Clinical trial NCT06424236
Conditions: Alzheimers Disease Dementia Alzheimers Disease, Familial
Keywords: Alzheimer's Alzheimer's Disease Dementia Mutation Genetic Mutation Dominantly Inherited Alzheimer's Disease Dominantly Inherited Alzheimer Network Autosomal Dominant Alzheimer's Disease Early Onset Alzheimer's Disease DIAN DIAN-TU DIAN TU DIAD
Sponsor: Washington University School of Medicine
Start date: 2020-06-03; Completion date: 2023-11-13
Enrollment: 73 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to assess the safety, tolerability, biomarker, cognitive and clinical efficacy of investigational products in participants with an Alzheimer's disease-causing mutation by determining if treatment with the study drug slows the rate of progression of cognitive/clinical impairment or improves disease-related biomarkers.

Detailed description:
Alzheimer's disease (AD) is defined by the presence of abnormal accumulations of amyloid protein (plaques) and tau protein (tangles) in the brain. The double-blind arm of DIAN-TU-001 Master protocol (NCT01760005) tested whether gantenerumab provided a clinical benefit by slowing the onset or the worsening of the disease. A clinical benefit was not observed in the double-blind part of the DIAN-TU-001 study. However, gantenerumab was associated with improvements in measures of amyloid and tau and an improvement in an overall measure of neurodegeneration (when nerve cells in the brain lose function over time). It is not known whether these changes may provide future clinical benefits. Based on this information, an exploratory Open Label Extension (OLE) will further study the effect of gantenerumab on these Alzheimer-related proteins and their relationship to disease progression.

After this final evaluation of study treatment with gantenerumab used in the gantenerumab / solanezumab double-blind arm of the Master protocol (NCT01760005), eligible participants from the placebo, solanezumab, and gantenerumab treatment groups in double-blind period were invited to participate in an OLE period to receive active gantenerumab study treatment as part of the DIAN-TU-001 Master protocol. The OLE period of the study planned to provide study treatment with gantenerumab for up to 3 years (36 months).

This study collected brain scans, blood, and spinal fluid tests (also called biomarkers), as well as safety, clinical and cognitive testing. The goal is to determine if gantenerumab has favorable effects on these tests to determine if and how much treatment may prevent or delay the symptoms of AD.

Update:

Based on the results of the completed studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer's disease (DIAD) participants in the DIAN-TU-001 OLE study were substantially clinically benefiting from gantenerumab high-dose treatment before the trial reached completion as the Gant program was being stopped.

An interim efficacy analysis of the DIAN-TU-001 OLE was performed to:

1. determine if gantenerumab OLE treatment and/or long-term treatment results in clinical benefit and determine the extent of amyloid removal compared to the double-blind period.
2. determine the potential effects of gantenerumab on clinical and cognitive measures to support decision-making regarding next steps for the DIAN-TU-001 OLE.

Arms: arm 1: Gantenerumab: Subcutaneously every 4 weeks, at escalating doses; at target, dosing was every 2 weeks
Interventions: intervention 1: Gantenerumab
Intervention descriptions: intervention 1: Open-label administered Subcutaneously every 4 weeks, at escalating doses; at target, dosing was every 2 weeks

Protocol documents:
Prot_000.pdf: 
 
 
Page 1 of 263 
Clinical Study Protocol:  
DIAN-TU-001 
A Phase II/III Multicenter Randomized, Double-Blind, Placebo-
Controlled Platform Trial of Potential Disease Modifying Therapies 
Utilizing Biomarker, Cognitive, and Clinical Endpoints in 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), E2814, and Lecanemab (BAN2401) 
Protocol Number: 
DIAN-TU-001 
Investigational Phase: 
II/III 
Protocol Version: 
Amendment 13 
Version Date: 
05 Apr 2023 
IND Number: 
EudraCT Number:  
115,652 
2013-000307-17 
 
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. 


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INVESTIGATOR’S STATEMENT 
I understand that all information concerning the product(s) 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 participants. 
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, 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 05 Apr 2023. 
Investigator’s 
Signature: 
 
 
 
Name (printed): 
 
 
Date 
 


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MASTER PROTOCOL PLATFORM SYNOPSIS 
Protocol Number 
DIAN-TU-001 
Protocol Title 
A Phase II/III multicenter, randomized, double-blind, placebo-controlled 
platform trial of potential disease modifying therapies utilizing biomarker, 
cognitive, and clinical endpoints in dominantly inherited Alzheimer’s disease 
Clinical Phase 
Phase II/III 
Investigators 
Investigators will be selected based on patient population and clinical 
research competency.   
Study Centers 
Approximately 40 sites globally.  The currently existing Dominantly Inherited 
Alzheimer Network Trials Unit (DIAN-TU) sites will continue to be active for 
new study drug enrollment and new sites will continue to be identified and 
qualified. 
Study Objective 
To assess the safety, tolerability, biomarker, cognitive and clinical efficacy of 
investigational products in participants with an Alzheimer’s disease-causing 
mutation by determining if treatment with the study drug slows the rate of 
progression of cognitive/clinical impairment or improves disease-related 
biomarkers.   
Study Population 
Participants 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 10 years younger (−10) 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).  Individual 
drug arms may require genetic disclosure to participate based on their 
specific design.   
For the cognitive run-in (CRI) period only, the study population will be 
expanded to include participants who have a DIAD mutation in the family 
AND are cognitively normal and who are 11 to 25 years younger (−25 to −11) 
than their estimated age of symptom onset in order to include participants 
for future trials that may have differences in the enrollment age of onset. 
Study Design 
This is an adaptive platform-based study, which allows flexibility to add a new 
compound to the same protocol, allowing participants to be randomized to 
study drug arms open to enrollment, and to maintain a cohort of trial ready 
participants with or at risk for DIAD mutations.  The study has three periods: a 
CRI period, a double-blind treatment period, and an open-label extension 
period, which may differ by drug arm.  Data may be pooled from the placebo 
groups of different drug arms, from the CRI period, and from the DIAN 
Observational (DIAN-OBS) study to serve as pooled controls for treatment 
efficacy evaluation per the inclusion and exclusion of each drug arm. 


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Previously, DIAN-TU-001 also included a double-blind gantenerumab, 
solanezumab, and atabecestat arm.  For further information relevant to these 
arms, see earlier versions of the protocol.   
Participants enrolled to double-blind drug arms are treated with active drug 
or placebo, while biomarker (e.g., positron emission tomography (PET) 
imaging, volumetric brain magnetic resonance imaging (MRI), cerebrospinal 
fluid (CSF), and plasma measures), clinical, cognitive, and safety assessments 
are monitored throughout the study period.   
Starting with Amendment 8 of this protocol, a CRI period was opened for 
recruitment if no relevant study drug arms are randomizing to drug or 
placebo.   
The biomarker, cognitive and clinical 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. 
The study has a common close design included in specified drug arms, in 
which double-blind treatment is continued for all participants until the last 
participant enrolled completes the 4-year randomized period of treatment or 
withdraws.    
Mutation positive participants will be randomized to active drug or placebo at 
a ratio specified in each drug-specific appendix.  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).  When not excluded in an 
individual drug arm, participants who are mutation negative will be assigned 
placebo. 
At the request of participants, mutation negative participants may be 
included to maintain blinding as to genetic status for those who do not wish 
to know their genetic status.  Mutation negative participants may be included 
in individual drug arms when feasible and appropriate.  Participants who are 
mutation negative will be assigned placebo.  Data from mutation negative 
participants will be used to develop models for longitudinal changes in 
biomarkers and cognition in healthy adult controls. 
Number of 
Participants 
This study will recruit participants from the Dominantly Inherited Alzheimer 
Network observational study (DIAN-OBS), 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. 


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The number of participants for each drug arm is specified in each drug-
specific appendix.  Recruitment is limited to those with a baseline CDR 0 to 1 
(inclusive). 
There may be up to 740 participants recruited into the CRI period while new 
drugs are implemented.  Up to 500 Secondary Prevention CRI participants 
may be enrolled for (estimated years from symptom onset (EYO) −10 to +10) 
drug arms, in order to ensure that a sufficient number of active and eligible 
participants qualify for entry into a study drug arm during randomization. In 
addition, up to 240 Primary Prevention (EYO −25 to −11 and cognitively 
normal [Clinical Dementia Rating (CDR) 0]) participants may be enrolled in the 
CRI period to establish a randomization-ready cohort of participants.  
Main Inclusion 
Criteria 
Participants must meet ALL inclusion criteria.  The main inclusion criteria are 
as follows:   
• 
–10 to +10 EYO (secondary prevention population): within −10 to +10 
years (inclusive) of the estimated age at symptom onset, CDR 0 to 1, 
inclusive, known eligible mutation carrier or at 50% risk (affected parent 
or sibling) 
• 
−25 to −11 EYO (primary prevention population): within 11 to 25 years 
younger than their 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, participant will be withdrawn from 
study  
• 
Willing to complete the main study-related testing, evaluations, and 
procedures 
Main Exclusion 
Criteria 
Participants will be excluded if they have a major or unstable illness that 
would prevent trial participation or are unable to complete main study-
related testing.  Exclusions include MRI contraindications, required 
anticoagulation therapy, and pregnancy.  Participants who know they are 
mutation non-carriers are not eligible. 
Route and Dosage 
Form 
Route and dosage forms are included in each drug-specific appendix.  There is 
no study drug administered during the CRI period. 
Dosage 
Dosage is included in each drug-specific appendix. 
Duration of 
Treatment 
The total treatment duration for any blinded study drug arm is determined by 
the enrollment duration, and is not expected to exceed the sum of the 
enrollment duration and the planned double-blinded period (e.g. if the 
enrollment duration is 2 years and treatment is 4 years, the total treatment 
duration will not exceed 6 years).   
If the CRI period is open to enrollment, participants may be enrolled in the CRI 
period.  Participants will continue in the CRI period until a study drug arm is 
opened for randomization, but no longer than approximately 3 years.  If a 
participant is in a CRI period, a minimum of 8 weeks must elapse between the 
participant’s last administration of the cognitive battery during the CRI period 


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and administration of the baseline (V2) cognitive battery for a blinded study 
drug arm. 
If a study drug arm demonstrates a potential for clinical benefit at the end of 
the double-blind treatment period, eligible participants may be offered to 
continue or start treatment, via an open-label extension (OLE) period in which 
all participants will receive active study drug.  The OLE period may last up to 
an additional 3 years (36 months) or more, or until the treatment becomes 
commercially available in a participant’s country, whichever occurs first. 
Primary Outcome 
Measure 
The Primary Outcome is defined in each drug-specific appendix, and may 
include biomarker, cognitive, or clinical outcomes.  Comparisons will be made 
between each active drug, mutation positive placebos, and control groups, 
e.g. eligible DIAN-OBS participants. 
The OLE endpoints are outlined in each drug-specific appendix, if applicable. 
Additional Outcome 
Measures 
Additional outcome measures, which may be further categorized as 
secondary or exploratory in the drug-specific appendices in this or prior 
amendments, and/or 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 
with biomarker endpoints specified for each drug based on mechanism of 
action.  Assess AD biomarkers, including soluble biochemical measures 
(e.g. amyloid-beta and tau), imaging measures of pathology (e.g. amyloid 
and tau PET), and AD biomarker changes (e.g. atrophy measured by MRI, 
hypometabolism by FDG PET, and neurodegeneration measured by 
Neurofilament light).  
3. Comparisons between each drug and the placebo arm in change from 
baseline for the following clinical and cognitive measures listed below:   
a. Clinical measures to be obtained at baseline, and annual visits will be 
administered at the host DIAN-TU site include: 
 
Clinical Dementia Rating™ (CDR), including Clinical Dementia 
Rating Sum of Boxes™ (CDR-SB)  
 
Clinician’s diagnostic assessment 
 
Geriatric Depression Scale (GDS) 
 
Neuropsychiatric Inventory Questionnaire (NPI-Q) 
 
Functional Assessment Scale (FAS) 
 
Mini-Mental State Examination (MMSE) – also measured at the 26 
week (6 month) time point between annual visits with the below 
cognitive battery. 
b. Cognitive measures to be obtained at baseline and every 26 weeks 
(approx. 6 months) will be administered at the DIAN-TU site or via 
home health nurse trial-certified cognitive rater include: 


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 
Memory Complaint Questionnaire (MAC-Q) 
 
Buschke and Grober Free and Cued Selective Reminding Test-
Immediate Recall (FCSRT-IR) 
 
Wechsler Memory Scale-Revised (WMS-R) Logical 
Memory/Paragraph Memory (Immediate & Delayed Recall), 
Alternate Paragraph for Logical Memory I & II - Version A 
(Immediate and Delayed) and Alternate Paragraph for Logical 
Memory I & II - Version B (Immediate and Delayed) 
 
Category Fluency (Animals) 
 
Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit-Symbol 
Substitution Test 
 
Trailmaking Test Parts A & B 
 
Wechsler Memory Scale-Revised (WMS-R) Digit Spatial Span 
Forward and Backward 
 
Ambulatory Research in Cognition (ARC) smartphone-based 
cognitive assessments (Grids, Prices, Symbols) 
4. Imaging measures obtained in drug arms include the following (see drug-
specific appendices and SAPs for outcome classification):  
a. Glucose metabolism positron emission tomography (PET) imaging 
with FDG-PET  
b. Amyloid PET imaging with [11C]PiB-PET 
c. Tau PET imaging with [18F]MK-6240 
d. Structural brain measures with volumetric MRI 
e. Functional connectivity MRI (fc-MRI) 
f. Diffusion Tensor Imaging (DTI) MRI, including diffusion basis spectrum 
imaging (DBSI) 
g. Blood flow measures by Arterial Spin Labeling (ASL) MRI 
h. Assessment of MRI features, such as microhemorrhages (MCH), white 
matter hyperintensities (WMH), cerebral infarctions, and Amyloid 
Related Imaging Abnormalities (ARIA) on conventional MRI 
sequences. 
5. Fluid biomarker measures that may be included as secondary or 
exploratory endpoints as specified in the drug-specific appendix and/or 
SAP, include the following: 
a. CSF and plasma amyloid species analyses 
b. CSF and plasma tau species analyses 
c. CSF and plasma neurofilament light chain analyses 
d. Additional CSF and blood biomarkers of AD, neurodegeneration, 
neuroinflammation, or other biomarkers.  
6. Assess longitudinal change in biomarker, cognitive, and clinical measures 
in individuals who do not have mutations causing DIAD (mutation-
negative placebo group). 


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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 
The data collected in the CRI period are able to be used for analysis in the 
respective drug arm under which participants are randomized and treated 
and as control data for the DIAN-TU platform. 
Descriptive statistics:  Descriptive statistics will be provided for both safety 
and efficacy variables at each time point collected by treatment groups and 
across 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 be drug-specific and in general include all 
participants 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 control groups.  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 significant changes in 
cognitive decline.  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 participants who are randomized, treated, 
and assessed for their primary outcomes at least once after the baseline 
assessment. 
Efficacy analyses for the primary endpoint: The primary endpoint efficacy 
analyses will be conducted on the modified intent-to-treat (mITT) population, 
unless defined otherwise in the drug-specific appendix or SAP.  The primary 
efficacy hypothesis will be tested by comparing the active drug arm to the 
control group. 


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Sample Size 
Considerations 
Drug arm specific sample size considerations are in drug-specific appendices 
and associated SAPs. 


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TABLE OF CONTENTS 
INVESTIGATOR’S STATEMENT .................................................................................................... 2 
MASTER PROTOCOL PLATFORM SYNOPSIS ................................................................................ 3 
TABLE OF CONTENTS ................................................................................................................ 10 
LIST OF APPENDICES ................................................................................................................. 14 
LIST OF FIGURES ....................................................................................................................... 15 
ABBREVIATIONS/GLOSSARY OF TERMS .................................................................................... 16 
1 
INTRODUCTION ............................................................................................................. 24 
 
Background ........................................................................................................ 24 
 
Drug-specific Background ................................................................................... 26 
 
Rationale for Biomarkers.................................................................................... 26 
 
Rationale for Cognitive Run-in Assessments ....................................................... 31 
 
Rationale for Open-label Extension .................................................................... 32 
2 
STUDY OBJECTIVE ......................................................................................................... 32 
3 
STUDY DESIGN .............................................................................................................. 33 
 
Overall Design .................................................................................................... 33 
 
Rationale for Study Design ................................................................................. 35 
 
Number of Participants and Sites ....................................................................... 37 
 
Participant Enrollment and Randomization ........................................................ 38 
 
Measured Study Endpoints ................................................................................ 40 
 
Safety Endpoints ................................................................................................ 43 
 
Study Schedule................................................................................................... 44 
 
Total Study Duration and Duration of Treatment ............................................... 44 
 
Open-label Extension ......................................................................................... 45 
4 
STUDY POPULATION AND SITES .................................................................................... 46 
 
Inclusion Criteria ................................................................................................ 46 
 
Exclusion Criteria ............................................................................................... 48 
 
Participant Recruitment and Screening .............................................................. 52 
 
Discontinuation/Early Withdrawal of Participants .............................................. 52 
4.4.1 
Criteria for Discontinuation............................................................... 52 


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4.4.2 
Replacement of Participants ............................................................. 53 
 
Transfer of Participants between Sites ............................................................... 53 
 
Expectations and Withdrawal of Sites ................................................................ 54 
5 
STUDY DRUGS ............................................................................................................... 54 
 
Blinding .............................................................................................................. 54 
 
Breaking the Blind .............................................................................................. 55 
 
Concomitant Medications .................................................................................. 55 
 
Treatment Compliance ....................................................................................... 56 
6 
STUDY PROCEDURES ..................................................................................................... 57 
 
Procedures ......................................................................................................... 57 
6.1.1 
Participant Informed Consent ........................................................... 57 
6.1.2 
Family History/Age at Onset Assessment/Demographics/Study 
Partner Information .......................................................................... 58 
6.1.3 
Medical/Treatment History, Concomitant Medications, Adverse 
Event Assessment ............................................................................. 58 
6.1.4 
Clinical Assessment ........................................................................... 59 
6.1.5 
Physical and Neurological Examination ............................................. 59 
6.1.6 
Vital Signs ......................................................................................... 59 
6.1.7 
Electrocardiogram ............................................................................ 60 
6.1.8 
C-SSRS .............................................................................................. 60 
6.1.9 
Genetic Testing ................................................................................. 60 
6.1.10 
Clinical Laboratory Tests ................................................................... 61 
6.1.11 
Drug-specific Testing......................................................................... 62 
6.1.12 
Stored Samples (Blood and DNA) ...................................................... 62 
6.1.13 
Study Drug Administration ................................................................ 63 
6.1.14 
Cognitive Testing .............................................................................. 63 
6.1.14.1 
Gantenerumab OLE Period .................................................... 63 
6.1.14.2 
Cognitive Run-In Period and Tau Drug Arms: DIAN-TU 
Harmonized Cognitive Battery ............................................... 65 
6.1.15 
Baseline and Annual Magnetic Resonance Imaging (MRI) ................. 66 
6.1.16 
Safety Magnetic Resonance Imaging (MRI) ....................................... 67 


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6.1.17 
Lumbar Puncture (LP) – Cerebrospinal Fluid (CSF) ............................. 68 
6.1.18 
Positron Emission Tomography ......................................................... 69 
6.1.19 
Brain Donation Program ................................................................... 73 
 
Overview of Visit Flow ........................................................................................ 74 
 
