagnosis and clinician judgment of 
symptoms  
o Neuropsychiatric Inventory Questionnaire (NPI-Q) 
o Geriatric Depression Scale (GDS) 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Exam (MMSE) 
NOTE: For each subject, the CDR and assessment of clinical diagnosis should be 
administered by the same experienced clinician at all visits.  Whenever possible, the CDR 
rater should not be involved in other clinical assessments (e.g., MMSE, FAS, GDS, NPI-Q) 
or in cognitive testing. 
• Complete cognitive battery (per section 6.1.14 of main protocol) 
• Annual MRI (including structural and functional MRI), which should be uploaded 
immediately to ensure reading obtained prior to dosing.  This MRI includes safety MRI 
sequences.  MRI should be performed before LP, if on the same date 
• PET imaging:  
o [11C]PiB-PET scan 
o FDG-PET (subject should be fasting 4 hours prior to FDG-PET) 
o [18F]AV-1451 tau PET scan  
• Blood draw (serum and plasma) for biomarker analyses 
• Lumbar Puncture (LP) should be conducted as close to the subject’s double-blind Visit 2 
(Baseline) collection time as possible and under fasting conditions (water is allowed and 
encouraged). LP should be performed as specified in the main protocol, section 6.1.17. 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events 

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3.4.6 Early Termination Visit 
If a subject withdraws or is terminated from the OLE period prior to completion every effort 
should be made to schedule an early termination visit that will include all procedures done at 
OLE visit 27.  Procedures may also be eliminated on a case-by-case basis, as determined by the 
sponsor. 
3.4.7 Safety Magnetic Resonance Imaging MRI 
A safety MRI (SM) visit will be scheduled approximately 1 week after 2 doses of 1600 mg have 
been administered.  Safety MRIs on 3T scanners will be done primarily to monitor for ARIA. 
Location: Safety MRIs may be done at the host DIAN-TU site or, for subjects who live at a 
distance from the host DIAN-TU site, safety MRIs may be performed at an ADNI/ADCS site if 
possible or at a 3T scanner near the subject’s home. 
Timing:  OLE V1 (baseline) and 21 weeks +/- 4 days from OLE V1 (calculated from day of first 
dose).  Sites must ensure that study visits are scheduled so that MRI images are uploaded and 
available for central read at least 10 working days before next administration of study drug for 
parenterally administered drugs.  If MRI findings prior to dosing warrant more frequent MRIs 
during the dose escalation period of the open-label extension, the PI may request for review 
and approval by the sponsor medical monitoring team. 
Procedures:  Safety MRIs on 3T scanners will be done primarily to monitor for ARIA.  See 
section 6.1.16 of the main protocol for more information.  Detailed requirements are provided 
in the MRI Technical Manual. 
4 DRUG-SPECIFIC ANALYSIS PLAN 
 Cognitive Endpoint (DIAN-MCE) Power Analysis and Sample Size Determination 
The power was estimated based on the multivariate disease progression model (MDPM) and 
the DIAN-MCE primary endpoint with four arms: the gantenerumab active drug arm, the 
solanezumab active drug arm, the mutation positive placebos and the eligible DIAN-OBS 
subjects.  For details, refer to the SAP and solanezumab-specific SAP appendix. 
 Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification 
4.2.1 Biomarker Endpoint Power Analysis 
Power analysis for the biomarker endpoints suggests 42 mutation positive subjects in the 
solanezumab group along with 27 mutation carriers in the pooled placebo group will provide 
over 99% power to detect the projected effect size for changes in total CSF Aβ42.  Recruitment 
goal is for 69 mutation positive subjects; 52 on solanezumab and 17 on placebo, for a total of 
34 in the pooled placebo group.  These recruitment goals will allow for 5% annual attrition rate. 