Study Visits ........................................................................................................ 75 
6.3.1 
Cognitive Run-in Period .................................................................... 76 
6.3.2 
General Platform Procedures for Screening (Visit 1) in Double-
Blind Treatment Periods ................................................................... 76 
6.3.3 
General Platform Procedures for Baseline (Visit 2/First Dose) in 
Double-Blind Treatment Periods ....................................................... 78 
6.3.4 
Double-blind Treatment Period ........................................................ 80 
6.3.5 
End-of-Treatment / Safety Follow-up Visit ........................................ 81 
6.3.6 
Open-label Extension ........................................................................ 82 
6.3.7 
Early Termination Visit and Post-treatment Follow-up Period ........... 84 
 
Termination of the Study ................................................................................... 85 
7 
SAFETY AND ADVERSE EVENTS ..................................................................................... 85 
 
Definitions ......................................................................................................... 85 
7.1.1 
Adverse Events ................................................................................. 85 
7.1.2 
Serious Adverse Event ...................................................................... 86 
 
Adverse Event (AE) Severity ............................................................................... 87 
 
Relationship to Study Drug ................................................................................. 88 
 
Adverse Event Collection Period......................................................................... 88 
 
Adverse Event Reporting .................................................................................... 89 
 
Serious Adverse Event Reporting ....................................................................... 89 
 
Pregnancy Reporting .......................................................................................... 90 
 
Hy’s Law ............................................................................................................. 90 
 
Adverse Events of Special Interest...................................................................... 90 
 
Data Safety Monitoring Board (DSMB) ............................................................... 90 
8 
STATISTICAL PLAN ......................................................................................................... 90 
 
Descriptive Statistics .......................................................................................... 91 


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Safety Analysis ................................................................................................... 91 
 
Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification .... 91 
 
Primary Efficacy Endpoint Statistical Analysis, Power and Sample Size 
Justification ........................................................................................................ 92 
 
OLE Outcomes ................................................................................................... 92 
9 
DATA HANDLING AND RECORD KEEPING ...................................................................... 92 
10 
STUDY MONITORING, AUDITING AND INSPECTING ...................................................... 93 
 
Protocol Deviations ............................................................................................ 93 
 
Study Reporting Requirements .......................................................................... 94 
 
Investigator Documentation .............................................................................. 94 
11 
ETHICAL CONSIDERATIONS ........................................................................................... 94 
12 
STUDY FINANCES .......................................................................................................... 95 
13 
PUBLICATION PLAN ....................................................................................................... 95 
14 
REFERENCES .................................................................................................................. 96 
 


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LIST OF APPENDICES 
APPENDIX 1: COGNITIVE RUN-IN PERIOD ................................................................................ 101 
APPENDIX 2: MAIN PROTOCOL SCHEDULE OF VISITS: SCREENING AND BASELINE ................... 115 
APPENDIX 3: GANTENERUMAB ............................................................................................... 117 
APPENDIX 4: E2814 ................................................................................................................. 174 
 


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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 ........................................................................................................ 27 
Figure 2 Stages of Tau Pathology and Potential Mechanisms to Target Tau ............................ 29 
Figure 3  DIAN-TU-001 Master Protocol AD Prevention Platform Design ................................. 34 
Figure 4 Overview of Participant Visit Flow ............................................................................. 75 
 


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ABBREVIATIONS/GLOSSARY OF TERMS 
Abbreviation/ 
Term 
Definition 
[11C]PiB  
 [11C]-Pittsburgh Compound B (PiB) amyloid PET imaging tracer 
[18F]AV-1451 
Flortaucipir, a [18F] tau PET imaging tracer, aka T807 
[18F]-FDG 
Fluorodeoxyglucose PET imaging tracer 
[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  
ADAS-Cog 
Alzheimer's Disease Assessment Scale - Cognitive Subscale 
ADCS 
Alzheimer’s Disease Cooperative Study 
ADCS-ADL 
Alzheimer's Disease Co-operative Study - Activities of Daily Living Inventory 
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 


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Abbreviation/ 
Term 
Definition 
ARIA-H 
Amyloid-related imaging abnormality characterized by hemorrhage, including 
microhemorrhage, macrohemorrhage (e.g., lobar hemorrhage) and superficial 
hemosiderin deposits 
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) 
AUCInf 
Area under the concentration – time curve for a drug between time 0 and time 
infinity 
BACE 
β-secretase enzyme 
BP 
Blood pressure 
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 participants 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 
CRI 
Cognitive run-in 
CRP 
C-reactive protein 
CSF 
Cerebrospinal fluid 
CSR 
Clinical Study Report 
C-SSRS 
Columbia suicide severity rating scale 


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Abbreviation/ 
Term 
Definition 
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 
DBSI 
Diffusion basis spectrum imaging 
DCA 
Dominantly Inherited Alzheimer Network Central Archive 
DIAD 
Dominantly inherited Alzheimer’s disease 
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 participants that were randomized to the 
blinded placebo for a specific treatment 
DNA 
Deoxyribonucleic acid 
DSMB 
Data Safety Monitoring Board 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DTI 
Diffusion Tensor Imaging 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EAD 
Early Alzheimer’s disease 
EDC 
Electronic data capture 


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Abbreviation/ 
Term 
Definition 
Eligible DIAN-OBS 
participants 
The group of mutation-positive participants 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 Termination 
EYO 
Estimated years from symptom onset 
FAS 
Functional Assessment Scale (previously Functional Assessment Questionnaire 
[FAQ]) 
fc-MRI 
Functional connectivity MRI 
FCSRT-IR 
Free and Cued Selective Reminding Test-Immediate Recall 
FDA 
Food and Drug Administration 
FLAIR 
Fluid-attention inversion recovery 
GCP 
Good Clinical Practice 
GDS 
Geriatric Depression Scale 
Global Manual of 
Operations 
Manual describing details of DIAN-TU trial operations; see also the arm-specific 
DIAN Trials Unit Cognition Core Procedures Manuals, central laboratory manual, 
MRI Technical Manual, PET Technical Procedures Manual and Pharmacy 
Manual. 
GRE 
Gradient-recalled echo (MRI sequence) 
GUID 
Globally Unique Identifier  
HCLF 
High-concentration liquid formulation 
Hgb 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
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 participant’s home and/or other trial-identified locations.  Home health 
nurses may also complete training to become trial-certified cognitive raters. 


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Abbreviation/ 
Term 
Definition 
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 Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
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 
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 
MAPT 
Microtubule-associated protein tau  
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-) 
MCI 
Mild cognitive impairment 
MCM 
Microhemorrhages 
MDPM 
Multivariate Disease Progression Model 


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Abbreviation/ 
Term 
Definition 
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 Monitors 
The DIAN-TU Medical Director and Project Arm Leaders (PALs) available 24 
hours/7 days a week to serve as first contact for sites regarding medical issues.   
mITT 
Modified intent-to-treat 
MMA 
Methylmalonic acid 
MMRM 
Mixed model for repeated measures 
MMSE 
Mini-Mental State Exam  
MRI Technical 
Manual 
Manual providing specific information on procedures for MRI 
MRI 
Magnetic resonance imaging 
MTBR 
Microtubule binding region 
Mutation positive 
placebos 
Combination of direct placebos and concurrently randomized placebos 
NfL 
Neurofilament light chain 
NFT 
Neurofibrillary tangle 
NONMEM 
A non-linear mixed effects modeling software tool used in population 
pharmacokinetic-pharmacodynamic analysis 
NPC 
Neuropathology Core 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
NYHA 
New York Heart Association  
OLE 
Open-label extension 
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. 
Participant 
An individual who is or becomes a participant in clinical research, either as a 
recipient of the investigational product(s) or as a control.   


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Abbreviation/ 
Term 
Definition 
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 
POCBP 
Person of childbearing potential: A post-menarchal, pre-menopausal person 
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 
amenorrhea1.   
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 
ptau217 
Tau protein phosphorylated at threonine 217 
PT, PTT 
Prothrombin time (PT) and partial thromboplastin time (PTT) are measures of 
blood clotting 
Q2W 
Every two weeks 
Q4W 
Every four weeks 
QC 
Quality control 
QT and QTc 
Period from the beginning of the QRS complex to the end of the T wave on the 
ECG 
QW 
Each week 
RBBB 
Right bundle branch block 
                                                        
1 Post-menarchal, pre-menopausal people who have undergone tubal ligation should have pregnancy testing done 
at all visits as indicated for a person of childbearing potential.   


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Abbreviation/ 
Term 
Definition 
sAD 
Sporadic Alzheimer’s disease 
SAD 
Single ascending dose  
SAE 
Serious adverse event   
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
Study partner 
A person identified by the participant who agrees to accompany the participant 
on annual study visits and is able to provide accurate information as to the 
participant's cognitive and functional abilities to enable completion of scales 
which require informant, and who signs the necessary consent form if 
applicable 
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 
Tg 
Transgenic 
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 
V 
Visit (number) 
vMRI 
Volumetric magnetic resonance imaging 
WAIS-R 
Wechsler Adult Intelligence Scale-Revised  
WMH 
White matter hyperintensities 
WMS-R 
Wechsler Memory Scale-Revised 


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1 INTRODUCTION 
 Background 
This study will recruit participants 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, participants undergo 
longitudinal assessments that include clinical assessment, cognitive testing, magnetic resonance 
imaging (MRI) and amyloid and tau positron emission tomography (PET) imaging, and analysis of 
blood and cerebrospinal fluid (CSF). 
Participants 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 enrolls individuals who are either known to have a disease-causing mutation 
or who are at risk for such a mutation (the descendant 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 study (DIAN-OBS) protocol.  This study will enroll participants 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) and predict the 
age of onset 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 participants in this 
study will not yet have any cognitive symptoms of AD; they will be “asymptomatic” carriers of 
mutations that cause DIAD 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, when allowable in individual drug arms, 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 these participants to avoid coercion (e.g., 
potential participants may be pressured into genetic testing to learn their genetic status in order 
to be eligible for the trial) unless the drug-specific design includes open-label treatment.  These 
mutation negative individuals will be assigned to the placebo group and data will be used to 


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determine normal ranges of outcome measures.  Participants 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 participants 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 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) which may be shared by 
study drug arms.  Mutation positive participants will be assigned to a study drug arm and 
subsequently randomized within that arm to the active drug to placebo ratio specified in each 
drug-specific appendix.  When included in individual drug arms, mutation negative participants 
will all receive placebo treatment.  Participants and study staff will not be blinded as to which 
study drug arm each participant has been assigned; they will be blinded as to whether 
participants have been randomized to active drug or placebo.   
Biomarker, cognitive, and/or clinical 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 other AD biomarker outcomes.  
Interim analyses of the imaging or fluid biomarker endpoint will assess safety and whether each 
study drug engages its biological targets.  The clinical and cognitive assessments are designed to 
assess subtle cognitive changes that may be detectable before the onset of dementia as well as 
cognitive and clinical decline in symptomatic groups.   
After the last participant in a study drug arm completes the 4-year treatment period, 
participants in that study drug arm may be eligible to receive active study drug in an open-label 
extension period (Section 3.9). 
Starting with Amendment 8 of this protocol, a cognitive run-in (CRI) period was implemented to 
allow for enrollment during periods when study drug arms are not randomizing.  This enables 
the DIAN-TU platform to have continuous enrollment during periods before or in-between drug 
arm randomization. 
The CRI period of cognitive, clinical, and imaging data collection was designed as part of the 
platform study to utilize the time in between enrollment of study drug arms for the purposes 
outlined in Section 1.4 of this protocol.  The CRI period was incorporated into the protocol as 
specified in the US NIH NexGen grant, which was reviewed and awarded in August 2017 (US NIH 
Grant R01 AG053267, PI RJ Bateman).  Based on the early discontinuation of the atabecestat 
drug arm in July 2018, the cognitive run-in period was implemented to recruit until the next 
study drug arm is randomizing to drug and placebo.  The CRI period will enhance study 


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enrollment by identifying eligible participants and engaging them with the cognitive assessments 
and can reduce practice effects by allowing participants to habituate to the testing process.  The 
CRI further provides important baseline and run-in data that adds control data to the platform 
and informs about the effects of tested drugs. 
In addition, the CRI period was expanded with Amendment 9 of this protocol to allow for 
inclusion of the DIAD population in the primary prevention stage; further defined in Amendment 
11 as the population from 11 to 25 years before estimated symptom onset (−25 to −11, primary 
prevention population).  The CRI period will provide engagement opportunities for the primary 
prevention population while increasing power and decreasing enrollment timelines for the US 
NIH trial Grant U01 AG059798 (PI EM McDade), which was reviewed and awarded September 
2018. 
The data collected in the CRI period will be used for analysis in the respective drug arm under 
which participants are randomized and treated. 
 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.  Once any specific drug arm is completed, it may be removed 
in subsequent amendments therefore the applicable details can be found in prior versions of the 
protocol.  Refer to the respective Investigator’s Brochures (provided separately) for additional 
information. 
 Rationale for Biomarkers 
More than half of the mutation positive participants 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 to 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 estimated symptom onset in the DIAN cohort.  Fluid and 
imaging biomarkers of amyloid include positron emission tomography (PET) using the amyloid-
binding agent [11C]-Pittsburgh Compound B (PiB) ([11C]PiB-PET) (Mintun, Larossa et al. 2006) and 
cerebrospinal fluid (CSF) levels of amyloid beta peptide 1-42 (Aβ42) (Fagan et al, 2006) and the 
ratio of Aβ42/Aβ40 (Lewczuk et al, 2016).  CSF total tau (Fagan, Head et al. 2009) and 
phosphorylated tau181 (ptau181), have shown early asymptomatic changes in DIAD (Bateman et 
al., 2012,  et al, 2020) and when combined with Aβ42 can predict cognitive decline (Fagan, et al. 
2007; Schindler et al., 2017). 
Studies in individuals who carry a mutation linked to early onset AD suggest that these 
biomarker changes are detectable 20 or more years before the anticipated time of disease onset 
(Figure 1) (Bateman, Xiong et al. 2012; Portelius, Fortea et al. 2012; Ringman, Coppola et al. 


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2012).  Data from the DIAN-OBS study suggests that changes in biomarkers begin with [11C]PiB-
PET measures of amyloid burden in the precuneus (Figure 1) followed by changes in CSF total 
tau, FDG-PET, and cerebral atrophy before clinical decline (Bateman, Xiong et al. 2012). 
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. 
 
Neurofilament light chain (NfL) is an 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 


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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 
Human Immunodeficiency Virus (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 PET visualization 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 signal 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 amyloid PET have poorer 
performance on episodic memory testing and are more likely to experience cognitive decline 
(Doraiswamy, Sperling et al. 2012; Sperling, Johnson et al. 2012).   
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 due 
to AD, with higher levels observed in individuals 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 in the DIAN Observational (DIAN-OBS) study support this idea 
(Bateman, Xiong et al. 2012; Benzinger, Blazey et al. 2013; Fagan, Xiong et al. 2014).  This 
understanding of sequential changes in tau biomarkers identifying tau stages in DIAD, and a 
four-fold higher change in tau PET signal in DIAD compared to sporadic AD among symptomatic 
participants, has greatly improved the potential to detect drug effects in DIAD (Barthélemy et 
al., 2020, Gordon et al., 2019). 
Tau pathology in the brain correlates more closely with clinical status and dementia in AD than 
amyloid plaques, atrophy, or glucose metabolism (Ossenkoppele et al., 2016).  Tau aggregation 
correlates with onset, progression, and neurologic type and has large significant increases in 
DIAD relative to healthy normal individuals.  Recent evidence demonstrates that tau 


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pathophysiology evolves through distinct phases in DIAD (Barthélemy et al., 2020), suggesting 
three sequential phases in biomarker-based models of AD progression as depicted in Figure 2: 1) 
amyloid accumulation triggers initiation of tau pathophysiology including phosphorylation of 
soluble tau; 2) soluble tau increases beginning 10-20 years before onset of clinical symptoms 
based on increases in CSF phosphorylated-tau (soluble tau phase); and 3) tangle spread begins 
concurrently with clinical symptom onset based on tau PET (tau aggregation phase) (Gordon et 
al., 2019).  The dynamic and diverging patterns of soluble and aggregated tau first begin in close 
relationship with amyloid pathology with soluble phosphorylation at specific tau sites and 
sequentially change over the course of the disease (Barthélemy et al., 2020). 
Figure 2 
Stages of Tau Pathology and Potential Mechanisms to Target Tau  
 
Tau pathophysiology evolves through distinct phases in DIAD.  Tau sequentially changes by stage of disease.  Starting with the development 
of fibrillar amyloid pathology, levels of phosphorylation of pT217 (purple) and pT181 (blue) begin to increase.  Then, with the increase in 
neuronal dysfunction (decreased cortical metabolism), levels of pT205 (green) begin to increase, along with soluble t-tau (orange).  Lastly, 
with the onset of neurodegeneration (based on cortical atrophy and clinical decline), tau-PET tangles (red) begin to develop, while pT217 and 
pT181 phosphorylation ratios decrease. 
Source:  Barthélemy et al., 2020 
The imaging and CSF biomarkers measure different aspects of the AD pathogenic cascade and 
are correlated with underlying brain pathology.  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; Mintun, Larossa et al. 2006; Klein et al. 2021).     
The DIAN-TU-001 trial provides an opportunity to investigate the potential for tau imaging to 
enhance basic understanding of the evolution of tau pathology during the AD disease process, to 


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understand the relationship between tau imaging and tau measurements in CSF and may 
support a role for tau imaging as a new surrogate biomarker in interventional studies. 
The CRI period and future tau NexGen drug arms in the trial platform will use the PET tracer, 
[18F]MK-6240 (an [18F] tau imaging agent, Cerveau Technologies), that has high affinity for the 
human phosphorylated tau deposits in AD brain (Hostetler, Walji et al. 2016, Lohith, Bennacef et 
al. 2016, Walji, Hostetler et al. 2016, Lohith, Bennacef et al. 2017, Neelamegam, Yokell et al. 
2017). The inclusion of tau PET imaging will be limited to participants between −10 to +10 years 
of their estimated years to symptom onset (secondary prevention population) and will provide 
important data for the longitudinal evolution of tau pathology during the AD disease process, 
and the relationship of Aβ and tau in disease pathophysiology.  Tau imaging during the CRI 
period will help assess the rate of change in tau pathology in untreated participants, enable 
appropriate designs of tau-based therapeutics, and provide longitudinal run-in control data to 
be compared during the randomization period of the study.  Tau imaging at the end of the CRI 
period and during the course of the subsequent treatment period will help assess long-term 
effects of potentially disease modifying drugs and the rate of change in tau pathology in both 
treated and untreated (placebo group) participants. 
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;  Barthélemy 2020; Mattsson et all, 2020) 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). 
Antibodies targeting amyloid plaques have impacted the removal of plaques and showed some 
change in other biomarkers.  For example, an OLE of gantenerumab in sporadic AD, with 
treatment over 36 months after starting up-titration substantially lowered PiB-PET to below the 
level of amyloid positivity (Klein et al. 2021).  A number of other compounds have also shown 
effects on these biomarkers (Knopman DS, 2021; Mintun MA, 2021; Salloway S, 2021; Swanson 
CJ, 2021). 
These studies 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 


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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).   
 Rationale for Cognitive Run-in Assessments 
A CRI period may be opened to enrollment prior to randomization into study drug arms added to 
the platform trial.  Run-in periods have several practical advantages, including increasing 
engagement of participants, establishing rapport with site personnel and personnel for home 
visits (if applicable), and familiarization of participants with the processes and procedures of the 
trial (Schechtman et al., 1993; Pablos-Méndez, et al., 1998).  One of the most important 
scientific advantages is a decrease in variability in cognitive test performance.  Most participants 
are unfamiliar with the cognitive testing process and some may be anxious during cognitive 
testing.  Scores from measures acquired during their first exposure to the testing process can 
therefore be influenced by random and systematic within-person variability.  For example, daily 
variability in sleep quality, fatigue from traveling to a DIAN-TU performance site, or a recent 
exposure to a stressful event can introduce random variability to assessments.  There may also 
be other factors introduced into cognitive testing that may contribute to variability.  Practice 
effects refer to increases in cognitive scores that appear upon retesting as participants become 
familiar with the test content, the testing environment, and test concepts and strategies.  
Typically, these practice effects peak after two to three exposures to test stimuli and diminish 
with further retesting (Hassenstab et al., 2015; Ivnik et al. 2000).  There may be additional 
variability in test performance due to demand characteristics (the perceived expectation by 
participants to perform in a certain way to “please” the examiner) or to factors that influence so-
called “white-coat” hypertension, where performance may be affected by anxiety about 
undergoing testing and “exposing” latent cognitive deficits that many participants from DIAD 
families are highly concerned about.  The combined effect of high variability on cognitive 
performance may impact reliability in cognitive outcomes.  A CRI period can reduce the effects 
of temporal fluctuations in performance by allowing participants to habituate to the testing 
process, thereby reducing practice effects, demand characteristics and test anxiety.  Moreover, 
results from clinical trials testing the β-secretase enzyme (BACE) inhibitors in those with and at 
risk for AD have identified evidence of an unanticipated cognitive impairment (Novak, et al., 
2020).  A CRI period will also offer the opportunity to more easily detect a deleterious drug 
effect by establishing a reliable baseline in participants where the majority are cognitively 
normal at trial entry.  This is particularly important for those participants that are much younger 
than their estimated age of onset where a decline in cognition would represent a significant 
deviation from the expected performance.  The CRI period could help identify potential 
deleterious side effects of therapies at an earlier point and reacting appropriately. 