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4.2.2 Biomarker Endpoint Sample Size Justification 
Table 8 summarizes the power analysis by presenting the estimated SD from the DIAN cohort 
and the effect size on the annual rate of change for the CSF biomarker that can be detected by 
42 subjects in the active drug group (52 subjects enrolled, assumes 5% annual dropout rate 
during the trial) and 27 subjects in the pooled placebo group (34 subjects enrolled; assumes a 
5% annual dropout) with at least 80% power.  For comparison, Table 8 also lists the effect size 
on the rate of change reported in a prior study.  The projected effect size for 400 mg Q4W is 
conservatively estimated and is smaller than the reported effect size in the prior study.  
Therefore, the proposed sample size should provide adequate statistical power to detect the 
projected effect size.  For example, for the biomarker endpoint used at the interim analysis, the 
proposed sample size (i.e., 52 in the active drug group and 34 in the pooled placebo group) 
provides more than 99% statistical power to detect two-thirds of the reported effect size in the 
prior study.  The projected effect size is expected to be larger after dose escalation to 
1600 mg Q4W, thus the proposed sample size will provide more power to detect the treatment 
effect after dose escalation. 
In summary, recruitment of 52 mutation positive subjects to the active drug group (at least 
42 completers assuming 5% annual attrition during the study period) and 34 mutation positive 
subjects to the pooled placebo group (at least 27 completers assuming 5% annual attrition 
during the study period) would provide adequate statistical power both before and after dose 
escalation to test the biomarker engagement hypotheses. 
Table 8 
The effect size with 80% power in comparison to the reported effect size in a 
prior study and the corresponding power with the proposed sample size 
Active Drug 
Efficacy 
outcome 
SD for the 
rate of 
change/year 
among 
untreated 
carriers 
(estimated 
from DIAN 
data) 
Effect size that 
can be 
detected with 
n=42 (active 
drug) vs. 27 
(placebo) 
completers 
Reported 
effect size 
(p=p-value,  
n= sample 
size of the 
reported 
trial) 
Estimated 
power with 
n=42 
(treatment)
and n=27 
(placebo) 
for the 
reported 
effect size 
Estimated 
power with 
n=42 
(treatment) 
and n=27 
(placebo) to 
detect 2/3 of 
the reported 
effect size 
Authors 
of the 
reported 
trials 
(year) 
Solanezumab 
(LY2062430) 
CSF Aβ42 
(pg/mL) 
(Primary) 
75  
52.588 
170 (p<0.001, 
n=10 vs.10 for 
400 mg Q4W 
and placebo) 
>99% 
>99% 
(Farlow 
et al., 
2012) 
Effect size = difference between active drug and placebo on the annual rate of change for the corresponding efficacy 
endpoint that can be detected by 52 subjects in the active drug group (42 after 5% annual attrition) and 34 subjects in the 
mutation positive (pooled) placebo group (27 after 5% annual attrition)  
4.2.3 Interim Analysis 
One interim biomarker analysis will be conducted to assess whether this study drug is engaging 
its biological target.  The analysis will be conducted when 100% of active subjects complete 
2 years of randomized treatment (Visit 28). 

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At this interim analysis, the pre-specified biomarker of interest will be examined.  If the drug 
does not meet any of the pre-specified criteria for stopping or modification (as detailed in the 
DSMB Charter or as defined in the solanezumab-specific SAP appendix), the DIAN-TU 
Coordinating Center and/or DSMB may recommend that the study drug arm continue until the 
pre-planned trial duration is completed. 
 Other Drug-specific Analyses  
The biomarker endpoint used at the interim analysis will be analyzed based on the randomized 
population of active vs. placebo, as specified in section 8.3 of the main protocol.  The biomarker 
analysis endpoint may include baseline total CSF Aβ42 levels as a covariate.   
To evaluate the changes in immunogenicity data (Anti-LY) after treatment, 2 separate analyses 
will be done.  The first analysis will compare the proportion of positive results with proportion 
of negative results between treatment groups using Fisher’s exact test.  This analysis will be 
done at each of the time points (12, 28, 52, 80 and 104 weeks after randomization and at the 
end of treatment safety follow-up) separately for each immunogenicity analyte. 
For the second analysis, treatment emergence of immunogenicity will be compared between 
treatment groups.  Treatment emergence will be defined as any of the following: 
i. 
negative baseline result and a positive post-baseline result with a titer >10 
ii. 
positive baseline result and a positive post-baseline result with a greater than a 
2-fold increase in titers (for example, baseline titer of 10 increasing to >20 post-
baseline) 
The treatment-emergent analysis will be done at each visit post-baseline and also at any time 
post-baseline. 
In addition, samples for immunogenicity analysis will be collected at each of the 2 visits of the 
double-blind period at which subjects receive 800 mg and at the first, second, and fourth visits 
at which subjects receive 1600 mg during the dose escalation period.  These data will be 
summarized by treatment group at the visits at which they were collected. 
Although dose escalation will have occurred in the trial, the primary outcome will still be 
analyzed based on the randomized population of active vs. mutation positive placebos and 
eligible DIAN-OBS subjects, as specified in section 8.4 of the main protocol. 
 Changes to the Data Analysis 
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be 
described in the final SAP and clinical study report (CSR).  Additional analyses of the data will be 
conducted as deemed appropriate. 

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5 DRUG-SPECIFIC ADVERSE EVENTS AND REPORTING 
Reporting of ARIA events is detailed in the main protocol.  Infusion reactions will be reported as 
adverse events as detailed in the main protocol. 