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Since the launch of the DIAN-TU-001 study there have been significant advancements in the 
development of tau PET imaging tracers, including the development of multiple tracers with 
different properties.  Given the recent introduction of [18F]MK-6240 into the DIAN-TU program, 
there remains some uncertainty relative to the characteristics of earliest detectable levels and 
the longitudinal change in this tau PET tracer across the different clinical stages of disease.  
Therefore, the CRI period provides the opportunity to establish a better understanding of the 
baseline and longitudinal changes of [18F]MK-6240 in the DIAD population and further inform 
the power estimates for future NexGen study arms in the platform.  It also provides improved 
power to detect drug effect changes on tau PET measures of NFT accumulation.  
Recent technological advancements in mass spectrometry have led to increased sensitivity and 
precision for the longitudinal detection of AD biomarkers in plasma. The pathological cascade of 
events begins with altered CSF and plasma Aβ42/Aβ40 ratio in the preclinical phase of disease.  
Studies of phosphorylated tau species (e.g., pT217, pT181) in CSF and plasma have 
demonstrated a strong temporal correlation with Aβ plaque formation, suggesting that certain 
secondary p-tau measures may also provide information on prevention of Aβ 
aggregation/accumulation (Barthélemy, et al., 2020). Blood collection in the CRI period provides 
an opportunity to determine how early in the pathological cascade changes in Aβ, tau, p-tau and 
MTBR species can be detected and learn more of their predictive capacity of disease onset 
and/or stage.   
 Rationale for Open-label Extension 
In dominantly inherited Alzheimer’s disease, participants who carry the disease-associated 
mutation will ultimately develop dementia unless disease modification occurs.  This trial is 
testing the hypothesis that the study drugs can change the course of disease progression and 
delay or prevent dementia.  If the trial demonstrates an intervention has potential clinical 
benefit and is reasonably safe, an open-label extension for mutation carriers provides the 
potential for benefit to participants and the opportunity to determine long term effects and 
assess disease modification.  Thus, at the end of the double-blind treatment period, participants 
may have the opportunity to receive active drug with appropriate safety monitoring; details are 
provided in Section 3.9. 
2 STUDY OBJECTIVE 
To assess the safety, tolerability, biomarker, cognitive, and clinical efficacy of investigational 
products in participants with an Alzheimer’s disease-causing mutation by determining if 
treatment with the study drug improves disease-related biomarkers and slows the rate of 
progression of cognitive or clinical impairment. 


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3 STUDY DESIGN 
 Overall Design 
This is a Phase II/III multicenter randomized, double-blind placebo-controlled, platform trial of 
potential disease modifying therapies utilizing biomarker, cognitive, and clinical endpoints, in 
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 10 years younger (−10) up 
to 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. 
In drug arms not requiring genetic disclosure for inclusion, some participants in this study 
choose to remain blinded to their genetic status (where permitted in the study drug arm(s) 
design) which may be due to concerns of the impact on their mental well-being, financial, 
insurance and other life factors.  These participants and study staff will remain blinded to their 
genetic status throughout the study.  Mutation negative participants will not receive active 
study drug, but in order to maintain blinding as to genetic status, mutation negative participants 
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 participants will not be included in the primary efficacy or 
futility analyses.  These participants will provide valuable biomarker data that will be useful for 
future studies in both DIAD and sporadic DAT.  Mutation positive participants will be randomized 
into actively enrolling study drug arms and within a study drug arm the participant will be 
randomized at a ratio specified in each drug-specific appendix.  Therefore, both mutation 
positive and negative participants 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.  Participants and study staff will be blinded as to 
whether participants are on active drug or placebo but will not be blinded as to the treatment 
route and interval.   
This is an adaptive platform-based study, with flexibility to add new investigational products to 
the protocol, allowing participants to be randomized to study drug arms open to enrollment, 
and for the study to maintain a cohort of trial ready participants with or at risk for DIAD 
mutations.  Data from the platform’s placebo drug arms will continue to be utilized by 
subsequent drug arms as control data, in addition to the DIAN-OBS matched control data.  


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Figure 3  
DIAN-TU-001 Master Protocol AD Prevention Platform Design 
 
The first two drug arms tested in the platform were the gantenerumab and solanezumab study 
drug arms, with each enrolled participant randomized to active drug or the corresponding 
placebo (“direct placebo”).  The double-blind periods concluded for both drug arms with an 
open-label extension (OLE) of gantenerumab opened to any of the participants enrolled in either 
of the double-blind drug arms.  Changes, such as to the enrollment criteria (e.g., the EYO range 
for inclusion), may be made based on the specific therapeutic compounds being tested and the 
stage of disease that is most likely to be targeted by a therapy.  Results from the completed 
solanezumab and gantenerumab arms in DIAN-TU-001, which included an EYO range of −15 to 
+10, found that close to 30% of participants at an EYO range of −15 to −10 had very low amyloid 
PET levels, and thus had minimal to no detectable tau pathology.  Therefore, the change to the 
EYO entry criteria for CRI and future tau-based therapeutics to −10 to +10 in Amendment 11 will 
increase the likelihood of participants having some tau-related changes that can be measured 
during the double-blind period of the trial.  The third drug arm added to the platform was the 
atabecestat arm which was prematurely discontinued due to safety (Novak, G, et al. 2020).  For 
further information relevant to the completed testing periods of these study drug arms, see 
earlier version(s) of the protocol.  
Additional study drug arms will continue to follow the same core procedures for measuring 
biomarker, cognitive, and clinical measurements, thereby allowing continued sharing/pooling of 
placebo data across study drug arms.   
Starting with Amendment 8, a CRI period was opened for recruitment and enabled for future 
drug arms.  With Amendment 9, the CRI period was expanded to include 2 participant 


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populations; the original population of participants within −15 to +10 years of the predicted or 
actual age at cognitive symptom onset (secondary prevention population) and a younger 
primary prevention population 18 years of age or older that are younger than −15 years from 
estimated cognitive symptom onset and CDR 0 (primary prevention population).  Amendment 11 
refines the primary and secondary prevention populations to −25 to −11, and −10 to +10, 
respectively.  CRI participants must have a minimum of 8 weeks between the participant’s last 
administration of a complete cognitive battery during the CRI period and administration of the 
baseline (V2) complete cognitive battery.  The CRI period will continue until a study drug arm is 
opened for randomization, but no longer than approximately 3 years. Amendment 13 extends 
the duration of CRI up to 3 years. Participants having completed 2 years in CRI before 
Amendment 13 approval may be reconsented once approved for Amendment 13; participants 
should resume their study visits based on their original CRI Entry date. 
The platform is designed to test drugs’ engagement of its respective targeted biomarker (phase 
II period) and those successful in engaging their biomarker target will continue to a clinical 
and/or cognitive outcome (phase III period).  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 and/or cognitive endpoints.  
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.  
 Rationale for Study Design 
Two unusual features of this study population influenced the study design: 1) maintaining the 
blind to mutation status, and 2) participant burden.  First, many individuals who are at risk for 
dominantly inherited Alzheimer’s disease do not want to know their mutation status.  The study 
design has allowed for enrollment of these individuals as it permits participants and study staff 
to remain blinded to mutation status.  Mutation negative participants will not be exposed to 
active study drug.  However, for each additional drug arm, requirements for participants to 
know their mutation status may change based on the design (i.e. a drug arm may require a drug 
treatment for all participants as part of the protocol, such as in a combination therapy 
approach).  Mutation positive participants 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 


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with fewer total participants and allows more than 50% to be on an active drug, a feature often 
requested by potential research participants.   
Second, families with mutations linked to DIAD are rare and participants typically live at a 
significant distance from DIAN-TU sites.  Because participants typically work and have family 
responsibilities, there is increased burden of travel and time spent on study activities; however,  
a high level of participant retention is essential for the success of the study. Therefore, 
participants 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 Good Clinical 
Practice (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 participant’s host DIAN-TU site or a trial-identified location qualified for the study 
near the participant’s home.  For all study drug arms, the annual MRI session will be performed 
at a DIAN-TU site. 
Further, this platform study design 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 
participants could be randomized to the actively enrolling study drug arms or a CRI period may 
open for recruitment.  
A more traditional study design with separate biomarker and cognitive endpoints would be 
extremely difficult in this cohort for two reasons:  1) The participant 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 an asymptomatic cohort.  The inclusion of these cognitively normal participants is 
very important, as they may be most likely to benefit from disease-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 participants enrolled.  One 
method to improve the power to detect treatment effects is to include additional control 
participants.  The DIAN Observational study (DIAN-OBS) has been following nearly the same 
protocol as DIAN-TU-001 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 a significant 
proportion of the participants to the DIAN-TU-001, data will continue to be used from DIAN-
OBS participants who meet the inclusion criteria for DIAN-TU-001 to track disease progression, 
regardless of the specific therapy being tested.  The DIAN-OBS data will be used as additional 
control participants and will be utilized as a control group to improve power. 
Cognitive Run-in Period to Establish Trial-Ready Cohort 
A CRI period may be opened prior to randomization into drug arms added to the platform trial.  
To determine the potential benefits for statistical power, a detailed simulation analyses was 


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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). 
The CRI period will also allow participants that do not currently qualify for DIAN-TU-001 studies 
(e.g., more than 10 years younger [> −10] than estimated years at symptom onset) to 
contribute to the understanding of patterns of cognition at the earliest stages of the disease 
providing scientific contributions.  With the development of primary prevention studies in 
DIAN-TU (US NIH Grant U01AG059798, PI EM McDade), defined as studies in a population at 
risk for DIAD but known to be mostly free of any detectable pathology at trial entry, there is a 
strong interest in establishing a trial ready cohort to accelerate recruitment into the 
therapeutic trial once launched.  Furthermore, it also allows at-risk persons that have not yet 
participated in the DIAN network to experience one component of the clinical trial process.  
This can help to identify those participants unlikely to be able to stay in a long prevention trial if 
they are able to start CRI but not continue.  These latter two considerations help with trial 
efficiency. 
For further rationale, see Section 1.4. 
 Number of Participants 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 participants is with baseline CDR 0 to 1 (inclusive).  Mutation 
positive groups (active vs. placebo) will be enrolled to meet the respective enrollment numbers 
of asymptomatic (CDR 0) and symptomatic (CDR > 0) participants. 
For the gantenerumab and solanezumab arms, a total of 193 participants were enrolled into the 
double-blind period (144 mutation carriers and 49 mutation non-carriers) with 52 mutation 
carriers on active gantenerumab, 52 mutation carriers on active solanezumab, and 40 mutation 
carriers in the pooled placebo arm. 
The CRI period may recruit up to 740 participants during any time where a drug arm is not 
actively randomizing to meet the enrollment required for the three tau-targeted drug arms 
slated for secondary prevention enrollment (Tau NexGen) and the drug arm(s) slated for primary 
prevention.  Up to 500 participants between 10 years younger than their estimated years to 
symptom onset (EYO) and 10 years after estimated symptom onset (−10 and + 10 EYO) may be 


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enrolled in the CRI period if no study drug arm is available for immediate enrollment into DIAN-
TU-001, or if a future study drug arm is stopped prior to the planned completion (e.g., at 
biomarker interim, drug toxicity), to ensure that a sufficient number of active and eligible 
participants qualify for entry into a drug arm once opened for randomization.  In addition, up to 
240 participants may be enrolled in the CRI period to establish a trial-ready cohort of 
participants who are 11 to 25 years younger than their estimated symptom onset (EYO −25 to 
−11) and are at least 18 years old and cognitively normal (CDR 0) (primary prevention 
population). 
See drug specific appendices for specific enrollment numbers of participants.  The number of 
DIAN-TU sites is estimated to be approximately 40 sites globally.  The CRI Entry visit, baseline 
study visit (V2) and annual visits for the CRI period and/or 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 participant’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 participants 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 (Section 6.1.16). 
 Participant Enrollment and Randomization 
Participants will be recruited from or may be referred to a DIAN-TU site for screening.  The 
complexity of the study and the likelihood that many participants 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. 
The participant’s personal information will be used to create the Globally Unique Identifier 
(GUID), which consists of random characters.  Once the GUID is created, qualified researchers 
can use it to link an individual’s research data across studies, including DIAN-OBS, DIAN-EXR and 
future studies, without using identifying personal information.  
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 main ICF will provide information on the route of administration, 
potential side effects associated with drugs that target Aβ or tau, and study procedures.  The 
ICF will explain that participants will be assigned randomly to an eligible study drug arm and if 
more than one of the study drug arms is recruiting simultaneously, they will not be able to 


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choose a specific study drug arm.  If only one drug is enrolling, one ICF may be utilized.  Local 
regulations and ethics committee requirements must be followed and may require alternate 
consent structure and/or practices.  
For participants enrolling into the CRI period, an ICF specific to the CRI period will be used.  The 
CRI ICF will provide detailed information on study design, duration, number and timing of visits, 
procedures, and potential side effects associated with drugs that target amyloid-beta or tau, 
and intent for participants to enroll in a study drug arm when one becomes available.  It will 
also include the main requirements of future potential drug arm(s) (e.g., duration and 
frequency of procedures).  The CRI ICF will explain that participants who continue to meet 
eligibility criteria may be randomized to a study drug arm once a drug arm is open.  The ICF 
should be clear that there is the potential to be excluded from the study drug arm if any entry 
criteria are not met, and it is in the best interest of the participant not to participate.  
Participants will be re-consented prior to randomization to a study drug arm. 
Participants (and their legally authorized representative if the participant is cognitively 
impaired) will review the ICF and discuss with study staff on the phone or in-person.  The 
participant 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 participant 
will be assigned a unique study number and screening visit (V1) procedures will be completed 
either in the participant’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 to 8 weeks after completion of the screening visit procedures, and 
no earlier than 6 weeks after the genetics blood collection, unless the participant enrolled in 
CRI and genetic testing was completed.  After all baseline measures have been completed, and 
adherence to inclusion and exclusion criteria has been verified, the participant will be 
randomized to a study drug arm via the Interactive Web Response System (IWRS).  The 
participant and study staff at the site will know which study drug arm the participant was 
assigned but will not know whether the participant was assigned to active drug or placebo.  If 
more than one study drug arm is enrolling participants, the participant 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. 
Participants will receive their first dose of study drug after all visit procedures have been 
completed and the participant has been randomized and/or assigned treatment per the IWRS.  
If a participant 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 participant randomization in each drug-specific appendix. 


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If enrolling into the CRI period, after informed consent is obtained, each participant will be 
assigned a unique study number and CRI screening visit (CRI Screen) procedures will be 
completed in the participant’s home, other trial-identified satellite site, or at the DIAN-TU site.  
Once a new study drug arm(s) is open, participants will have a screening visit (V1) conducted 
either in their home by a home health nurse, or at the DIAN-TU site to collect safety labs and to 
reassess the suitability of the participant for entry into the new study drug arm(s). 
If enrolling into an OLE period, a separate consent will be obtained, which will be available at 
the time of OLE enrollment. 
 Measured Study Endpoints 
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 designation of primary, secondary, and exploratory endpoints are 
also specific for each drug and are listed in the drug-specific appendices and/or drug-specific 
SAP appendices.   
Note – measures and endpoints for completed drug arms can be found in prior protocol 
amendments and SAPs; the gantenerumab open label extension endpoints are in Appendix 3.  
The E2814 measures and endpoints with concurrent lecanemab treatment are in Appendix 4. 
Additional outcome measures include comparisons between each drug and placebos and 
eligible DIAN-OBS participants for measures listed below if/as specified in the drug-specific SAP 
appendix.  
Clinical Measures 
Clinical measures to be obtained at the CRI Entry, baseline (V2), and annual visits for both the 
CRI period and treatment periods will be administered at a 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)*  
*In addition, the MMSE will be administered at the site or via home visits for secondary 
prevention population only by a DIAN-TU certified rater at the 26-week visit in between the 
annual visits, as specified in the CRI and drug-specific appendices. 
Cognitive Measures 
Cognitive batteries are defined in respective arm-specific appendices.  Refer to the arm-specific 
DIAN Trials Unit Cognition Core Procedures Manuals for additional information.  Refer to prior 


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amendments for details on the cognitive battery administered in completed or closed drug arm 
periods. 
Cognitive Battery for Gantenerumab Open-Label Extension Period 
Cognitive measures collected in gantenerumab and solanezumab double-blind period, and 
continued into the gantenerumab open-label extension (OLE) period, are listed below and 
include the iPad-administered and conventional cognitive (pen/paper) tests.  Refer to Section 
6.1.14.1 for the frequency of the assessments in the gantenerumab OLE and the drug-specific 
appendix (Appendix 3) for detailed visit numbers and timing.  Testing is administered at a DIAN-
TU site and/or via home health nurse certified raters.    
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)  
• Cogstate Detection Task 
• Cogstate Identification Task 
• Cogstate One Card Learning Test 
• Cogstate One-Back Task 
• Behavioral Pattern Separation Object Task 
• Memory Complaint Questionnaire (MAC-Q) 
Conventional Cognitive Testing (Pen/Paper):  
• Trailmaking Test parts A & B 
• Wechsler Memory Scale-Revised (WMS-R) Digit Spatial Span Forward and Backward 
• Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit-Symbol Substitution Test 
• Raven’s Progressive Matrices (Set A) 
• Category Fluency (Animals & Vegetables) 
• WMS-R Logical Memory/Paragraph Memory (Immediate & Delayed Recall) 
DIAN-TU Harmonized Cognitive Battery for Cognitive Run-In (CRI) Period and Tau Drug Arms 
Cognitive measures collected in the CRI period and tau drug arms are administered at regular 
intervals as directed in the arm-specific appendix by a trial-certified cognitive rater, at either a 
DIAN-TU site or via home health nurse, and include the below cognitive battery harmonized 
with the DIAN Observational (DIAN-OBS) study and primary prevention treatment protocol 
(DIAN-TU-002).  Refer to the CRI appendix (Appendix 1) and E2814 appendix (Appendix 4) for 
detailed visit numbers and timing.  
• MAC-Q 
• Buschke and Grober Free and Cued Selective Reminding Test-Immediate Recall (FCSRT-
IR) 


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• WMS-R Logical Memory/Paragraph Memory (Immediate & Delayed Recall), Alternate 
Paragraph for Logical Memory I & II – Version A (Immediate and Delayed) and Alternate 
Paragraph for Logical Memory I & II – Version B (Immediate and Delayed) 
• Category Fluency (Animals) 
• WAIS-R Digit-Symbol Substitution Test 
• Trailmaking Test Parts A & B 
• WMS-R Digit Spatial Span Forward and Backward) 
  
Smartphone-based cognitive assessments will be administered to participants in the CRI period 
and/or randomized to an enrolling study drug arm using a mobile phone application, 
Ambulatory Research in Cognition (ARC).  These tests will include measures of episodic 
memory, attentional control, and processing speed.  These assessments will be self-
administered by the participants on their personal smartphones.  If participants do not own a 
smartphone or their device does not meet minimum specifications, a study phone will be 
provided. 
Compliance with the smartphone-based cognitive measures is considered exploratory and non-
participation will not be considered reason for discontinuation in the study and will not be 
considered protocol deviations.  Based on operational and regulatory considerations, the study 
sponsor will determine which sites will administer smartphone-based cognitive assessments, 
with the explicit goal of full site participation. 
Participants will complete ARC assessments at regular intervals as specified in the drug-specific 
appendix. 
Imaging Biomarker Measures:  
The following imaging endpoints may be assessed in any period or study drug arm, as specified 
in the protocol appendices.  Refer to the final drug-specific SAP appendix for differentiation of 
endpoint classification based on the respective drug’s target and mechanism of action. 
• Amyloid load based on imaging with [11C]PiB-PET 
• FDG-PET metabolism  
• Change in Tau PET measures of neurofibrillary tangle (NFT) burden 
• Clinical MRI features such as microhemorrhages (MCH), white matter hyperintensities 
(WMH), cerebral infarction, and amyloid-related imaging abnormality (ARIA). 
• Functional Connectivity MRI measures (fc-MRI) 
• Diffusion Tensor Imaging (DTI) MRI, including diffusion basis spectrum imaging (DBSI) 
• Blood flow measures by Arterial Spin Labeling (ASL) MRI 
• Brain atrophy as measured by structural MRI (volumetric MRI) 
• Novel MRI quantitation techniques of neurodegeneration or AD 
• Novel PET quantitation techniques of neurodegeneration or AD 
 


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Fluid Biomarker Measures: 
The following biomarker endpoints may be assessed in any period or study drug arm, as 
specified in the protocol appendices.  Refer to the final drug-specific SAP appendix for 
differentiation of endpoint classification based on the respective drug’s target and mechanism 
of action. 
• CSF amyloid-beta species 
• CSF tau species (including ptau) 
• CSF NfL and measures of neurodegeneration 
• Blood amyloid-beta species 
• Blood tau species (including ptau) 
• Blood NfL and measures of neurodegeneration 
• Other CSF biomarkers of AD 
• Other blood biomarkers of AD 
Additional Measures: 
• Genetic, epigenetic, or genomic analyses of co-factors for rate of progression and response 
to treatment.   
• Additional genetic analyses that may be done include whole genome sequencing, RNA 
transcripts (cells and extracellular vesicles), bulk RNAseq, and single cell RNAseq 
• Other drug-specific biomarkers, as specified in each drug-specific appendix 
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. 
 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) measures are a safety endpoint in studies of 
amyloid removing drugs.  Based on the assigned study drug arm, periodic MRI scans may 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 
areas of edema (ARIA-E) will be monitored at entry and throughout the trial.  Incidence of ARIA 
and comparison to placebo will be made. 


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A report of new ARIA changes in a participant 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 participant or caregiver to assess for any symptoms associated with 
the changes and discussion with the central readers.  The PAL, as a site independent clinician, 
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 (Appendix 3 for gantenerumab and Appendix 4 for E2814). 
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 7.10 and the DSMB charter for additional information. 
 Study Schedule 
The schedule of visits, including drug-specific tests and frequency for each drug, is provided in 
each appendix.   
 Total Study Duration and Duration of Treatment 
The total study duration depends on the time in CRI, the duration of each drug arm, and any 
extensions or OLE for the associated drug arm.  For drug arms utilizing a common-close design, 
the treatment duration of each study drug arm may vary depending on the duration of 
enrollment 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. 
Participants in double-blind periods will continue to receive blinded treatment until the last 
participant enrolled completes the randomized period of treatment or withdraws (“common 
close”).  Based on the time required for full recruitment, the total duration may vary from 48 to 
80 months.  For example, participants enrolled in the first month may receive treatment for 
approximately 72 months (if recruitment takes 24 months + 48 months of treatment); for those 
enrolled in the last month, the duration of treatment would be 48 months. 


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If the CRI period is open to enrollment, a CRI period may last until a study drug arm opens for 
randomization, but no longer than approximately 3 years.  If a participant is participating in a 
CRI period, a minimum of 8 weeks must elapse between the participant’s last administration of 
the cognitive battery during the CRI period and administration of the baseline (V2) cognitive 
battery of a treatment arm. 
Once a decision is made for an OLE of a study drug arm, participants may be eligible to continue 
or start treatment in an open-label extension period (Section 3.9) if the study drug arm 
demonstrates potential clinical or cognitive benefit. 
Details regarding study duration and duration of treatment are described in the CRI and drug-
specific appendices in Appendix 1, Appendix 3, and Appendix 4. 
 Open-label Extension 
Upon completion of the double-blind treatment period for each study drug arm (i.e., last 
enrolled participant has completed), an open-label extension (OLE) period may be initiated for 
drugs that demonstrate a potential for clinical benefit, with approval from the sponsor.  In the 
OLE period, participants may be eligible to receive active study drug for an additional treatment 
period as specified in the drug-specific appendices. 
Only DIAD mutation positive participants will be eligible for an OLE period; mutation negative 
participants (non-carriers) will be excluded.  Participants who do not want to know their 
mutation status will not be eligible.  Further details are outlined in Section 6.3.6.  Participants 
are encouraged to proceed with genetic counseling, at a minimum, in preparation for disclosure 
of DIAD mutations, before the end of the double-blind treatment phase to enable more rapid 
entry into the OLE.  Consent forms for OLE periods will be available towards the timeframe 
when an OLE is planned to commence. 
All OLE participants and study sites will be kept blinded to prior drug assignment until the end 
of the OLE period to protect study integrity. 
For drug arms that demonstrate potential for clinical benefit, participants from a concurrent 
negative drug arm(s) may have the option of enrolling into an open OLE period after the drug-
specific washout period from their last double-blind dose. 
Participants entering the OLE will follow the drug-specific schedule of visits for the OLE in each 
drug-specific appendix. 
Access to study drug may be terminated if any of the following occur: a) the study drug arm is 
terminated due to lack of efficacy and/or safety concerns; b) the medication is commercially 
available in the country where the participant lives, i.e., the participant can obtain medication 
from a government sponsored or private health program; or c) therapeutic alternatives become 
available in the local market.  Furthermore, the sponsor can terminate the OLE at any time for 
any reason. 


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4 STUDY POPULATION AND SITES 
It is anticipated that participants eligible for the CRI period will also meet entry criteria at 
baseline (V2).  However, it is possible that a participant enrolled in the CRI period will not meet 
entry criteria at baseline (V2).  Any entry criteria for which the participant no longer qualifies 
for at baseline (V2) will be assessed and reviewed by the DIAN-TU Medical Director to 
determine if entry into a study drug arm is appropriate.  
The following inclusion and exclusion criteria do not apply to OLE periods; eligibility criteria for 
OLE period are presented in the respective drug-specific appendices (e.g. in Appendix 3 for 
gantenerumab). 
 Inclusion Criteria 
A participant may be included in the CRI period or double-blind periods active as of this 
amendment if the following Inclusion Criteria are met: 
1. Written informed consent is signed and dated by the participant, study partner (if 
applicable) and/or by the participant’s legally authorized representative according to 
local regulations for the core trial ICF and, if applicable, the CRI ICF and/or the drug-
specific ICFs. 
2. Participant is 18 to 80 years of age (inclusive). 
3. People of childbearing potential (POCBP), if partner is not sterilized, must agree to use 
highly effective contraceptive measures (e.g., hormonal contraception, intra-uterine 
device, sexual abstinence, vasectomized partner) from screening (V1) until five (5) half-
lives after last dose of any study drug. Refer to the Global Manual of Operations for 
acceptable methods of contraception. 
4. Mutation status (must fulfill criteria a or b, based on estimated years from symptom 
onset [EYO]): 
a. −10 to +10 EYO (secondary prevention population): 
i. 
Participant is a carrier2 of a mutation in PSEN1, APP or PSEN2 gene that is 
associated with dominantly inherited Alzheimer’s disease3 OR, when allowed 
for individual arms, at 50% risk for such a mutation (e.g., does not know their 
                                                        
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 participant.  Participants 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 
participant.  Note that participants 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 participant’s family is on the 
current mutation list.   


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mutation status AND is a child or sibling of known mutation carrier).  Note: 
Participants who are aware that they are mutation negative are not eligible for 
enrollment. 
ii. 
Participant is within −10 to +10 years (inclusive) of the predicted (parental or 
mutation) or actual (participant) age at cognitive symptom onset.  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. −25 to −11 EYO (primary prevention population):  
i. 
Participant is a carrier2 of a mutation in PSEN1, APP or PSEN2 gene that is 
associated with dominantly inherited Alzheimer’s disease3 OR does not know 
their mutation status AND there is a mutation in their family pedigree) 
ii. 
Participant is between −25 to −11 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). 
Note: If the at-risk parent is deemed a non-carrier at any time during the study, the 
participant will be withdrawn 
5. Cognitive status must fulfill criteria a or b, based on EYO: 
a. −10 to +10 EYO (secondary prevention population): Cognitively normal or with mild 
cognitive impairment or mild dementia, CDR 0 to 1 (inclusive).   
b. −25 to −11 EYO (primary prevention population): Cognitively normal (CDR 0). 
6. Fluency in DIAN-TU trial approved language and evidence of adequate premorbid 
intellectual functioning.  Participants must be fluent in languages for which cognitive 
and clinical measures have been translated and validated for use in the DIAN-TU. 
Fluency is generally defined as daily or frequent functional use of a language generally 
from birth or a young age.  In cultures where multiple languages are spoken or for 
participants who are multilingual, determination as to whether a participant’s level of 
fluency in languages for which clinical and cognitive measures are available meets 
qualification for the study should be made by the site principal investigator.   
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 CRI Entry visit and 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: 


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a. The participant has been taking these medications for at least 90 days prior to CRI 
Entry visit and baseline visit (V2) and has been on a stable dose for at least 2 months 
(60 days) prior to CRI Entry visit and baseline visit (V2). 
b. The participant is free of any clinically important side effects attributable to the 
drug.  Side effects that are intermittent, stable or well-tolerated by the participant 
are not exclusionary. 
9. Has a study partner who in the investigator's judgment is able to provide accurate 
information as to the participant'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.  Donation of blood or blood products for transfusion is allowed during the 
CRI period. 
11. In the opinion of the investigator, the participant will be compliant and have a high 
probability of completing the study. 
12. Willing to complete all study-related testing, evaluations, and procedures. 
 Exclusion Criteria 
A participant will be excluded from the double-blind period if any of the following Exclusion 
Criteria are met.  Refer to the drug-specific appendix for any additional drug-specific exclusion 
criteria outlined in the baseline visit (V2) assessments.    
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 participant’s ability to complete the 
study.  This may include clinically significant disorders such as: recent or severe head 
trauma causing cognitive change, uncontrolled seizure disorder, non-AD 
neurodegenerative disease, hydrocephalus, cerebral/spinal hematoma, 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 participant’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. 


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2. At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 
months, current major depression (as defined in DSM-V), or increased suicide risk based 
on CRI Entry visit 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 required anticoagulation, documented 
transient ischemic attack [TIA] in the last 12 months).  Low dose aspirin (≤ 325 mg daily) 
is not exclusionary. 
4. Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past 1 
year. 
Imaging-related Exclusion Criteria: 
5. History of brain MRI scan indicative of any other significant abnormality, 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.      
Note:  For participants 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 CRI Screen or screening (V1) and CRI Entry or 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. For male participants that may be exposed to [18F]MK‐6240 PET scan: 
a. Male participants with female partners who are pregnant or of childbearing 
potential must agree to refrain from sexual activity for 24 hours following 
administration of [18F]MK‐6240 injection. 
b. Additionally, males must agree not to donate sperm for 24 hours following 
administration of [18F]MK‐6240 injection. 
Cardiovascular Disorders 
8. Uncontrolled hypertension within 6 months prior to CRI Screen visit or screening (V1) 
(e.g., sustained systolic BP > 160 mm Hg or diastolic BP > 95 mm Hg). 


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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 participants 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 CRI Entry 
and 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 Project 
Arm Leader and Medical Director or designee, will decide if the participant 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 participant 
management.  Interpretations from the cardiologist at the central ECG laboratory will be 
used for data analysis and report writing purposes. 
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 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 CRI Entry visit and baseline (V2) visit (topical and nasal 
corticosteroids and inhaled corticosteroids for asthma are permitted) or 
chemotherapeutic agents for malignancy within the last 3 years. 


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Metabolic/Endocrine Disorders 
19. Current clinically significant abnormalities of thyroid function studies, clinically 
significant deficiency in B12.  B12 less than the lower limits of normal with normal 
methylmalonic acid (MMA)/homocysteine is not deemed clinically significant, therefore 
not exclusionary4. 
20. HbA1c >8% (retesting is permitted if slightly elevated) or poorly controlled insulin-
dependent diabetes (including hypoglycemic episodes).  Participants 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, or five half-lives from screening visit (V1), whichever is longer. 
24. Received any other investigational treatment within 3 months or 5 half-lives of CRI 
Screen and screening visit (V1), whichever is longer. 
Note: Use of some treatments for AD and other medications may be permitted in this study in 
accordance with the guidelines in Concomitant Medications, Section 5.3. 
Other 
25. Lack of sufficient venous access. 
26. Clinically relevant abnormalities in hematology, coagulation studies or clinical 
chemistry. 
27. 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. 
28. 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 
participant to a significant degree or put the participant at special risk. 
                                                        
4 If B12 is less than the lower limits of normal, a follow-up test of MMA and/or homocysteine should be performed 
to assess MMA/homocysteine 


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29. Currently, or within the last month prior to CRI Screen or screening (V1), participated in 
a clinical trial including a nonpharmacological trial with a key objective of improving 
cognition. 
30. Positive urine or serum pregnancy test or plans or desires to become pregnant during 
the course of the trial. 
31. Currently breastfeeding.  Participants must agree to refrain from breastfeeding during 
their participation in the trial and until 5 half-lives after the last dose of any study drug. 
32. Unable to complete CRI Entry visit or baseline visit (V2) procedures with appropriate 
cognitive and clinical scores for eligibility (e.g., mild dementia). 
 Participant Recruitment and Screening 
This study will recruit participants 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 DIAN-TU site for screening.  A list of screening labs and assessments for 
the CRI period is included in Section 6.3.1 and a list of screening labs and assessments for the 
double-blind treatment period is included in Section 6.3.2. 
 Discontinuation/Early Withdrawal of Participants 
4.4.1 Criteria for Discontinuation 
Participants could be discontinued from the double-blind period or OLE for any of the following 
reasons; discontinuation criteria for individual drug arms may also be specified in the drug-
specific appendices: 
1. Participants 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, Project Arm Leader (PAL), and Medical Director or designee 
decides participant should be discontinued, e.g., after an SAE or other clinically 
significant event or laboratory finding.  Refer to drug-specific appendices for any drug-
specific discontinuation criteria related to adverse events and laboratory findings. 
3. Participant or participant research proxy (if participant is cognitively impaired and 
unable to provide their own consent) decides to withdraw consent, including declining 
to consent to any protocol amendments. 
4. Participant becomes pregnant. 
5. Participant non-compliance, based on decision of site study staff or Medical Director.  
Determination of non-compliance would not apply to doses that are missed or reduced 


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when the site principal investigator/sub-I, PAL, and Medical Director or designee decide 
that changes in study drug dosing are necessary for medical or safety reasons.  During 
the CRI period, participants who miss more than two consecutive visits should be 
evaluated for continued suitability in the trial by the principal investigator/sub-
investigator, PAL, and Medical Director or designee. 
6. Participant can no longer contribute to the collection of key outcomes data.  Thus, a 
participant who cannot contribute to key endpoints would be discontinued from the 
double-blind treatment period but eligible for continued clinical and/or cognitive follow-
up and/or OLE* (Section 6.3.7). 
7. Known negative mutation carrier status or determination that they are no longer at-risk 
(negative risks status).  For example, if a participant enters the study unaware of their 
mutation status (when allowed), but later learns that they are mutation negative, they 
would be discontinued from the study. 
If a participant discontinues early from a double-blind or OLE 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 participants who are withdrawn because they 
become unblinded to genetic status and are found to be mutation negative. 
If a participant discontinues early from the CRI period, no additional testing or termination 
procedures are required, unless deemed necessary by the sponsor medical monitoring team. 
*Post-Treatment Follow-Up Period: Any participant 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 assessments and 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 Participants  
Enrollment for each study drug arm will be ongoing until all groups within the study drug arm 
are filled.  Participants may be replaced if they withdraw prior to randomization. 
 Transfer of Participants between Sites  
A participant 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, participants from the closing site would be offered the option 
of remaining in the study and transferring to another site to complete study procedures.   
Participants transferring to another site must continue to be administered the same country-
specific language and locally adapted cognitive and clinical assessments as they had been 
completing at their prior site for consistency in data collection. 


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Participants may have some study procedures performed at other DIAN-TU sites if the 
procedure cannot be performed at the DIAN-TU site under which they enrolled (e.g., due to 
equipment failure or PET tracer availability).  These participants would remain enrolled at their 
original 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, participants 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 participants, 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 
During double-blind periods, participants and study staff will remain blinded as to whether 
participants are on active drug or placebo.  Participants and staff will not be blinded as to the 
treatment route and interval.  The procedures taken to maintain blinding are detailed in each 
drug-specific appendix and/or associated DIAN-TU Pharmacy Manual. 
During double-blind periods in which non-carriers are eligible to participate, genetic status will 
not be disclosed to either the participant or study staff.  Mutation positive participants may 
already be aware of their genetic status and choose to disclose this to study staff.  The 
mutation positive participants will be encouraged not to disclose their genetic status to study 
staff.  For participants 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. 
Should any drug arm continue into an open-label extension period, treatment assignment from 
the double-blind period may remain blinded to investigators and participants based on the 
goals of the OLE period.  