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REFERENCES  
Bales KR et al.  (2006) Cholinergic dysfunction in a mouse model of Alzheimer disease is 
reversed by an anti-A beta antibody.  J Clin Invest 116:825-832. 
Bard F et al.  (2000) Peripherally administered antibodies against amyloid beta-peptide enter 
the central nervous system and reduce pathology in a mouse model of Alzheimer disease.  Nat 
Med 6:916-919. 
DeMattos RB et al.  (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta 
clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease.  Proc 
Natl Acad Sci USA 98:8850-8855. 
DeMattos RB et al.  (2002) Brain to plasma amyloid-beta efflux: a measure of brain amyloid 
burden in a mouse model of Alzheimer's disease.  Science 295:2264-2267. 
Dodart JC et al.  (2002) Immunization reverses memory deficits without reducing brain Abeta 
burden in Alzheimer's disease model.  Nat Neurosci 5:452-457. 
Farlow M et al.  (2012) Safety and biomarker effects of solanezumab in patients with 
Alzheimer’s disease.  Alzheimers Dement. 8:261–271. 
Schenk D et al.  (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like 
pathology in the PDAPP mouse.  Nature 400:173-177. 
Siemers ER et al.  (2010) Safety and changes in plasma and cerebrospinal fluid amyloid beta 
after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer 
disease.  Clin Neuropharmacol 33:67-73. 
Sperling R et al.  (2012) Amyloid-related imaging abnormalities in patients with Alzheimer's 
disease treated with bapineuzumab: a retrospective analysis.  Lancet Neurol 11:241-149. 
 

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SOLANEZUMAB SCHEDULE OF VISITS: 4 YEAR DOUBLE-BLIND TREATMENT PERIOD  
Solanezumab Schedule of Visits:  4 Year Double-blind Treatment Period – Page 1 of 4 
PROCEDURE: 
VISIT SITE1 
Home 
(H)3 
DIAN
-TU 
H 
H 
H 
MRI57F2 
H 
H 
H 
MRI2 
H 
H 
H 
MRI2 
H 
H 
H 
Visit No 
V1 
(screen) 
V2 
V3 
V4 
V5 
SM1 
V6 
V7 
V8 
SM2 
V9 
V10 
V11 
SM3 
V12 
V13 
V14 
Timing (weeks)4 
-8 to -2 
0 
4 
8 
12 
13 
16 
20 
24 
25 
28 
32 
36 
37 
40 
44 
48 
Informed Consent5 
X 
X6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Family History/Age at Onset Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Study Partner Information7
f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment History8 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Adverse Event Assessment 
 
X9 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Genetic Testing/APOE 
X 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry, Urinalysis 
X11 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Pregnancy Testing12 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Drug-specific Testing13 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Stored Plasma and Serum14 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
C-SSRS 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Vital Signs15 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Physical/Neurological Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment16  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
Cognitive Testing17 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Annual/Safety/Volumetric MRI 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar Puncture (CSF)18 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[11C]PiB-PET 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FDG-PET 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Florbetapir 18F PET 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For sites approved for participation in the 
Tau Addendum: [18F]AV-145119 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3T Safety MRI20 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Randomization21 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation22 
 
See Table 5 or Table 6 - DIAN-TU-001 Solanezumab Protocol Schedule of Visits: Dose Escalation Period 
Study Drug Administration 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Coordinator Phone Call23 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 

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Solanezumab Schedule of Visits:  4 Year Double-blind Treatment Period – Page 2 of 4 
PROCEDURE: 
VISIT SITE1,2 
DIAN-
TU 
H 
H 
H 
MRI2 
H 
H 
H  
MRI2 
H 
H 
H 
MRI2 
H 
H 
H 
DIAN-
TU 
Visit No 
V15 
V16 
V17 
V18 
SM4 
V19 
V20 
V21 
SM5 
V22 
V23 
V24 
SM6 
V25 
V26 
V27 
V28 
Timing (weeks)4 
52 
56 
60 
64 
65 
68 
72 
76 
77 
80 
84 
88 
89 
92 
96 
100 
104  
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment History 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Genetic Testing/APOE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, Chemistry, Urinalysis 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Pregnancy Testing12 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Drug-specific Testing13  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Stored Plasma and Serum 14 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
C-SSRS 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Vital Signs15 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Physical/Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment16  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Cognitive Testing17 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
Annual/Safety/Volumetric MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Lumbar Puncture (CSF)18 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
[11C]PiB-PET 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FDG-PET 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Florbetapir F 18 PET 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
For sites approved for participation 
in the Tau Addendum: [18F]AV-145119 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
3T Safety MRI20 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation22 
 