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 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 
participants, the study blind will not be broken until all participants 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 participant, may the investigator 
unblind a participant’s treatment assignment. 
Prior to any unblinding, the investigator is strongly advised to discuss options with the PAL, 
Medical Director or designee.  As soon as possible, and without revealing the participant’s study 
drug assignment (unless important to the safety of participants 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 
participant. 
 Concomitant Medications 
All concomitant medication taken during the study must be recorded on the Concomitant 
Medication electronic case report form (eCRF).  Participants 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 certain approved treatments for AD is permitted 
in this study, but use of additional anti-amyloid therapies i.e. Aduhelm™ (aducanumab), are 
exclusionary and may not be used during trial participation.  This section provides additional 
guidance on managing concomitant medication use during the trial.  Before starting any 
Alzheimer’s disease medication, participants should be informed to discuss with their site study 
team, and sites should discuss with the sponsor, to determine if the medication use affects the 
participant’s continued eligibility.  Taking a drug that conflicts with the trial design may exclude 
continued participation, e.g., taking an approved anti-amyloid treatment while participating in 
an anti-amyloid study treatment arm. 
Allowed Medications.  Use of the following approved treatments for AD 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 CRI Entry and Visit 2:  donepezil (Aricept), 
rivastigmine (Exelon), galantamine (Razadyne, RazadyneER), and memantine (Namenda).  
Doses of these medications should remain constant throughout the study. 
If a participant has recently stopped acetylcholinesterase inhibitors (AChEIs) and/or 
memantine, he or she must have discontinued treatment at least 90 days before CRI Entry and 


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Visit 2.  Other vitamins or nutraceuticals given for their possible effects on AD may be 
continued on stable doses beginning 90 days before CRI Entry and Visit 2. 
Starting, stopping, or changing doses of AChEIs and/or memantine during the study might 
interfere with outcome measures and therefore could result in discontinuation of the 
participant from the study. 
Before a participant starts, stops, or changes doses of AChEIs and/or memantine or other 
treatments for their AD, the PAL, Medical Director or designee should be contacted to 
determine whether or not the participant should continue in the study and whether or not 
clinical outcome measures should be performed.  It should be documented if sponsor 
discussion and approval in advance of starting, stopping, or changing doses is in place prior to 
any change.  Changes may be tracked as a protocol deviation for analysis purposes. 
If changes are made without prior contact with the PAL, Medical Director or designee, the 
principal investigator/sub-investigator, once informed of these changes, should contact the 
PAL, Medical Director or designee to discuss and jointly determine whether or not the 
participant should continue in the study and whether or not clinical outcome measures should 
be performed.  It will be 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 CRI Entry and 4 weeks before baseline (Visit 2). 
To avoid effects on cognitive measures, participants 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 PAL, Medical Director or designee must be contacted to 
determine whether or not the participant 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 
The procedure schedule described in this section includes any procedures that may be 
performed in treatment arms and/or CRI periods.  The inclusion of specific procedures and 
timing for completion are described in the respective protocol appendices. 
 Procedures 
6.1.1 Participant 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 participant (and/or caregiver/legally 
authorized representative if the participant is cognitively impaired) and by the study partner (if 
required).  Study staff must document the informed consent process in the participant’s source 
document.  A copy of the signed and dated ICF will be provided to the participant 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.  In addition, a separate informed consent will 
be obtained for CRI and/or OLE periods. 
For participants enrolling into the CRI period, an ICF specific to the CRI period will be used.  The 
CRI ICF will provide detailed information on study design, duration, number and timing of visits 
and procedures, and potential side effects associated with drugs that target amyloid-β or tau, 
and intent for participants to enroll in a study drug arm when one becomes available.  It will 
also include the main requirements of future potential drug arm(s) (e.g., duration, frequency of 
procedures, etc.).  The CRI ICF will explain that participants who continue to meet eligibility 
criteria may be randomized to a study drug arm once a drug arm is open.  The ICF should be 
clear that there is the potential to be excluded from the study drug arm if any entry criteria are 
not met and it is in the best interest of the participant not to participate.  Participants will be re-
consented prior to enrollment to a study drug arm. 
For participants enrolling into a treatment period when more than one drug arm is enrolling, a 
main ICF and supplemental drug-specific ICF may both 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.  Participants 
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 participant (and/or caregiver/legally authorized representative 
if the participant is cognitively impaired).  This supplemental ICF will contain additional details 
about the procedures, risks and benefits of the specific study drug arm.  Participants 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 participants will only be assigned to one study drug arm, and also keeps confidential 


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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 participant, study 
partner, and caregiver/legally authorized representative (if the participant is cognitively 
impaired).  The investigator or designee shall give the participant adequate opportunity to read 
the ICF before 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.  Participants must 
also be given ample opportunity to inquire about details of the study. 
If eligibility criteria for an open-label extension period are met, a new written ICF will be 
obtained from the participant, study partner (if applicable) and/or by the participant’s legally 
authorized representative accordingly. 
The opportunity to donate post-mortem brain tissue will be discussed.  Interested participants 
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 participant 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 the right half of 
the brain and fixing the left hemibrain in formalin according to the DIAN-TU NPC manual 
instructions) 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 Brain Donation and 
Neuropathology Program 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 CRI screening visit (CRI Screen) or 
treatment screening period (V1) and confirmed at the CRI Entry or 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 participant’s clinically significant medical history and names and dosages of all 
medications will be reviewed.  Medications taken within 90 days of any screening visit (CRI 
Screen/V1) will be obtained at the respective visit (CRI Screen/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. 


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6.1.4 Clinical Assessment 
The full clinical assessment is performed by interviewing the study partner and participant at 
CRI Entry, baseline (V2), and annual visits for both the CRI and treatment periods; for certain 
populations, the MMSE is to be completed at the 26 week (approx. 6-month) visit between 
annual visits (timing for specific study populations is provided in the CRI appendix and each 
drug-specific appendix).  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 participant, 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 CRI entry and/or 
baseline, any clinically significant changes will be documented and reported. 
6.1.6 Vital Signs 
During the CRI period, blood pressure, heart rate, respiratory rate, temperature, and weight will 
be collected at CRI Screen, CRI Entry, and annual visits.  Height will be collected at CRI entry and 
annual visits only. 
During the treatment period, blood pressure, heart rate, respiratory rate and temperature will 
be collected at all visits.  Height will be measured at least at baseline (V2), and weight will be 
measured approximately every 3 months starting at baseline unless otherwise specified in the 
drug-specific appendix.  Weight collected between on-site annual visits may be obtained at a 
medical facility where participants receive safety MRIs or at the participants’ homes. 


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6.1.7 Electrocardiogram 
A standard 12-lead ECG will be performed at the indicated visits based on the CRI period and 
study drug arm requirements.  Refer to each drug-specific appendix for more details. 
For the CRI period and gantenerumab OLE, ECGs will be performed and read locally by a 
qualified physician or cardiologist, and investigators are to ensure no evidence of exclusionary 
findings. 
For other treatment arms, 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 PAL, Medical Director or designee, will decide if the 
participant 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 participant 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) and 
baseline (V2), and generally approximately every 3 months thereafter for the first 2 years 
during the treatment period.  The C-SSRS may then be administered less frequently, i.e. 
approximately every 6 months and/or annually for the remaining duration of the study.  Refer 
to the drug-specific appendices for exact timing. 
The C-SSRS will be administered at CRI Entry during the CRI period. 
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 CRI Screen visit 
or 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 
participants or sites.  Participants who wish to learn their DIAD mutation status, or when 
required for study entry, will be referred for genetic counseling and testing. 


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Blood samples for provenance5 testing will be obtained at the CRI Entry visit or baseline visit.  
Genetic testing results from the CRI period may be used to fulfill the required testing at 
screening and baseline for the treatment period. 
For an open-label extension (OLE) period, if the participant 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 may be provided to the appropriate party managing the genetic 
counseling and disclosure for the participant, i.e., the PI or genetic counselor. 
In addition to mutation status, genetic factors that may affect or explain responses to 
treatments will be explored.  Specifically, the genetic profile (both RNA and DNA) of cells found 
in both CSF and blood samples collected during the trial will be studied.  These data will not 
inform participant care but have the potential to inform researchers of the mechanisms of the 
study drug on important aspects of Alzheimer’s disease biology.  
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, vitamin B12 
levels, hemoglobin A1c, PT, PTT, and INR are obtained only at the CRI Screen and screening visit 
(V1).  Drug-specific appendices may require additional testing; refer to the drug-specific 
appendices and central laboratory manual for a complete list of analytes to be tested for each 
drug arm. 
Clinical laboratory samples will be obtained and sent to a central laboratory for analysis.  During 
the CRI period, laboratory values obtained at CRI Screen must be reviewed prior to completion 
of CRI Entry.  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 participant 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 study 
(after screening) should be repeated within an appropriate time frame (as determined by the 
site principal investigator or designated sub-investigator and/or PAL, Medical Director or 
designee). 
Refer to Section 7 (Safety and Adverse Events) for further details regarding adverse events. 
                                                        
5 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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Pregnancy testing – people of childbearing potential only 
During the CRI period, serum pregnancy testing will be performed at the CRI Screen visit and 
urine pregnancy testing will be performed at annual visits for women scheduled for 
[18F]MK-6240 PET scans.  During the treatment period, serum pregnancy testing will be 
performed at screening (V1) and the safety follow-up visit; 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.  Refer to drug-specific appendices for OLE collection 
timing.  
NOTE:  Post-menarchal, pre-menopausal people who have undergone tubal ligation are 
required to have pregnancy testing performed as scheduled at treatment visits.  In cases where 
urine collection proves difficult based on a participant’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] and 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. 
6.1.12 Stored Samples (Blood and DNA) 
Selected samples (e.g., plasma, DNA, buffy coats, and CSF cell pellets), 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, single cell RNA).  Stored samples may also be used to address regulatory 
inquiries or for additional monitoring of anti-drug antibodies or other drug-specific analyses.  
Because of future trials platform needs, samples will not be discarded or destroyed unless the 
DIAN-TU determines there is no use for them, or they can no longer be stored. 
Types 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 participant identification number.  Samples will be 
stored indefinitely unless otherwise specified, and samples will not be discarded or destroyed 


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unless the DIAN-TU determines there is no use for them or they can no longer be stored.  
Collection and storage of these samples is mandatory unless prohibited by local laws. 
6.1.13 Study Drug Administration 
Study drug dosing may be performed at the DIAN-TU site, or for participants who live at a 
distance from the host DIAN-TU site, dosing may be administered by the trial-designated home 
health nurses or at other trial-identified locations.  Study staff who administer study drugs will 
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 participants 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 
Cognitive batteries administered in the gantenerumab and solanezumab double-blind 
treatment arms can be found in previous protocol versions. Cognitive testing should be 
performed early in the day before other invasive or stressful procedures. 
6.1.14.1 
Gantenerumab OLE Period 
The Complete Cognitive Battery will be performed annually at the DIAN-TU site, and a subset of 
the testing battery (the Cognitive Battery Subset) will be performed approximately every 6 
months.  See the Gantenerumab OLE DIAN Trials Unit Cognition Core Procedures Manuals for 
additional details and suggested timing for administration of cognitive testing. 
All staff administering these batteries must be appropriately trained and certified as specified in 
the Gantenerumab OLE DIAN Trials Unit Cognition Core Procedures Manuals.  The following 
tests will not be administered at any visit to participants who had a CDR of 1 at gantenerumab 
or solanezumab double-blind baseline (V2) visit: Groton Maze Learning Test, Behavioral Pattern 
Separation Object Task, and MAC-Q. 
Complete Cognitive Battery (annual visits) 
Cognitive measures to be obtained at the OLE baseline visit (OLE V1) and annual OLE visits are 
administered at a DIAN-TU site and include the iPad-administered and conventional cognitive 
(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)  
• Cogstate Detection Task 
• Cogstate Identification Task 
• Cogstate One Card Learning Test 
• Cogstate One-Back Task 
• Behavioral Pattern Separation Object Task* 
• MAC-Q* 
Conventional Cognitive Testing (Pen/Paper):  
• Trailmaking Test parts A & B 
• WMS-R Digit Spatial Span Forward and Backward 
• WAIS-R Digit-Symbol Substitution Test 
• Raven’s Progressive Matrices (Set A) 
• Category Fluency (Animals & Vegetables) 
• WMS-R Logical Memory/Paragraph Memory (Immediate & Delayed Recall) 
*These tests should not be administered at any visit to participants who had a CDR of 1 at 
their original double-blind period baseline (V2) visit. 
Cognitive Battery Subset (every six [6] months when not annual): 
The subset of the complete cognitive battery will be administered by the site or trial-certified 
cognitive rater at the gantenerumab OLE visits occurring at the approximate 6-month 
treatment visits between annual visits and includes the iPad-administered and conventional 
cognitive (pen/paper) tests listed below.  
Conventional Cognitive 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) 
In addition, the cognitive measures listed below will be administered by the site or trial-
certified cognitive rater:  
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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• Cogstate Detection Task 
• Cogstate Identification Task 
• Cogstate One Card Learning Test 
• Cogstate One-Back Task 
*These tests should not be administered at any visit to participants who had a CDR of 1 at 
their original double-blind period baseline (V2) visit. 
6.1.14.2 Cognitive Run-In Period and Tau Drug Arms: DIAN-TU Harmonized Cognitive Battery 
The DIAN-TU Harmonized Cognitive Battery will be performed approximately every 26 weeks 
(~6 months) for the CRI secondary prevention population and for tau drug arms; and every 52 
weeks (annually) for the CRI primary prevention population by a trial-certified cognitive rater at 
either the host DIAN-TU site or home health nursing visit.  
Cognitive measures to be obtained in the Cognitive Run-In (CRI) and tau-targeted study drug 
arms include the below listed tests. 
DIAN-TU Harmonized Cognitive Battery: 
• Memory Complaint Questionnaire (MAC-Q) 
• Buschke and Grober Free and Cued Selective Reminding Test-Immediate Recall (FCSRT-
IR)   
• WMS-R Logical Memory/Paragraph Memory (Immediate & Delayed Recall), Alternate 
Paragraph for Logical Memory I & II – Version A (Immediate and Delayed) and Alternate 
Paragraph for Logical Memory I & II – Version B (Immediate and Delayed) 
• Category Fluency (Animals) 
• WAIS-R Digit-Symbol Substitution Test 
• Trailmaking Test Parts A & B 
• WMS-R Digit Spatial Span Forward and Backward 
 
IMPORTANT for baseline treatment visit 2 (V2):  If the CRI period is open to enrollment, a CRI 
period may last until a study drug arm opens for randomization, but no longer than 
approximately 3 years.  If a participant is taking part in a CRI period, a minimum of 8 weeks 
must elapse between the participant’s last administration of a cognitive battery during the CRI 
period and administration of the baseline (V2) cognitive battery. 
Smartphone-based Cognitive Assessments  
Smartphone-based cognitive (Ambulatory Research in Cognition [ARC]) assessments will be 
administered to participants using a mobile phone application, developed at Washington 
University in St. Louis.  These tests will include measures of episodic memory, attentional 
control, and processing speed and are administered multiple times per day over the course of 
several days.  These assessments will be self-administered by the participants on their personal 


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smartphones.  If participants do not own a smartphone or their device does not meet minimum 
specifications, a study phone will be provided. 
Compliance with the smartphone-based cognitive measures is considered exploratory and non-
participation will not be considered reason for discontinuation in the study and will not be 
considered protocol deviations.  Based on operational and regulatory considerations, the study 
sponsor will determine which sites will administer the smartphone-based cognitive 
assessments, with the explicit goal of full site participation. 
Participants will be instructed on installation and setup of the ARC application at their CRI 
screening visit (CRI Screen) or drug arm screening visit (V1).  Participants will complete the first 
week of assessments immediately following the CRI screening visit or screening visit (V1) of a 
treatment arm.  Participants will continue to complete assessments approximately every 26 
weeks (approximately 6 months) for the secondary prevention population and every 52 weeks 
(annually) for the primary prevention population after the CRI entry visit (CRI Entry) and/or 
baseline (V2) of a treatment arm. 
6.1.15 Baseline and Annual Magnetic Resonance Imaging (MRI)  
For all drug arms, MRIs performed at the DIAN-TU site at annual visits starting with CRI Entry 
and/or baseline [V2] 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), 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., participants 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 participant 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 
Archive [DCA]). 
Images should be uploaded within 24 to 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 CRI Entry, CRI annual visits, baseline MRI (V2), and all annual visit MRIs 
should be uploaded immediately after these scans are completed as the findings of these MRIs 


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can impact inclusion in the study (CRI Entry and 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).  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. 
Additional MRI examinations for the OLE period will be listed in the drug-specific appendices. 
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 participants who live at a distance from the host DIAN-TU 
site, at a site closer to the participant’s home in order to reduce participant 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 participant’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.  Sites must ensure that study visits are scheduled so that 
MRI images are uploaded and available for central read at least 3 to 5 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; and within 24 hours for the 
MRIs done for all drug arms at CRI Entry, and treatment period baseline (V2), and annual visits 
preceding dose administration. 
A central read for safety purposes may also be completed for annual OLE visits and routine 
exams as specified in the drug-specific appendices.   
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 


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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 
subsequent time points as outlined in the drug-specific appendices.  Lumbar puncture (LP) is to 
be performed at the DIAN-TU site to collect 25 mL of CSF while the gantenerumab open-label 
extension arm will continue to collect at least 15 to 20 mL of CSF. 
A sample of CSF will be sent to a local lab for cell counts and differential as well as glucose and 
protein measurement (estimated at approximately 2 mL); each site should confirm with their 
local lab the volume of CSF needed for these studies.  Because CSF biomarkers are the 
biomarker endpoint for some of the study drug arms, at least 23 mL CSF should be sent for 
biomarker analysis (15 mL CSF for gantenerumab OLE); this is in addition to the CSF obtained 
for the local lab studies.  Cell pellets will be obtained from the 23 mL of CSF collected for 
biomarker analysis for genetic analysis and mechanistic studies of drug actions; cell pellets will 
not be collected for participants in the gantenerumab OLE arm.  It is essential that at least 23 
mL of CSF is collected at baseline of any blinded study periods before any dosing occurs.  If less 
than 23 mL is collected for biomarker analysis at the baseline visit, contact the sponsor prior to 
dispensing/administration of study drug to determine if participant is eligible to remain in the 
trial.  See central laboratory manual and the Global Manual of Operations for additional details 
regarding required LP and collection procedures and materials, processing instructions, and 
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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 the CRI period, positron emission tomography (PET) with the [18F]MK-6240 tracer will be 
performed for participants that are within −10 to +10 (inclusive) of EYO (secondary prevention) 
at CRI Entry and annual CRI visits as specified in the appendix.  Tau PET is not completed for 
participants in the primary prevention population (−25 to −11 EYO). 
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 double-blind periods; additional imaging 
time points may be required as specified in each drug-specific appendix. 
In OLE periods, PET imaging with selected tracers will be performed per drug-specific 
appendices. 
The type of PET imaging is drug-specific (see each drug-specific appendix) and may include 
one or more of the following: 
Pittsburgh Compound B ([11C]PiB-PET) PET Imaging – Excluding CRI Period 
[11C]PiB-PET imaging will be performed at DIAN-TU qualified sites at baseline (V2) and at the 
weeks 52 (V15), 104 (V28), and 208 (V54) visits of the double-blind period, at minimum, and at 
baseline and annually during OLE. Additional time points may be required as specified in each 
drug-specific appendix. 
[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 participant, 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.  A DIAN-TU radiochemistry review team 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 to the imaging data management 
system, DCA.  Image processing and analyses will be performed by Washington University. 
For people of childbearing potential (POCBP), 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. 