See Table 5 or Table 6 - DIAN-TU-001 Solanezumab Protocol Schedule of Visits: Dose Escalation Period 
Study Drug Administration 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Coordinator Phone Call23 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
  

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Solanezumab Schedule of Visits:  4 Year Double-blind Treatment Period – Page 3 of 4 
PROCEDURES: 
VISIT SITE1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No 
V29 
V30 
V31 
V32 
V33 
V34 
V35 
V36 
V37 
V38 
V39 
V40 
V41 
Timing (weeks)4 
108 
112 
116 
120 
124 
128 
132 
136 
140 
144 
148 
152 
156 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pregnancy Testing12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug-specific Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Plasma and Serum 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment16  
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Testing17 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Safety/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Lumbar Puncture (CSF)18 
 
 
 
 
 
 
 
 
 
 
 
 
 
[11C] PiB-PET  
 
 
 
 
 
 
 
 
 
 
 
 
 
FDG-PET  
 
 
 
 
 
 
 
 
 
 
 
 
 
Florbetapir F 18 PET  
 
 
 
 
 
 
 
 
 
 
 
 
 
For sites approved for participation in 
the Tau Addendum: [18F]AV-145119 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Escalation22 
 
See Table 5 or Table 6 - DIAN-TU-001 Solanezumab Protocol Schedule of Visits: Dose Escalation Period 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 

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Protocol #: DIAN-TU-001
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Solanezumab Schedule of Visits:  4 Year Double-blind Treatment Period – Page 4 of 4 
PROCEDURES: 
VISIT SITE1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No 
V42 
V43 
V44 
V45 
V46 
V47 
V48 
V49 
V50 
V51 
V52 
V53 
V54/ET24 
Timing (weeks)4 
160 
164 
168 
172 
176 
180 
184 
188 
192 
196 
200 
204 
208 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Pregnancy Testing12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug-specific Testing13 
 
 
 
 
 
 
 
 
 
 
 
 
X25 
Stored Plasma and Serum14 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C-SSRS 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Vital Signs15 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment16  
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Testing17 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Safety/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Lumbar Puncture (CSF)18 
 
 
 
 
 
 
 
 
 
 
 
 
X 
[11C] PiB-PET  
 
 
 
 
 
 
 
 
 
 
 
 
X 
FDG-PET  
 
 
 
 
 
 
 
 
 
 
 
 
X 
Florbetapir F 18 PET  
 
 
 
 
 
 
 
 
 
 
 
 
X 
For sites approved for participation in 
the Tau Addendum: [18F]AV-145119 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dose Escalation22 
 
See Table 5 or Table 6 DIAN-TU-001 - Solanezumab Protocol Schedule of Visits: Dose Escalation Period 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X26 
Coordinator Phone Call23 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ET = Early Termination 
Footnotes: 
1. 
Annual visits will be conducted at the host DIAN-TU site (DIAN-TU).  For subjects who live at a distance from the DIAN-TU site, other visits may be conducted at a 
site nearer to their home (H); safety magnetic resonance imaging (MRI) may be performed at a study-approved facility nearer to their home.  See next two 
footnotes for additional detail. 
2. 
Safety MRI will be done at the DIAN-TU site or at a qualified imaging center in reasonable proximity to the subject’s home for those not close to their DIAN-TU site.  
When possible, these will be done at an ADNI and/or ADCS site qualified imaging center. 