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Scan Acquisition: Participant preparation consists of intravenous catheterization followed by 
the bolus injection (over 10 to 60 sec) of [11C]PiB at dosage: 8 to 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. 
Participants should be scanned on the same scanner as was utilized at the baseline visit, unless 
the participant 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. 
Fluorodeoxyglucose PET (FDG-PET) – Excluding CRI Period 
For treatment arms, uptake of 2-[18F]fluoro-2-deoxy-D-glucose (FDG-PET) will be performed for 
participants enrolled in selected study drug arms at baseline (V2) and at minimum, the week 52 
(V15), 104 (V28), and 208 (V54) visits of double-blind periods, and annually during OLE, or as 
described in the schedule of visits in each drug-specific appendix.   
FDG-PET will be done at DIAN-TU qualified 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 participant, the same scanner should be used for all FDG-PET imaging sessions.  
Participants 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 POCBP, 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. 
Scan Acquisition:  Typically, the PiB-PET scans will precede the FDG scans on the same day; 
however, this arrangement is for convenience to the participant and coordinators but is not a 
requirement (see Global Manual of Operations for schema).  After completion of PiB-PET 
scanning, participants 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, 
participants 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 


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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 the CRI period, positron emission tomography (PET) with the [18F]MK 6240 tracer will be 
performed at CRI Entry, week 52 (CRI 5) and week 104 (CRI 9) visits for participants in the 
secondary prevention population (−10 to +10 EYO). 
For the double-blind period of the study drug arms, tau scans will be performed at DIAN-TU 
qualified sites at minimum, at baseline (V2), and week 52 (V15), 104 (V28), and 208 (V54) visits; 
and may be performed annually in open label periods.  Refer to the below individual tracer 
details and drug-specific appendices for the individual tracer to be used and schedule to be 
followed. 
Based on the currently available data for tau PET in the DIAN-OBS study, it is highly unlikely that 
participants considered for primary prevention will have evidence of tau PET abnormalities.  
Therefore, those qualifying for CRI period who are younger than −10 years from estimated age 
at symptom onset (−25 to −11 EYO; primary prevention population) will not undergo tau PET. 
[18F]AV-1451 PET – Gantenerumab OLE Only 
The gantenerumab and solanezumab double-blind treatment arms utilized the [18F]AV-1451 
tracer (Avid Radiopharmaceuticals, Inc.) via protocol addendum for the double-blind period 
rather than as part of the main study protocol due to tracer access constraints.  For consistency, 
the gantenerumab OLE period will continue to collect [18F]AV-1451 tau PET annually however, it 
will be included in the drug-specific appendix. 
Avid Radiopharmaceuticals, Inc., or a DIAN-TU radiochemistry review team, will audit and 
qualify [18F]AV-1451 manufacturing and conduct ongoing QC of [18F]AV-1451 batch records.  
The University of Michigan will provide quality control on [18F]AV-1451 images.  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 participant’s treatment assignment (e.g., whether participant is on active or placebo 
treatment in the DIAN-TU-001 study). 
POCBP 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: 


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1. The preferred option will be for participants 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 participant 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 participants 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 participant will be requested to void after 
completion of the PET scans.  Participants 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.   
[18F]MK-6240 PET - Cognitive Run-In Period and Tau Drug Arms 
The CRI period and tau drug arms will utilize [18F]MK-6240 tau PET tracer, if/as specified in the 
drug-specific appendices.  [18F]MK-6240 may be optional for some global sites based on its 
availability at the discretion of the sponsor and will be limited to the secondary prevention 
population (i.e., participants within −10 to +10 years (inclusive) of the predicted or actual age at 
cognitive symptom onset).  [18F]MK-6240 PET will be done at qualified DIAN-TU sites using 
DIAN-TU protocol as specified in the PET Technical Procedures Manual.  [18F]MK-6240 PET 
imaging may be performed at other trial-qualified sites to ensure participants at sites with no, 
or limited, access to the tracer can still complete the scan. 
[18F]MK-6240 will be produced by a study-approved manufacturing cyclotron facility.  Images 
will be uploaded to the imaging data management system, DIAN Central Archive (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 participant’s treatment assignment (e.g., whether 
participant is on active or placebo treatment in the DIAN-TU-001 study). 
POCBP are to have a confirmed negative urine pregnancy test (HCG) on the day of [18F]MK-6240 
PET imaging session, before [18F]MK-6240 dose administration.  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. 


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[18F]MK-6240 administration:  Participants will receive a single intravenous bolus injection of 
185 MBq (5 mCi).  The injected activity will not be less than 159.1 MBq (4.3 mCi) and no more 
than 222 MBq (6 mCi).  The total injected volume will not be more than 10 mL followed by a 
10 mL normal saline (0.9% NaCl) flush. 
The injection site will be observed for evidence of inflammation or damage to the surrounding 
tissue where the dose was injected.  Participants will be observed continuously for signs of 
adverse events (AE) or serious adverse events (SAE). 
Scan Acquisition: See PET Technical Procedures Manual for additional details.  PET/CT is the 
preferred imaging modality for [18F]MK-6240 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. 
Participants will receive the [18F]MK-6240 injection and rest quietly in an uptake room.  At 
exactly 80 minutes following the injection, participants will undergo a continuous 30-minute 
brain scan consisting of 6 x 300 sec frames. 
Standard Brain Attenuation Scan for attenuation correction: 
•
PET/CT scanner:  Acquire a low dose CTAC scan with topogram just prior to the emission
data acquisition scan for [18F]MK-6240.
•
PET only scanner:  Acquire a transmission scan using rod source for 5 to 10 minutes just
prior to the emission data acquisition scan for [18F]MK-6240.
•
A second CT or transmission scan must be acquired if the participant is removed from
the scanner and resumes scanning after a break.
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. 
6.1.19 Brain Donation Program 
The brain donation program allows the entire brain to be forwarded to the DIAN-TU 
Neuropathology Core (NPC); site-specific arrangements will be made to maximize tissues 
donated from international sites that have legal restrictions on unconditional whole brain 
donation.  The DIAN-TU NPC will perform a standardized comprehensive neuropathological 
assessment, implementing the same protocol that is utilized for brain specimens evaluated in 
the DIAN Observational (DIAN-OBS) study, and coordinate with DIAN-TU Imaging Core to 
perform post-mortem magnetic resonance imaging of the fixed hemibrain.  This approach will 
facilitate direct comparisons of DIAN-TU cases to the DIAN-OBS cases, which represent the 
“natural spectrum” of DIAD pathology.  
Neuropathological findings in DIAN-TU cases will be evaluated for associations with clinical, 
genetic, neuropsychological, and neuroimaging data obtained from DIAN-TU investigative sites.  
Special handling or blinding of the resulting data may be required if the study arm that the 


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participant was enrolled in is actively ongoing; this is necessary to protect the integrity of the 
DIAN-TU trial data and alleviate any possibility of compromise.   
All operational and logistical details regarding the brain donation program are located within 
the DIAN-TU Brain Donation and Neuropathology Program Manual. 
Eligibility: Participants from any DIAN-TU study, or DIAD individuals participating in external 
studies evaluating the same drugs as in the DIAN-TU platform, are eligible to participate in the 
DIAN-TU Brain Donation Program. 
Overview of Visit Flow 
A participant enrolled in a CRI period can transition from the CRI to an open study drug arm at 
any time, as long as there is a minimum of 8 weeks between the participant’s last 
administration of a complete cognitive battery or subset, or the DIAN-TU Harmonized Cognitive 
Battery during the CRI period and administration of the baseline (V2) complete cognitive 
battery.  As long as at least 8 weeks have elapsed, the participant can complete their baseline 
(V2) assessments, including the DIAN-TU Harmonized Cognitive Battery, and continue with the 
regular drug-specific schedule of events.  This 8-week lapse is intended to mitigate carryover 
effects from repeated testing while also ensuring that participants can be randomized without 
any significant delays. 
Figure 4 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 4 shows the visit flow for participants 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 participants who live nearby or, for 
participants who live at a distance from the host DIAN-TU site, in the participant’s home or 
another trial-identified location more convenient for the participant.  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 4 
Overview of Participant Visit Flow 
 
 Study Visits 
The schedule of visits for the CRI period is provided in Appendix 1 and 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.  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 
of the cognitive testing administered during the CRI Entry visit should be used to determine 
timing of subsequent visits during the CRI period.  The specific date during the baseline visit 
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. 
DIAN-TU-001 Protocol:  Participant Visit Flow for REMOTE Participants
CRI Entry &/or       
Week 0 (V2 /
Baseline /
Randomization): 
DIAN-TU Site
CRI Screen &/or 
Screen (V1) 
[Week -8 to -2]: 
HHN or local site
Initial 
Contact
DIAN-TU 
Trial Site
DIAN-TU or 
Satellite MRI 
[Pre-Certified
by DIAN-TU]
Monthly Site or 
Home Health 
Nurse Visit 
[or Site call]
Home Health Nurse (HHN) 
(GCP, study-trained, cognitive 
rater) visits participant’s home 
OR local, approved AD 
satellite site
Investigational Site 
contacts participant  
via PHONE
Participant’s 
DIAN-TU Trial Site
• Contact participant via phone; discusses interest and send appropriate consent (CRI, Main &/or drug-specific consent [based on enrolling arms], and brain 
donation).
• Site study staff review consent via phone, answer questions; once complete, participant signs/dates ICF and sends original back to site.  
• Obtains preliminary information related to inclusion/exclusion (including family mutation documentation and age at onset).
• Assess participant & scanner availability for baseline (V2); schedule screen 2-8 wks before CRI Entry or Baseline (V2) [genetics required 6 wks before V2].
• Verify signed appropriate consent(s), including opportunity for brain donation consent and review
• Verify updates to conmeds and medical history
• Lab Draws (needed for inclusion/exclusion):
            - Clinical safety labs (hem, chem, UA, coag, HbA1c, TSH, serum hCG, etc.)
            - Genetics labs (mutation status; APOE) → AT LEAST 6 WKS PRIOR TO BASELINE (V2) [no time minimum prior to CRI]
• ARC smartphone-based cognitive assessment instructions / set-up; and testing
• Participant travels (drive/fly) to DIAN-TU site (approx. 4 day visit)
• Re-review consent (including signature on drug-specific consent once randomized, if applicable)
• Safety/vMRI 1st day to enable central read for verification of MCH count prior to randomization
• All safety & efficacy assessments [PET (Amyloid, Tau, FDG PET, where applicable); LP; Clinical 
Assessments and Cognitive Battery;  ECG; drug-specific labs]
• Randomize & dispense/administer first dose of study drug
• Monitor participant for any post-dose reaction
Per drug-specific appendix: 
3T MRI scan @ DIAN-TU 
site or trial-qualified satellite 
center [sent to Mayo Clinic 
for central read]
Monthly Home 
Health Nurse visit 
[or local AD 
satellite site] 
CRI Entry, Year 0 (V2, 
Baseline) & 
Annual Visits
at DIAN-TU Site
• Every Month:  AE/SAE Assessment, ConMed Review
• As specified in drug-specific appendix:  Vitals; safety labs; drug-
specific labs; UPT; CSSRS;  12-lead ECG 
• Every 6 mo: DIAN-TU Harmonized Cognitive Battery, MMSE, and 
ARC smartphone testing
Annual Visits:
• Annually (CRI and treatment periods’ Years 0-4+):  3T vMRI [including safety read];  CRI: includes MRI at CRI Entry visit only for primary 
prevention participants (-25 to -11 EYO)
• Annually (CRI and treatment periods’ Years 0-4+): Clinical Assessment & Cognitive Battery
• Years 0, 1, 2 and 4 (approx.):  PET [Amyloid, Tau, and FDG PET, per drug-specific appendices]; LP (not performed in CRI)
• Specific to each drug arm, as required in the drug-specific appendices
• Mayo performs central safety read
• To be conducted every few months for specified duration per drug-specific appendices 
• Assessment of any dose adjustments based on MRI findings and clinical symptoms


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6.3.1 Cognitive Run-in Period 
If no study drug arm is available for immediate enrollment or if a future drug arm is stopped 
prior to the planned completion (e.g., at biomarker interim, drug toxicity), participants may 
enter into a CRI period which will consist of screening, entry, and follow-up visits. See Appendix 
1, Cognitive Run-in Period, for the specific assessments that are required at each visit. 
Once a drug arm is open, participants will have a screening visit (V1) conducted either in their 
home by a home health nurse, or at the DIAN-TU site, to collect safety labs and to reassess the 
suitability of the participant for entry into the trial (Section 6.3.2). 
6.3.2 General Platform Procedures for Screening (Visit 1) in Double-Blind Treatment Periods 
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). 
Note: The schedule of visits for screening (V1) and baseline (V2) identify procedures that do not 
need to be repeated if collected during the CRI period, e.g., genetic testing, family history, 
demographic and study partner information, medical and treatment history and assignment of 
study-specific participant identification number. 
Location: Visit 1 procedures may be accomplished at the DIAN-TU site or at the participant’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 participant may be contacted by 
their host DIAN-TU site by telephone or during a regular DIAN Observational study visit.  The 
participant is given the opportunity to review the informed consent form(s), ask questions 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 participant and study partner.  Unless otherwise specified, all other Visit 1 
procedures may occur throughout the screening period (2 to 8 weeks before baseline [V2]).  
IMPORTANT: Results from screening clinical laboratory tests and genetic testing must be 
available before baseline (V2); blood collection for genetic testing must be completed at least 6 
weeks before V2 to ensure genetic results are available for baseline randomization.  Genetic 
testing results from the CRI period may be used.  The screening visit in the home ensures 
participant 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 The arm-
specific DIAN Trials Unit Cognition Core Procedures Manuals for additional details on order and 
timing of procedures): 


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• 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 
participant’s actual age at onset (DIAN-TU site staff), if not collected during a CRI period.  
Estimated age at onset should be determined as outlined in the Global Manual of 
Operations. 
• Verify documentation of participant’s trial eligible mutation status OR, when allowable 
per drug-specific appendix, confirm via family pedigree and mutation documentation 
(proband) that the participant is at 50% risk for a trial-eligible mutation, if not collected 
during a CRI period 
• Collect demographic information and study partner information, if not collected during 
a CRI period 
• Obtain medical and treatment history, including assessment/recording of pre-existing 
conditions or adverse events; results from CRI period may be used unless the participant 
or study partner becomes aware of new information. 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature).  Weight is 
not required at this visit, but the participant’s self-reported weight may be noted if 
required for laboratory tests. 
• Blood collection: 
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; results from 
the CRI period may be used.) 
o clinical laboratory tests, including TSH, vitamin B12, hemoglobin A1c, PT, PTT, and 
INR 
o serum pregnancy test for POCBP 
o drug-specific analytes (refer to drug-specific appendices) 
• Urine collection for urinalysis 
• Administration of C-SSRS 
• ARC smartphone-based cognitive assessment: 
o Set-up and training 
o Participants will be prompted to begin the testing and will continue to complete the 
test over a continuous 7-day period.   
A study-specific participant identification number is assigned to the participant 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.  
Genetic testing results from CRI period may be used.  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, when applicable, however may be provided 
for OLE qualification as specified in Section 6.1.9. 


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6.3.3 General Platform Procedures for Baseline (Visit 2/First Dose) in Double-Blind 
Treatment Periods 
Location: DIAN-TU site including DIAN-TU qualified imaging centers. 
Time/Timing:  Approximately a 3- to 4-day visit that is scheduled 2 to 8 weeks after the 
screening visit and at least 6 weeks after the genetic sample collection, if genetic testing was 
not completed during a CRI period.  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 participant 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 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 participants 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 or approved imaging location. 
Notes: Although participating in the DIAN-TU study may not require that participants know 
whether they have a mutation associated with dominantly inherited Alzheimer’s disease, it will 
be recommended that all participants undergo genetic counseling prior to starting assigned 
study drug.  Participants 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 participants 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 POCBP 
• Blood collection for the following:  
o provenance6 testing of Screening genetic sample [to confirm specimen identity]; 
results from a CRI period may be used 
o clinical laboratory tests (hematology, chemistry, urinalysis) 
                                                        
6 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 participant, 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 
• DIAN-TU Harmonized Cognitive Battery (per Section 6.1.14.2) 
• 12-lead ECG 
• 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. MRI 
findings 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 participant 24 to 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 
• 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, participant and legally authorized 
representative (if the participant is cognitively impaired) should review and sign the 
supplemental drug-specific informed consent form (if applicable); study staff should be 
available to answer all questions regarding the study.  Study drug should not be administered 


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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 
participant was enrolled and may last from 4 up to 7 years (364 weeks [V93]) or until early 
termination, whichever is sooner.  Participants will continue treatment with the assigned study 
drug until every participant 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, participants 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 
participant’s home, or other trial-identified location with the trial-designated home health 
nurse.  Annual visits will take place at DIAN-TU qualified sites. 
Time/Timing:  Generally every 4 weeks (± allowed visit window) until the last participant in a 
study drug arm has completed their year 4 visit, or the study drug arm has been terminated.   
Some drug arms may require a different frequency of visits based on study drug administration 
requirements; these will be specified in the drug-specific appendices including any 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 to 4 days.  For participants 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 participant, 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 
• DIAN-TU Harmonized Cognitive Battery 
• ARC smartphone-based cognitive assessment  
• MRI (should be performed before lumbar puncture, if on the same date)  
• Lumbar Puncture (LP) for CSF collection should be performed in the morning, at 
approximately 8 am local time, under fasting conditions (water is allowed and 
encouraged).  Site staff should contact the participant 24 to 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-participant contact 
should occur at least once every 3 months throughout the study): the DIAN-TU site 
coordinator calls participant 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 participant may vary based on when the participant 
was enrolled and may last from 4 (208 weeks [V54]) up to 7 years (364 weeks [V93]) or until 
early termination, whichever is sooner.  Participants will continue treatment with the assigned 
study drug until every participant 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 participants in the study drug arm and all participants should be scheduled 
for an end-of-treatment/safety follow-up visit, if/as specified in the drug-specific appendices.   
Location: Procedures/contacts may be accomplished at the DIAN-TU site or participant’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 approximately 12 
weeks (± 7 days) after the participant’s last dose of double-blind treatment, or as specified in 
the drug-specific appendices.  The sequence and timing of visit procedures is very important 
and are detailed in the Global Manual of Operations. 