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3. 
Infusions and safety visits (designated as occurring at home [H]) may occur at the DIAN-TU site or, for subjects who live at a distance from the DIAN-TU site, these 
visits may be conducted by a trial-designated home health nurse at the subject’s home or other trial-identified location.  These visits may include phone calls from 
the host DIAN-TU site staff. 
4. 
The specific date during the baseline visit (V2) when the first dose of study drug is administered should be used to determine timing of subsequent visits and for 
determining time between screening and baseline visits. 
5. 
Informed consent will be obtained in two steps.  Subjects will have the opportunity to review the main informed consent form (ICF) and the supplemental drug-
specific ICFs and to discuss with DIAN-TU site study staff on the phone or in-person.  They can sign the main ICF at home or at the DIAN-TU site.  The main ICF must 
be signed before any study procedures are performed.  After screening, clinical laboratory tests are obtained and the subject is randomized to a specific study drug 
arm at baseline (V2), subject will review and sign a supplemental study drug-specific consent that details specific risks/benefits and procedures for the study drug 
arm to which they were assigned. 
6. 
Study drug-specific supplemental consent should be reviewed and signed after randomization.   
7. 
Family history/age at onset and demographic information for subject and study partner will be collected during the screening period (V1) and confirmed at the 
baseline visit (V2).  This information will not be collected at subsequent visits unless the subject or study partner becomes aware of new information or the study 
partner changes during the study. 
8. 
Home health nurses will have specific scripts or forms to prompt assessment and collection of medical treatment history, health changes or complaints (for 
assessment of adverse events by the site) and concomitant medications. 
9. 
Preexisting conditions will be documented at screening visit (V1) and reviewed at baseline visit (V2) prior to study drug administration. 
10. 
Provenance testing to confirm specimen identity will be performed at baseline visit only (V2). 
11. 
Includes TSH, B12, Hemoglobin A1c, PT, PTT, and INR at screening (V1) only. 
12. 
Serum pregnancy testing will be performed at screening visit (V1), V54, V93, and at the safety follow-up.  Urine pregnancy testing will be performed at all other 
visits.  Pregnancy tests will be confirmed as negative prior to dosing with study drug.  Urine pregnancy test must be completed and confirmed as negative either the 
day of or the day prior to any PET scan; if PET scans occur on more than 2 consecutive days during annual visits more than one urine pregnancy test will be required.  
Women who have undergone tubal ligation are also required to have pregnancy tests performed.  Alternate tests may be used if urine collection is not feasible but 
must be approved by the sponsor in advance. 
13. 
Drug-specific tests include testing for plasma Aβ and other biomarkers, solanezumab levels and anti-solanezumab antibodies.  These labs may be drawn more 
frequently if treatment emergence of immunogenicity is detected.  See section 1.12.  Samples for plasma Aβ and biomarker storage should be collected before 
beginning infusion.  Samples for plasma solanezumab levels should be collected before infusion and within 30 minutes after completion of infusion for post-dose 
levels. 
14. 
For future studies, including future regulatory inquiries or additional monitoring of anti-drug antibodies or other drug-specific tests.  See main protocol 
section 6.1.12. 
15. 
Blood pressure, heart rate, respiratory rate, and body temperature will be collected at all visits.  Height will be measured at baseline (V2) and annual visits only; 
weight will be measured approximately every 3 months starting at baseline (V2). 
16. 
Clinical assessments: DIAN-TU clinical assessment battery includes: study partner interview and administration of CDR and supplemental CDR; clinician assessment 
of symptoms and diagnosis; Geriatric Depression Scale (GDS), Functional Assessment Scale (FAS), Neuropsychiatric Inventory (NPI-Q) and Mini-Mental State 
Examination (MMSE). 
17. 
The cognitive testing will include both computer-administered and conventional testing.  See section 6.1.14 of the main protocol and DIAN Trials Unit Cognition 
Core Procedures Manual for additional information.  The complete cognitive battery will be administered at baseline (V2), and at annual visits.  A cognitive battery 

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subset (see section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core Procedures Manual) will be administered by the home health nurse in the home 
at screening visit (V1), and at the 6-month visits, for visits not occurring at the DIAN-TU site.  Cognitive testing should be completed as early in the day as possible, 
before study drug infusion. 
18. 
Lumbar puncture (LP) should be performed after MRI, if on the same date.  Lumbar punctures should be conducted as close to the baseline (V2) collection time as 
possible at each subsequent visit and under fasting conditions (water is allowed and encouraged).  CSF will be sent to local laboratory for cell count and differential, 
glucose and protein as well as to central lab for sample management, including distribution to Washington University Core lab and designated research labs for 
biomarker and drug-specific analysis.  Site staff should contact the subject with a follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 
hours later, to review any adverse events. 
19. 
Only for subjects participating in the tau PET imaging addendum.  Participating subjects may have no more than three (3) scans at any of the indicated visits (refer 
to the tau protocol addendum). 
20. 
Safety MRIs will be done at the DIAN-TU site or at a qualified imaging center in reasonable proximity to the subject’s home (MRI) for those not close to their DIAN-
TU site.  When possible, these will be done at an ADNI and/or ADCS site qualified imaging center. 
21. 
Prior to randomization, verify that all inclusion/exclusion criteria are met, including ARIA findings on baseline (V2) MRI. 
22. 
The first dose of 800 mg and the first dose of 1600 mg for each subject will be given at the DIAN-TU site or a medically qualified facility such as an infusion clinic 
until blinded safety results are evaluated for the first 20 subjects (active or placebo) to receive escalated dose infusions.  After this evaluation, first doses of 800 mg 
and 1600 mg may be given by a home health nurse, if deemed appropriate. 
23. 
Site study coordinators should call subjects either during or within two weeks after V3, V4 and V5.  For V6 and subsequent home visits, coordinator calls can be 
made with less frequency at the discretion of the PI or designee, and/or coordinator, and subject, but should occur at least every 3 months.   
24. 
PET imaging studies may be omitted if visit due to early termination (ET) and occurs less than 6 months after the previous PET imaging or if precluded by local 
regulations/dosimetry limits.  In the event of ET, other procedures may also be eliminated on a case-by-case basis, as determined by the sponsor. 
25. 
See section 1.12 for details of drug-specific test samples at the ET visit. 
26. 
Study drug administration only if subject is continuing double-blind treatment beyond year 4. 

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SOLANEZUMAB SCHEDULE OF VISITS: DOUBLE-BLIND TREATMENT BEYOND YEAR 4  
Solanezumab Schedule of Visits:  Double-blind Treatment Beyond Year 4 – Year 5, if applicable 
PROCEDURES: 
Visit Site1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No. 
V55 
V56 
V57 
V58 
V59 
V60 
V61 
V62 
V63 
V64 
V65 
V66 
V67 
Timing (weeks)3 
212 
216 
220 
224 
228 
232 
236 
240 
244 
248 
252 
256 
260 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testing4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Testing7 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Safety/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dose Escalation8 
 
See Table 5 or Table 6 - DIAN-TU-001 Solanezumab Protocol Schedule of Visits: Dose Escalation Period 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
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Version Date: 20 Dec 2019
 
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Solanezumab Schedule of Visits:  Double-blind Treatment Beyond Year 4 – Year 6, if applicable 
PROCEDURES: 
Visit Site1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No. 
V68 
V69 
V70 
V71 
V72 
V73 
V74 
V75 
V76 
V77 
V78 
V79 
V80 
Timing (weeks)3 
264 
268 
272 
276 
280 
284 
288 
292 
296 
300 
304 
308 
312 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy Testing4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Cognitive Testing7 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Safety/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Dose Escalation8 
 
See Table 5 or Table 6 - DIAN-TU-001 Solanezumab Protocol Schedule of Visits: Dose Escalation Period 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Amendment 10
APPENDIX 3: Solanezumab 
Version Date: 20 Dec 2019
 
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Solanezumab Schedule of Visits:  Double-blind Treatment Beyond Year 4 – Year 7, if applicable 
PROCEDURES: 
Visit Site1,2 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
DIAN-TU 
Visit No. 
V81 
V82 
V83 
V84 
V85 
V86 
V87 
V88 
V89 
V90 
V91 
V92 
V93/ET 
Safety 
Follow-up10 
Timing (weeks)3 
316 
320 
324 
328 
332 
336 
340 
344 
348 
352 
356 
360 
364 
4-8 weeks 
post last 
dose 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy Testing4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug-specific Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
C-SSRS 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signs5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Assessment6 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Cognitive Testing7 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
Annual/Safety/Volumetric MRI 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Dose Escalation8 
See Table 5 or Table 6 - DIAN-TU-001 Solanezumab Protocol Schedule of Visits: Dose Escalation Period 
 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Coordinator Phone Call9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ET = early termination 
Footnotes: 
1. 
Annual visits will be conducted at the host DIAN-TU site (DIAN-TU).  For subjects who live at a distance from the DIAN-TU site, other visits may be conducted at a 
site nearer to their home (H); safety MRIs may be performed at a study-approved facility nearer to their home.  See next two footnotes for additional detail. 
2. 
Infusions and safety visits (designated as occurring at home [H]) may occur at the DIAN-TU site or, for subjects who live at a distance from the DIAN-TU site, these 
visits may be conducted by a trial-designated home health nurse at the subject’s home or other trial-identified location.  These visits may include phone calls from 
the host DIAN-TU site staff. 
3. 
The specific date during the baseline visit (V2) when the first dose of study drug is administered should be used to determine timing of subsequent visits and for 
determining time between screening and baseline visits. 
4. 
Urine pregnancy testing will be performed at all visits.  Pregnancy tests will be confirmed as negative prior to dosing with study drug.  Women who have undergone 
tubal ligation are also required to have pregnancy tests performed.  Alternate tests may be used if urine collection is not feasible, but must be approved by the 
sponsor in advance.   
5. 
Blood pressure, heart rate, respiratory rate, and body temperature will be collected at all visits.  Height will be measured at baseline (V2) and annual visits only; 
weight will be measured approximately every 3 months. 

Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Amendment 10
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6. 
Clinical assessments: DIAN-TU clinical assessment battery includes: study partner interview and administration of CDR and supplemental CDR; clinician assessment 
of symptoms and diagnosis; Geriatric Depression Scale (GDS), Functional Assessment Scale (FAS), Neuropsychiatric Inventory (NPI-Q) and Mini-Mental State 
Examination (MMSE). 
7. 
The cognitive testing will include both computer-administered and conventional testing.  See section 6.1.14 of the main protocol and DIAN Trials Unit Cognition 
Core Procedures Manual for additional information.  The complete cognitive battery will be administered at baseline (V2), and at the annual visits.  A cognitive 
battery subset (see section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core Procedures Manual) will be administered by the home health nurse in 
the home at 6-month visits, for visits not occurring at the DIAN-TU site.  Cognitive testing should be completed as early in the day as possible, and before study drug 
infusion. 
8. 
The first dose of 800 mg and the first dose of 1600 mg for each subject will be given at the DIAN-TU site or a medically qualified facility such as an infusion clinic 
until blinded safety results are evaluated for the first 20 subjects (active or placebo) to receive escalated dose infusions.  After this evaluation, first doses of 800 mg 
and 1600 mg may be given by a home health nurse, if deemed appropriate.  
9. 
Site study coordinators should call subjects either during or within two weeks after V3, V4 and V5.  For V6 and subsequent home visits, coordinator calls can be 
made with less frequency at the discretion of the principal investigator or designee, and/or coordinator, and subject, but should occur at least every 3 months. 
10. 
The end-of-treatment safety follow-up visit should be performed 4 to 8 weeks after the last dose of double-blind treatment.  The double-blind treatment period for 
each subject may vary based on when the subject was enrolled and may last from 4 up to 7 years (364 weeks [V93]) or until early termination, whichever is sooner.  
Any procedures done after the last dose, but before the safety follow-up visit, do not need to be repeated. 
 
 

Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Amendment 10
APPENDIX 3: Solanezumab 
Version Date: 20 Dec 2019
 
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SOLANEZUMAB SCHEDULE OF VISITS: OPEN-LABEL EXTENSION  
» 
Italicized procedures are only to be performed in the OLE period at the discretion of the sponsor and pharma partner contingent upon the 
individual biomarker or outcome measure demonstrating continued utility in OLE based on the results of the double-blind period of the 
study. 
 
Solanezumab Schedule of Visits:  Open-label Extension – Page 1 of 2 
PROCEDURE: 
VISIT SITE1,2 
DIAN-TU 
H 
H 
H 
H 
H 
 
MRI 
H 
H 
H 
H 
H 
H 
H 
Visit No 
OLE  
V1 
OLE  
V2 
OLE 
V3 
OLE  
V4 
OLE  
V5 
OLE  
V6 
OSM 1 
OLE 
V7 
OLE  
V8 
OLE  
V9 
OLE 
V10 
OLE 
V11 
OLE 
V12 
OLE 
V13 
Timing (weeks)3 
0 
4 
8 
12 
16 
20 
21 
24 
28 
32 
36 
40 
44 
48 
Informed consent4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verification of Eligibility for OLE5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testing6 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment: Full Battery1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment: MMSE Only1 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Cognitive Testing8 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
3T Safety MRI9  
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Annual/Volumetric MRI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
[11C]PiB-PET Scan10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
FDG-PET10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AV-1451 Tau PET Scans10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug-specific Testing and 
 Stored Serum and Plasma11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar Puncture11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration13 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Coordinator Phone Call14 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 

Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Amendment 10
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Version Date: 20 Dec 2019
 
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Solanezumab Schedule of Visits:  Open-label Extension – Page 2 of 2 
PROCEDURE: 
VISIT SITE1,2 
DIAN-TU 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
DIAN-TU 
Visit No 
OLE  
V14 
OLE 
V15 
OLE 
V16 
OLE 
V17 
OLE 
V18 
OLE 
V19 
OLE 
V20 
OLE 
V21 
OLE 
V22 
OLE 
V23 
OLE 
V24 
OLE 
V25 
OLE 
V26 
OLE V27/ 
ET 
Timing (weeks)3 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 
92 
96 
100 
104 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testing6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
C-SSRS 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment:  Full Battery1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Assessment: MMSE Only7 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Cognitive Testing8 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
Annual/Volumetric MRI9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
[11C]PiB-PET Scan10  
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FDG-PET10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AV-1451 Tau PET Scan10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Drug-specific Testing and  
Stored Serum and Plasma11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Lumbar Puncture11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Study Drug Administration13 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coordinator Phone Call14 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ET = Early Termination; OLE = open-label; OSM = Open-label Safety MRI visits for 3T Safety/Titration Safety MRI 
Footnotes: 
1. Annual visits will be conducted at the host DIAN-TU site (DIAN-TU).  For subjects who live at a distance from the DIAN-TU site, other visits may be conducted at a site 
nearer to their home (H).  Safety magnetic resonance imaging (MRI) (OSM visits) will be done at the DIAN-TU site or a qualified imaging center in reasonable proximity to 
the subject’s home for those not close to their DIAN-TU site.  When possible, these will be done at an ADNI and/or ADCS site qualified imaging center.  See next two 
footnotes for additional detail. 
2. Infusions and safety visits (designated as occurring at home [H]) may occur at the DIAN-TU site or, for subjects who live at a distance from the DIAN-TU site, these visits 
may be conducted by a trial-designated home health nurse at the subject’s home or other trial-identified location.  These visits may include phone calls from the host 
DIAN-TU site staff. 
3. The specific date during OLE V1 when the first dose of study drug is administered for the open-label treatment period should be used to determine timing of subsequent 
visits. 
4. The informed consent form (ICF) for the OLE period must be signed before any study procedures are performed.  This can be done once an approved OLE consent is 
available at the site, i.e., prior to this visit to enable time for consideration and review of the details. 
5. Subjects must be mutation positive. 

Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Amendment 10
APPENDIX 3: Solanezumab 
Version Date: 20 Dec 2019
 
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6. Serum pregnancy testing will be performed at OLE V1 and at OLE V27.  Urine pregnancy testing will be performed at all other visits.  Women who have undergone tubal 
ligation are also required to have pregnancy tests performed.  Alternate tests may be used if urine collection is not feasible but must be approved by the sponsor in 
advance 
7. Clinical assessments: DIAN-TU clinical assessment battery includes: study partner interview and administration of CDR and supplemental CDR; clinician assessment of 
symptoms and diagnosis; Geriatric Depression Scale (GDS), Functional Assessment Scale (FAS), Neuropsychiatric Inventory (NPI-Q) and Mini-Mental State Examination 
(MMSE). Clinical assessment: MMSE only will be performed at 24 weeks (OLE V7) and 76 weeks (OLE V20). 
8. The cognitive testing may include both computer-administered and conventional testing.  See section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core 
Procedures Manual for additional information.  The complete cognitive battery will be administered at Baseline (OLE V1), week 52 (OLE V14), and week 104 (OLE V27).  A 
cognitive battery subset (see section 6.1.14 of the main protocol and DIAN Trials Unit Cognition Core Procedures Manual) will be administered by the home health nurse 
in the home at week 24 (OLE V7), and week 76 (OLE V20), visits not occurring at the DIAN-TU site.  Cognitive testing should be completed as early in the day as possible, 
and before study drug infusion or injection. 
9. If MRI findings prior to dosing warrant more frequent MRIs during the dose escalation period of the OLE period, the PI may request for review and approval by the 
sponsor medical monitoring team. 
10. [11C] PiB-PET, FDG-PET, and AV-1451 tau PET scans should be performed unless the subject had these procedures performed in the prior 6 months preceding OLE V1. 
11. Drug-specific tests include testing for plasma Aβ and other biomarkers for future studies.  Samples should be collected before infusion of study drug administration. See 
main protocol section 6.1.12. 
12. Lumbar puncture (LP) should be performed unless the subject had this procedure done in the 6 months preceding OLE V1. Lumbar puncture should be performed after 
MRI, if on the same date.  Lumbar punctures should be conducted as close to the baseline collection time as possible at each subsequent visit and under fasting 
conditions (water is allowed and encouraged).  Cerebrospinal fluid (CSF) will be sent to local laboratory for cell count and differential, glucose and protein as well as to 
central lab for sample management, including distribution to Washington University Core lab and designated research labs for biomarker and drug-specific analysis.  Site 
staff should contact the subject with a follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours later, to review any adverse events. 
13. All subjects enrolled in the OLE period for solanezumab will start at the 400 mg dose level.  After receiving 400 mg every 4 weeks (± 4 days) for at least 2 infusions, 
subjects will be titrated to 800 mg dose level.  After receiving 800 mg every 4 weeks (± 4 days) for at least 2 infusions, subjects will be titrated to the 1600 mg dose level.  
Changes in dosage may be made in the event of ARIA as described in section 1.14 or for other safety reasons at the investigator’s discretion with notification of a 
Medical Director or designee.  If needed, the schedule of assessments will be adjusted.  Vital signs will be assessed per standard of care when administering IV product, 
however the data will not be collected. 
14. Site study coordinators should call subjects either during or within two weeks after OLE V2, OLE V3, OLE V4 and OLE V5.  For OLE V6 and subsequent home visits, 
coordinator calls can be made with less frequency at the discretion of the PI or designee, and/or coordinator, and subject, but should occur at least every 3 months.