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Procedures may include any of the following: 
• Concomitant Medications 
• Adverse Event Assessment 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight)  
• 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 Open-label Extension 
Study drug arms that demonstrate a potential for clinical benefit may offer an open-label 
extension (OLE) period at the discretion of the sponsor and respective pharma partner. 
Participants from concurrent negative arms may have the option of enrolling into the OLE of 
the study drug arm with positive results after at least a steady-state washout (five drug PK half-
lives) from their last double-blind dose.  
All OLE participants and study sites will be kept blinded to prior treatment assignment until the 
end of OLE to protect study integrity. 
Any mutation carrier who participated in the placebo-controlled portion of the trial in which 
the investigator and sponsor deem treatment is not contraindicated for safety and is capable of 
receiving drug and appropriate clinical safety assessments, is eligible. 
Written informed consent must be obtained from the participant, study partner (if applicable), 
and/or by the participant’s legally authorized representative accordingly (Section 6.1.1). 
Location:  Monthly procedures/contacts during the OLE may be accomplished at the DIAN-TU 
site, at the participant’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) beginning at dosing restart; refer to the 
drug-specific appendices for allowable visit windows. 
Visit duration depends on procedures required at the visit and study drug administration 
requirements (e.g., infusion time, observation time after infusion).  Note that annual visits may 
take place over 2 to 3 days.  For participants 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 however biomarker assessments and 
cognitive batteries will be performed during OLE at the discretion of the sponsor and pharma 


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partner contingent upon the individual measure demonstrating continued utility in OLE based 
on the results of the double-blind period of the study. 
• Obtain informed consent.  Participants who wish to join the OLE may sign consent once 
a decision regarding the initiation of an OLE has been communicated by the sponsor, 
and an approved OLE ICF is available at the site 
• Confirmation of having a trial-eligible pathogenic DIAD variant at the time of entry into 
OLE 
• Medical/treatment history, including: 
o Concomitant medications 
o Assessment /recording of adverse events 
• Urine pregnancy testing, if applicable 
• Laboratory sample collection for clinical laboratory tests and blood-based biomarker 
measures (e.g., drug-specific tests, stored plasma and/or serum) per drug-specific 
appendices, if/as determined by the sponsor and pharma partner 
• 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 participant, 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, if/as determined by the sponsor and pharma partner 
• PET imaging: 
o [11C]PiB  
o FDG-PET (participant should be fasting 4 hours prior to FDG-PET) 
o [18F]AV-1451 or [18F]MK-6240 
• LP (CSF collection)  
• MRI (should be performed before LP if on the same date) 
• Administer study drug 
• Coordinator phone call:  Site study coordinators should call participants either during or 
within two weeks after OLE V2, OLE V3 and OLE V4.  For OLE V5 and subsequent home 


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visits, coordinator calls can be made with less frequency at the discretion of the 
coordinator and participant, but should occur at least every 3 months 
6.3.7 Early Termination Visit and Post-treatment Follow-up Period 
If a participant withdraws, is terminated from the study prior to completion of a treatment 
period, or is in a study drug arm that is stopped prior to the end of the 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 participant that meets study drug discontinuation criteria per Section 4.4.1 (excluding 
participants 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 participant’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 participant’s status changes. 
Location:  DIAN-TU site or at the participant’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- to 4-day visit.  For participants 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 
• Laboratory sample collection (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 


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o FAS 
o MMSE 
o Assessment of clinical diagnosis and clinician judgment of symptoms.   
NOTE: For each participant, 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. 
• Cognitive testing  
• MRI (structural and functional) should be performed before lumbar puncture, if on the 
same date 
• Lumbar Puncture (LP) for CSF collection should be performed in the morning, at 
approximately 8 am local time, under fasting conditions (water is allowed and 
encouraged).  Site staff should contact the participant 24 to 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, and CRI period at any time.  
Furthermore, if it becomes apparent that participant 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.  Any time a 
study drug arm is not recruiting participants, opening recruitment to CRI period will be 
considered. 
7 
SAFETY AND ADVERSE EVENTS  
 
Definitions 
7.1.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a participant 
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 


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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 participant 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 participant) 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 participant’s medical condition should not be recorded as AEs, but should 
be documented in the participant’s source documents.  Complications resulting from an 
elective surgery should be reported as AEs or SAEs (depending on the severity). 
• 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: 


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• Death of participant.  An event that results in the death of a participant. 
• 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 
participant is hospitalized and prolongs the participant’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 participant.  
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 
participant and may require medical or surgical intervention to prevent any of the 
outcomes listed above (i.e., death of participant, 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. 
 
Adverse Event (AE) Severity 
The intensity of the AE will be rated by the investigator as mild, moderate, or severe using the 
following criteria: 
Mild:  an event that is transient and easily tolerated by the participant; requires minimal or 
no treatment and does not interfere with the participant’s daily activities. 
Moderate:  an event that causes the participant discomfort and may cause some 
interference in the participant’s usual activities. 
Severe:  an event that causes considerable interference with the participant’s usual 
activities, may require drug therapy or other treatment, and may be incapacitating or 
life-threatening. 


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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 site 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 participant’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 participant’s clinical condition, or with other medication taken by the 
participant. 
 
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 (or 30 days after the last visit if in the CRI period only) will be collected, 
whether elicited or spontaneously reported by the participant.  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.   


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At every study visit, participants 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 participant 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 IQVIA Safety (formerly known as Quintiles) 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 learns about the 
event by entry into the study’s electronic data capture (EDC) system; in cases where a back-up 
submission method is needed the site must submit SAE documentation to the project mailbox:  
QLS_WashU@quintiles.com. 
Contact information for IQVIA Safety:  
IQVIA SAFETY: 
Toll-free for US sites: 
Phone: (866) 599-1341 
Fax: (866) 599-1342 
For all sites/international:   
+1 973-659-6677 or  
+1-570-819-8565 (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 


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documents for the demographics page(s), medical history page(s), AE page(s) and concomitant 
medication page(s).  If the participant is hospitalized because of or during the course of an SAE, 
then a copy of the hospital discharge summary should be faxed to IQVIA 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 participant 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 5 
half-lives 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 IQVIA Safety in the same manner and timing as for Serious Adverse 
Events specified in Section 7.6. 
 
Hy’s Law 
Suspected Hy’s law cases should be reported to IQVIA 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 IQVIA Safety in the same manner and timing as 
for Serious Adverse Events specified in Section 7.6. 
 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), SAEs, and AESIs will be 
reviewed quarterly by the DSMB.  Complete details are available in the DSMB charter.   
8 STATISTICAL PLAN 
The data collected in the CRI period may be used for analysis in the respective drug arm under 
which participants are randomized and treated. 


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A detailed drug-specific statistical analysis plan will be used for interim and final efficacy 
analyses and for the biomarker interim analyses for each drug arm. 
 
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.  
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 be drug-specific and in general include all participants 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 
(TEAE), 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 
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 be used for dose-adjustment, remediation, or stopping a study drug arm for futility 
and will not be used to stop the study for efficacy on the primary 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.  Pre-specified definitions for early termination for futility will be drug-


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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 
protocol appendix and SAP appendices. 
 
Primary Efficacy Endpoint Statistical Analysis, Power and Sample Size 
Justification 
The primary efficacy endpoint may vary across study drug arms.  For each study drug, the 
corresponding primary efficacy endpoint, the statistical analysis, and the power and sample size 
justification will be presented in the drug-specific appendix.   
The modified intent-to-treat (mITT) population is defined as all participants who will be 
randomized, treated, and assessed for their primary cognitive outcomes at least once after the 
baseline assessment.  Refer to the drug-specific appendices for details as individual drug arms 
may further define their respective analysis populations. 
All efficacy analyses will be conducted on the mITT population and eligible external controls, if 
deemed necessary; as specified in the drug-specific appendices. 
Final analysis will be pre-specified in the SAP and/or drug-specific SAP appendices. 
 
OLE Outcomes 
Analyses for outcomes in any OLE period will be completed for the outcomes described in each 
drug-specific appendix. 
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 participants 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 participant 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) 


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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 participant 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, participant 
diaries, pharmacy dispensing and other records, recorded data from automated instruments, 
magnetic media, x-rays, etc. 
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 pertinent telephone, e-mail, and letter correspondence contact.  The monitor will 
maintain current 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 participant’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 and/or site management.  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. 


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 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. 
• 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 
participant/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.  Comparable document(s) 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 should 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 for 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 


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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 participants 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. 
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 
participant’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 the DIAN-TU retains 
the right to publish the results of this trial consistent with the policies of the DIAN-TU and any 
regional regulatory requirements. 
 
 


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Lewczuk P, Matzen A, Blennow K, Parnetti L, Molinuevo JL, Eusebi P, Kornhuber J, Morris JC, 
Fagan AM.   Cerebrospinal Fluid Aβ42/40 Corresponds Better than Aβ42 to Amyloid PET in 
Alzheimer's Disease.  Journal of Alzheimer’s Disease. 2016 Nov 19;55(2):813-822. 


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Li, G., I. Sokal, et al.  (2007).  "CSF tau/Aβ42 ratio for increased risk of mild cognitive 
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Lohith, T., I. Bennacef, C. Sur, R. Declercq, K. Serdons, G. Bormans, E. Hostetler, K. Van Laere, R. 
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targeting human neurofibrillary tangles (NFTs) in brain of healthy elderly and participants 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. 
Mattsson-Carlgren N, Andersson E, Janelidze S, et al. Aβ deposition is associated with increases 
in soluble and phosphorylated tau that precede a positive Tau PET in Alzheimer's disease. Sci 
Adv. 2020;6(16):eaaz2387. Published 2020 Apr 15. doi:10.1126/sciadv.aaz2387 
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 
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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 
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Radiopharmaceuticals 60(2): 140-146. 
Nelson, P. T., I. Alafzoff, et al.  (2012).  "Correlation of Alzheimer disease neuropathologic 
changes with cognitive status: a review of the literature." J Neuropathol Exp Neurol 71(5): 362-
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Novak, G., J.R. Streffer, et al. (2020). "Long-term safety and tolerability of atabecestat (JNJ-
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randomized, double-blind, placebo-controlled study and a two-period extension study." 
Alzheimer's Research & Therapy 12(58). 
Ossenkoppele, Rik et al. (2016).  “Tau PET patterns mirror clinical and neuroanatomical 
variability in Alzheimer's disease.” Brain  139(Pt 5): 1551-1567. 


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Ost, M., K. Nylen, et al.  (2006).  "Initial CSF total tau correlates with 1-year outcome in patients 
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Price, J. L., D. W. McKeel, Jr., et al.  (2009).  "Neuropathology of nondemented aging: 
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Sperling, R. A., K. A.  Johnson, et al.  (2012).  "Amyloid deposition detected with florbetapir F 18 
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APPENDIX 1: COGNITIVE RUN-IN PERIOD 
 
DIAN-TU-001:  A Phase II/III Multicenter Randomized, Double-Blind, 
Placebo-Controlled Platform Trial of Potential Disease Modifying 
Therapies Utilizing Biomarker, Cognitive, and Clinical Endpoints in 
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 Product: 
Not Applicable 
Protocol Number: 
DIAN-TU-001 
Protocol Version: 
Amendment 13 
Version Date: 
05 Apr 2023 
IND Number: 
115,652 
EudraCT Number:  
2013-000307-17 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .............................................................................................................. 102 
LIST OF FIGURES ..................................................................................................................... 103 
1 
INTRODUCTION ........................................................................................................... 104 
2 
STUDY DESIGN FOR COGNITIVE RUN-IN PERIOD ........................................................ 104 
3 
STUDY PROCEDURES ................................................................................................... 105 
 
Enrollment ....................................................................................................... 105 
 
Specific Study Visits  ......................................................................................... 106 
3.2.1 
CRI Screening Visit (CRI Screen) ...................................................... 106 
3.2.2 
CRI Entry Visit (CRI Entry) ................................................................ 107 
3.2.3 
CRI Visits 1, 3, 4, 6, 8, 10, and 12 ..................................................... 108 
3.2.4 
CRI Visits 2, 7, and 11 ...................................................................... 108 
3.2.5 
CRI Visits 5, 9, and 13:  ANNUAL VISIT AT HOST DIAN-TU SITE ......... 109 
4 
ANALYSIS PLAN ........................................................................................................... 110 
5 
ADVERSE EVENTS REPORTING .................................................................................... 110 
REFERENCES  ........................................................................................................................ 110 
SCHEDULE OF VISITS: COGNITIVE RUN-IN PERIOD ................................................................. 111 
 


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LIST OF FIGURES 
Figure 1 Cognitive Run-in Period Enrollment Scheme ........................................................... 105 
 
 
 


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1 INTRODUCTION 
The purpose of the cognitive run-in (CRI) period is to establish a trial-ready cohort of 
participants for enrollment into study drug arms appended to this DIAN-TU-001 protocol, or 
drug arms to be opened under US NIH Grant U01 AG059798 (PI EM McDade) based on eligibility 
at the time a study drug arm is open for enrollment. 
Run-in periods have several practical advantages, including increasing engagement of 
participants, establishing rapport with site personnel and personnel for home visits (if 
applicable), and familiarization of participants with the processes and procedures of the trial.  
One of the most important scientific advantages is a decrease in variability in cognitive test 
performance.  A CRI period can reduce the effects of temporal fluctuations in performance by 
allowing participants to habituate to the testing process, thereby reducing practice effects, 
demand characteristics and test anxiety. 
Moreover, results from clinical trials testing the β -secretase enzyme (BACE) inhibitors in those 
with and at risk for AD have identified evidence of an unanticipated cognitive decline.  A CRI 
period offers the opportunity to more easily detect a deleterious drug effect by establishing a 
reliable baseline in participants where the majority of participants in the primary prevention 
population are cognitively normal at trial entry.  This is particularly important for those 
participants that are much younger than their estimated age of onset where a decline in 
cognition would represent a significant deviation from the expected performance.  This could 
be very helpful in identifying potential deleterious side effects of therapies at an earlier point 
and reacting appropriately. 
The CRI period will help to ensure that a sufficient number of active and eligible participants 
qualify for entry into a study drug arm once opened to recruitment. 
2 STUDY DESIGN FOR COGNITIVE RUN-IN PERIOD 
If no study drug arm is available for immediate enrollment or if a future drug arm is stopped 
prior to the planned completion (e.g., at biomarker interim, drug toxicity), a CRI period may be 
opened for recruitment by the sponsor.  Participants considered for eligibility for the CRI period 
include participants 18 to 80 years of age 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: 
• cognitively normal or with mild cognitive impairment or mild dementia, Clinical 
Dementia Rating (CDR) 0 to 1 (inclusive) and within –10 to +10 years of the predicted or 
actual age at cognitive symptom onset (Secondary prevention population); target 
number of participants = 500 
• cognitively normal and within 11 to 25 years younger (−25 to –11) than their estimated 
age at symptom onset (Primary prevention population); target number of participants = 
240 


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The CRI period will consist of screening, entry, and  follow-up visits and may last until a study 
drug arm opens for recruitment, but no longer than approximately 3 years. 
Once a study drug arm is open for enrollment into the DIAN-TU-001 protocol, participants 
meeting the estimated years from symptom onset (EYO) entry criteria would be eligible for 
screening and a Screening visit (V1), conducted either in their home by a home health nurse or 
at the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) site, will be scheduled to 
collect safety labs and to reassess the suitability of the participant for entry into the trial 
(Section 6.3.2 of main protocol). A minimum of 8 weeks must elapse between the participant’s 
last administration of a cognitive battery in the CRI period and administration of a drug arm’s 
Baseline (V2) cognitive battery. 
Figure 1 
Cognitive Run-in Period Enrollment Scheme 
 
 
 
Following approval of the DIAN-TU-002 (primary prevention) protocol in a given region, 
participants in the EYO range of primary prevention in this DIAN-TU-001 (secondary prevention) 
protocol may transition to the DIAN-TU-002 protocol. Data collected in both the DIAN-TU-001 
and DIAN-TU-002 protocols will be shared. 
 
3 STUDY PROCEDURES 
 Enrollment 
See details in Sections 3.1 and 3.4 of the main protocol.   
DIAD CRI Period:
≥ 18 Yrs of Age;                     
−25 to +10 EYO;  CDR 0-1
N = 740
Primary Prevention
≥ 18 Yrs of Age;                         
−25 to −11 EYO;  CDR 0
n = 240
DIAN-TU-002 Protocol  
Drug Arm
[US NIH Grant                    
U01 AG059798]
Secondary Prevention
≥ 18 Yrs of Age;                
−10 to +10 EYO;  CDR 0-1
n = 500
DIAN-TU-001 Protocol  
Drug Arm
[US NIH Grant                         
R01 AG053267]


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 Specific Study Visits  
3.2.1 CRI Screening Visit (CRI Screen) 
The CRI screening period may last up to 8 weeks, starting at the collection of the first screening 
procedure (e.g., clinical safety lab collection).  The participant is enrolled using the Interactive 
Web Response System (IWRS). 
Location: CRI Screen procedures may be completed at a DIAN-TU qualified site or at the 
participant’s home or other trial-identified location with the trial-certified cognitive rater/home 
health nurse.  This visit also includes telephone calls with the DIAN-TU site staff.  The 
participant may be contacted by their DIAN-TU site by telephone or during a regular DIAN 
Observational (DIAN-OBS) study visit.  The participant is given the opportunity to review the 
informed consent form (ICF), ask questions and obtain answers, and sign the CRI ICF (only if the 
CRI period is enrolling). 
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 2 to 8-week screening period begins.  Informed consent should be 
obtained from both participant and study partner.  Unless otherwise specified, all other CRI 
Screen procedures may occur throughout the screening period (2 to 8 weeks before CRI Entry).  
The CRI Screening visit in the home ensures participant eligibility before travel (if applicable) to 
the DIAN-TU site for CRI entry testing and enrollment. 
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-TU 
Cognition Core Procedures Manual for additional details on order and timing of procedures): 
• Obtain informed consent (DIAN-TU site staff must be available to answer questions) 
• Enrollment in the IWRS 
• Obtain or confirm family history and determine parental estimated age at onset and 
participant’s actual age at onset, if symptomatic (DIAN-TU site staff).  Estimated age at 
onset should be determined as outlined in the Global Manual of Operations. 
• Verify documentation of participant’s trial eligible mutation status OR confirm via family 
pedigree and mutation documentation (proband) that the participant is at 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 
• Blood collection: 
o Genetic testing (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) 
o Clinical laboratory tests, including hematology, chemistry, liver enzyme, TSH, B12, 
hemoglobin A1c, PT, PTT, and INR 


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o Serum pregnancy test for people of childbearing potential (POCBP); people who 
have undergone tubal ligations are also required to have pregnancy test performed. 
• Urine collection for urinalysis 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight) 
• Ambulatory Research in Cognition (ARC) smartphone-based cognitive assessment: 
o Set-up and training per Section 6.1.14.2 of main protocol 
o Participants will complete the first week of assessments immediately following the 
CRI Screen Visit (per Section 6.1.14.2 of the main protocol).   
3.2.2 CRI Entry Visit (CRI Entry) 
Location: Host DIAN-TU site 
Time/Timing:  Approximately a two (2) day visit that is scheduled 2 to 8 weeks after the CRI 
screening visit.  The study partner participates in some of the procedures at CRI Entry and other 
annual visits at the DIAN-TU site.  If possible, the study partner should accompany the 
participant 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 CRI Entry and at 
subsequent annual visits are detailed in the Global Manual of Operations.  CRI Entry procedures 
may be scheduled over a longer time period of up to 2 weeks for participants living near the 
study site or if some study procedures (e.g., positron emission tomography [PET] scans) are 
done at a different DIAN-TU site. 
The date of the cognitive battery test administered at the CRI Entry visit should be used to 
determine timing of subsequent visits for the CRI period. 
Procedures: 
• In-person review of informed consent for participants who provided consent over the 
telephone 
• Medical/treatment history, including: 
o Concomitant medications 
o Assessment/recording of pre-existing conditions or adverse events 
• Blood collection for provenance7 testing of CRI Screening genetic sample (to confirm 
specimen identity) 
• Urine pregnancy test for POCBP scheduled for [18F]MK-6240 Tau PET 
• Administration of the Columbia Suicide Severity Rating Scale (C-SSRS) 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, and 
height) 
                                                        
7 Provenance testing is performed for quality assurance purposes to ensure that blood sample obtained at the CRI 
entry visit is from same individual as sample obtained at CRI screening visit. 


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• Blood collection (fasting) for plasma for biomarker analysis, stored plasma for future 
testing per Section 6.1.12. For participants having completed CRI Entry before approval 
of Amendment 13, this blood collection should be performed at the first opportunity, 
e.g. next site visit.  
• Physical and neurological examinations 
• Clinical assessments:  CDR, calculation of Clinical Dementia Rating Sum of Boxes (CDR-
SB), Geriatric Depression Scale (GDS), Functional Assessment Scale (FAS), 
Neuropsychiatric Inventory (NPI-Q) and Mini-Mental State Exam (MMSE), assessment of 
clinical diagnosis and clinician judgment of symptoms. 
Note: For each participant, 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 electrocardiogram (ECG) (local) 
• DIAN-TU Harmonized Cognitive Battery (per Section 6.1.14.2 of main protocol) 
• Magnetic resonance imaging (MRI), including safety MRI sequences, to be performed on 
the first day 
• [18F]MK-6240 Tau PET scan (based on tracer availability and limited to participants           
–10 to +10 EYO [NOT participants within –25 to −11 EYO at time of CRI Entry]) 
• Final verification that all inclusion and no exclusion criteria are met (including receipt of 
MRI read)     
3.2.3 CRI Visits 1, 3, 4, 6, 8, 10, and 12 
Location:  Visit will be conducted over the phone with the coordinator. 
Time/Timing:  Visits as listed below (calculated from day that the cognitive battery was 
completed at CRI Entry), with a visit window of ± 4 days. 
Visit No. 
1 
3 
4 
6 
8 
10 
12 
Week 
12 
32 
40 
64 
88 
116 
140 
Procedures:  
• Coordinator phone call to review any adverse events and concomitant medications 
3.2.4 CRI Visits 2, 7, and 11 
Location:  DIAN-TU trial site or at the participant’s home or other trial-identified location. 
Time/Timing:  Visits as listed below (calculated from day that the cognitive battery was 
completed at CRI Entry), with a visit window of ± 4 days. 
Visit No. 
2 
7 
11 
Week 
24 
76 
128 


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Procedures:  
• Secondary Prevention Population: 
o Concomitant medications 
o Assessment/recording of adverse events 
o DIAN-TU Harmonized Cognitive Battery (per Section 6.1.14.2 of main protocol) 
o Clinical assessment:  MMSE only 
o ARC smartphone-based cognitive assessments reminder for completion:  
participants will be prompted to begin the testing and will continue to complete 
the test over a continuous 7-day period.  The test can be started within a ± 2-
week window 
o Coordinator phone call to review any adverse events when the visit is conducted 
by a home health nurse 
• Primary Prevention Population: Concomitant medications and adverse events will be 
assessed/recorded over the phone with the coordinator 
 
3.2.5 CRI Visits 5, 9, and 13:  ANNUAL VISIT AT HOST DIAN-TU SITE 
Location:  DIAN-TU site 
Time/Timing:  Visits as listed below (calculated from day that the cognitive battery was 
completed at CRI Entry), with a visit window of ± 7 days.  Note that annual visits may take place 
over 2 or more days. 
Visit No. 
5 
9 
13 
Week 
52 
104 
156 
Procedures:  
• Concomitant medications 
• Assessment/recording of adverse events 
• Urine pregnancy test for POCBP scheduled for [18F]MK-6240 tau PET 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature, weight, and 
height) 
• Physical and neurological examination 
• Clinical assessment: Full Battery: CDR, calculation of CDR-SB, NPI-Q, GDS, FAS, MMSE, 
and assessment of clinical diagnosis and clinician judgment of symptoms.   
NOTE: For each participant, 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 and GDS) or 
in cognitive testing.  


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• DIAN-TU Harmonized Cognitive Battery (per Section 6.1.14.2 of main protocol) 
• ARC smartphone-based cognitive assessments (reminder for completion):  Participants 
will be prompted to begin the testing and will continue to complete the test over a 
continuous 7-day period.  
• Secondary Prevention Population only: 
o MRI, including safety MRI sequences, to be performed for participants scheduled 
for [18F]MK-6240 Tau PET Scan for V5 and V9.  
o [18F]MK-6240 Tau PET Scan (based on tracer availability at time of CRI Entry) for 
V5 and V9. No Tau PET scan at V13. 
4 ANALYSIS PLAN 
The data collected during the CRI period will follow the participant when enrolled to a study 
drug arm.   
The data from CRI primary prevention population will be used in the future drug arm in the 
primary prevention trial DIAN-TU-002. 
5 ADVERSE EVENTS REPORTING 
Adverse events will be reported as detailed in Section 7 of the main protocol. 
REFERENCES  
None. 
 


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SCHEDULE OF VISITS: Cognitive Run-In Period 
Schedule of Visits: Cognitive Run-in Period – Screening through Week 104 
Procedures 
VISIT SITE1,2  
Home (H) 
DIAN-TU 
Phone (Ph)  
Ph/H 
Ph 
Ph 
DIAN-TU 
Ph 
Ph/H 
Ph 
DIAN-TU 
Visit No. 
Cognitive 
Run-in 
Screening Visit 
(CRI Screen) 
Cognitive 
Run-in 
Entry Visit 
(CRI Entry) 
CRI 1 
CRI 2 
CRI 3 
CRI 4 
CRI 5 
CRI 6 
CRI 7 
CRI 8 
CRI 9 
Timing (weeks)3 
-8 to -2 
0 
12 
24 
32 
40 
52 
64 
76 
88 
104 
Informed Consent4 
X 
X 
 
 
 
 
 
 
 
 
 
Enrollment in IWRS 
X 
 
 
 
 
 
 
 
 
 
 
Verification of Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
Family History/Age at Onset Assessment5 
X 
 
 
 
 
 
 
 
 
 
 
Demographics/Study Partner Information5 
X 
 
 
 
 
 
 
 
 
 
 
Medical/Treatment History6 
X 
X 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genetic Testing 
X 
X8 
 
 
 
 
 
 
 
 
 
Clinical Laboratory Tests: Hematology, 
Chemistry, Urinalysis9 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing10 
X 
X 
 
 
 
 
X 
 
 
 
X 
C-SSRS 
 
X 
 
 
 
 
 
 
 
 
 
Vital Signs11 
X 
X 
 
 
 
 
X 
 
 
 
X 
Blood collection (fasting)  for plasma biomarkers 
and stored plasma19 
 
X19 
 
 
 
 
 
 
 
 
 
Physical/Neurological Exam 
 
X 
 
 
 
 
X 
 
 
 
X 
Clinical Assessment: Full Battery12 
 
X 
 
 
 
 
X 
 
 
 
X 
Secondary Prevention Population: Clinical 
Assessment: MMSE Only 
 
 
 
X 
 
 
 
 
X 
 
 
Local 12-Lead ECG13 
 
X 
 
 
 
 
 
 
 
 
 
Primary Prevention Population: DIAN-TU 
Harmonized Cognitive Battery14 
 
X 
 
 
 
 
X 
 
 
 
X 


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Schedule of Visits: Cognitive Run-in Period – Screening through Week 104 
Procedures 
VISIT SITE1,2  
Home (H) 
DIAN-TU 
Phone (Ph)  
Ph/H 
Ph 
Ph 
DIAN-TU 
Ph 
Ph/H 
Ph 
DIAN-TU 
Visit No. 
Cognitive 
Run-in 
Screening Visit 
(CRI Screen) 
Cognitive 
Run-in 
Entry Visit 
(CRI Entry) 
CRI 1 
CRI 2 
CRI 3 
CRI 4 
CRI 5 
CRI 6 
CRI 7 
CRI 8 
CRI 9 
Timing (weeks)3 
-8 to -2 
0 
12 
24 
32 
40 
52 
64 
76 
88 
104 
Secondary Prevention Population: DIAN-TU 
Harmonized Cognitive Battery14 
 
X 
 
X 
 
 
X 
 
X 
 
X 
Primary Prevention: ARC Smartphone-based 
Cognitive Assessments15 
X 
 
 
 
 
 
X 
 
 
 
X 
Secondary Prevention: ARC Smartphone-based 
Cognitive Assessments15 
X 
 
 
X 
 
 
X 
 
X 
 
X 
Volumetric MRI 
 
X 
 
 
 
 
X16 
 
 
 
X16 
Secondary Prevention: [18F]MK-6240 Tau PET 
(when available)17  
 
X 
 
 
 
 
X 
 
 
 
X 
Coordinator Phone Call18 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 


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Schedule of Visits: Cognitive Run-in Period – Week 116 through Week 156 
Procedures 
VISIT SITE1,2  
Ph 
Ph/H 
Ph 
DIAN-TU 
Visit No. 
CRI 10 
CRI 11 
CRI 12 
CRI 13 
Timing (weeks)3  
116 
128 
140 
156 
Concomitant Medications 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
Pregnancy Testing10 
 
 
 
X 
Vital Signs11 
 
 
 
X 
Physical/Neurological Exam 
 
 
 
X 
Clinical Assessment: Full Battery12 
 
 
 
X 
Secondary Prevention Population: Clinical 
Assessment: MMSE Only 
 
X 
 
 
Primary Prevention Population: DIAN-TU 
Harmonized Cognitive Battery14 
 
 
 
X 
Secondary Prevention Population: DIAN-TU 
Harmonized Cognitive Battery14 
 
X 
 
X 
Primary Prevention ARC Smartphone-based 
Cognitive Assessments15 
 
 
 
X 
Secondary Prevention ARC Smartphone-based 
Cognitive Assessments15 
 
X 
 
X 
Coordinator Phone Call18 
 
X 
 
 
 
 
 


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Schedule of Visits: Cognitive Run-in Period - Footnotes 
Footnotes: 
1. Annual visits will be conducted at the host DIAN-TU site.  For participants who live at a distance from the DIAN-TU site, other visits may be conducted at a site nearer to 
their home (H).  See next two footnotes for additional detail. 
2. Visits designated as occurring at home (H) may occur at the DIAN-TU site or, for participants who live at a distance from the DIAN-TU site, these visits may be conducted 
by a trial-designated home health nurse at the participant’s home or other trial-identified location.  These visits may include phone calls from the host DIAN-TU site staff. 
3. The specific date of the cognitive battery administration at the Cognitive Run-In (CRI) Entry visit should be used to determine timing of subsequent visits. 
4. The informed consent form (ICF) for CRI must be signed before any study procedures are performed. 
5. Family history/age at onset and demographic information for participant and study partner will be collected during the CRI Screen visit and confirmed at the CRI Entry 
visit.  This information will not be collected at subsequent visits unless the participant 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 CRI Screen visit and reviewed at CRI Entry visit. 
8. Provenance testing to confirm specimen identity will be performed at CRI Entry visit only. 
9. Clinical laboratory assessment scheduled for CRI Screen visit only; includes TSH, B12, Hemoglobin A1c, PT, PTT, and INR. 
10. Serum pregnancy testing will be performed at CRI Screening visit.  Women who have undergone tubal ligations are also required to have pregnancy tests performed.  
Urine pregnancy test for people of childbearing potential who are scheduled for a [18F]MK-6240 PET scan are to have a confirmed negative urine pregnancy test (HCG) on 
the day of PET imaging, before [18F]MK-6240 dose administration. 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. 
11. Vital signs include blood pressure, heart rate, respiratory rate, body temperature, and weight.  Height collected at CRI Entry and annual visits only. 
12. Clinical assessments at CRI Entry visit and annual visits.  Study partner interview and administration of CDR and supplemental CDR-SB; clinician assessment of symptoms 
and diagnosis; Geriatric Depression Scale (GDS), Functional Assessment Scale (FAS), Neuropsychiatric Inventory (NPI-Q), and Mini Mental State Examination (MMSE). 
13. Electrocardiogram (ECG) will be performed and read locally by a qualified physician or cardiologist.  Investigators are to ensure no evidence of exclusionary findings. 
14. Cognitive testing should be completed early in the day. 
15. Ambulatory Research in Cognition (ARC) smartphone-based cognitive assessment, if applicable: participant will be prompted to begin the testing and will continue to 
complete the test over a continuous 7-day period.  The test can be started with a ± 2-week window.  See Section 6.1.14.2 of the main protocol and the DIAN-TU 
Cognition Core Procedures Manual for additional information. 
16. Magnetic resonance imaging (MRI) required only for participants who are also scheduled for [18F]MK-6240 Tau PET scan. 
17. Sites with access to [18F]MK-6240 tau tracer will participate including arranging for participants to scan at another DIAN-TU qualified site if not available at their enrolling 
site.  Limited to participants who are −10 EYO to +10 EYO (not scheduled participants within –25 to –11 EYO at time of CRI Entry). 
18. Site study coordinators should call participants either during or within two weeks after CRI 2, CRI 7 and CRI 11, if conducted via home health nurses. For primary 
prevention population, concomitant medications and adverse events will be assessed/recorded over the phone with the coordinator.  
19. For participants having completed CRI Entry before approval of Amendment 13, this blood collection should be performed at the first opportunity, e.g., at the next site 
visit. 


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APPENDIX 2: 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 
DIAN-TU Harmonized Cognitive Battery17 
X 
X 
ARC Smartphone-based Cognitive Assessments21 
X 
X22 
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 participants who live at a distance 
from the DIAN-TU site, these visits may be conducted by a home health nurse at the participant’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.  Participants 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 participant is randomized to a specific study drug arm at V2, the participant 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 ‘main consent’ is referenced within. 


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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 participant and study partner will be collected during the 
screening period and confirmed at the baseline visit, if not already collected during the Cognitive Run-In (CRI) period.  
This information will not be collected at subsequent visits unless the participant or study partner becomes aware of 
new information or the study partner changes during the study.  
6. Home health nurses (HHNs) 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.  Results from CRI period may be used unless the participant or study partner becomes aware of new 
information. 
7. Preexisting conditions will be documented at screening visit and reviewed at baseline visit (V2) prior to study drug 
administration. 
8. Genetic testing does not need to be repeated if results from the CRI period are available. 
9. Provenance testing to confirm specimen identity will be performed at baseline visit only (V2), if not completed at the 
CRI Entry visit 
10. Includes TSH, B12, hemoglobin A1c, PT, PTT, and INR are collected at Visit 1 only 
11. Serum pregnancy testing will be performed at screening (V1) and safety follow-up visit.  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 and weight will 
be measured 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-SB; 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 DIAN-TU Harmonized Cognitive Battery will be administered by a trial-certified cognitive rater.  See Section 6.1.14.2 
of the main protocol and the arm-specific DIAN-TU Cognition Core Procedures Manual for additional information.  
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 participant 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. 
21. Ambulatory Research in Cognition (ARC) smartphone-based cognitive assessment: participant will be prompted to begin 
the testing and will continue to complete the test over a continuous 7-day period.  The test can be started with a ± 1-
week window.  See Section 6.1.14.2 of the main protocol and the DIAN-TU Cognition Core Procedures Manual for 
additional information. 
22. Participants who are CDR=1 at Baseline (V2) will not be expected to continue ARC assessments and will be asked to 
uninstall the application. 
 


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APPENDIX 3: GANTENERUMAB 
 
DRUG-SPECIFIC INFORMATION: 
Gantenerumab (RO4909832) 
 
DIAN-TU-001:  A Phase II/III Multicenter Randomized, Double-Blind, 
Placebo-Controlled, Platform Trial of Potential Disease Modifying 
Therapies Utilizing Biomarker, Cognitive and Clinical Endpoints in 
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 Product: 
Gantenerumab (RO4909832) 
Protocol Number: 
DIAN-TU-001 
Protocol Version: 
Amendment 13 
Version Date: 
05 Apr 2023 
IND Number: 
115,652 
EudraCT Number: 
2013-000307-17 
 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................................. 118 
LIST OF TABLES ....................................................................................................................... 121 
LIST OF FIGURES ..................................................................................................................... 122 
1 
DRUG-SPECIFIC INTRODUCTION ................................................................................. 123 
 
Background ...................................................................................................... 123 
 
Study Drug ....................................................................................................... 123 
 
Preclinical Data ................................................................................................ 123 
 
Clinical Data  .................................................................................................... 124 
 
Dose Selection/Rationale ................................................................................. 133 
1.5.1 
Double-Blind Period (1200 mg Q4W, G2 and G3 Formulations) ...... 133 
1.5.2 
Open-Label Extension (1500 mg Q2W, G4 Formulation) ................. 134 
1.5.2.1 
Dose Regimen ..................................................................... 134 
1.5.2.2 
PK/PD (Amyloid PET) Model-Based Dose Selection .............. 134 
1.5.2.3 
Safety Monitoring ............................................................... 135 
 
Risks/Benefits .................................................................................................. 136 
 
Drug-specific Study Design ............................................................................... 138 
 
Rationale for Biomarker Endpoint .................................................................... 138 
 
Primary Efficacy Endpoint  ............................................................................... 139 
1.9.1 
Double-Blind Period ........................................................................ 139 
1.9.2 
Open-Label Extension ..................................................................... 139 
 
Additional Endpoints and Biomarker Endpoint for Interim Analyses................. 139 
 
Primary Safety Endpoints ................................................................................. 140 
 
Drug-specific Tests ........................................................................................... 140 
1.12.1 
Pharmacokinetics (PK) .................................................................... 140 
1.12.2 
Anti-drug-antibodies (ADA) ............................................................. 141 
 
Drug-specific Safety Concerns .......................................................................... 142 
1.13.1 
Amyloid related imaging abnormalities (ARIA) ................................ 142 
1.13.2 
Injection site reactions .................................................................... 143 
1.13.3 
Neutropenia in the gantenerumab OLE period................................ 143 


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ARIA-Related Interventions Including Dose Changes and Discontinuation ........ 144 
 
Drug-specific Discontinuations or Withdrawal.................................................. 147 
2 
STUDY DRUG ............................................................................................................... 147 
 
Open-Label Extension: Drug Description .......................................................... 147 
 
Open-Label Extension: Drug Treatment Regimen ............................................. 148 
 
Open-Label Extension: Packaging, Preparation and Administration of Drug 
Product ............................................................................................................ 150 
 
Open-Label Extension: Blinding of Drug Product .............................................. 150 
 
Open-Label Extension:  Dispensing of Drug Product ......................................... 151 
 
Open-Label Extension: Assessing Compliance with Drug Product ..................... 152 
3 
STUDY PROCEDURES ................................................................................................... 152 
 
Enrollment ....................................................................................................... 152 
 
Specific Study Visits – Open-Label Extension Treatment Period........................ 152 
3.2.1 
OLE Visit 1 (baseline/first dose) ...................................................... 154 
3.2.2 
OLE Visits 2-6, 8-9, 11-12, 14-15, 17-19, 21-22, 24-26, 28-29, 31-
32, 34-35, and 37-39  ...................................................................... 156 
3.2.3 
OLE Visits 10, 16, 23, 30, and 36 ..................................................... 157 
3.2.4 
OLE Visit 7 ....................................................................................... 158 
3.2.5 
OLE VISITS 13, 27, and 40 or Early Termination: ANNUAL VISIT AT 
DIAN-TU SITE .................................................................................. 158 
3.2.6 
OLE Visits 20 and 33 ........................................................................ 159 
3.2.7 
Safety Follow-up Visit ..................................................................... 160 
3.2.8 
Early Termination Visit/Post-treatment Follow-up .......................... 160 
3.2.9 
Safety Magnetic Resonance Imaging MRI ....................................... 161 
3.2.9.1 
Regular Safety MRIs ............................................................ 161 
3.2.9.2 
Sentinel Cohort MRIs........................................................... 162 
4 
DRUG-SPECIFIC ANALYSIS PLAN .................................................................................. 162 
 
OLE Period ....................................................................................................... 162 
4.1.1 
Biomarker Endpoint Statistical Analysis, Power and Sample 
Size Justification .................................................................. 162 
4.1.2 
Biomarker Endpoint Power Analysis .................................... 162 


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4.1.3 
Biomarker Endpoint Sample Size Justification ..................... 163 
4.1.4 
Interim Analysis ................................................................... 163 
 
Changes to the Data Analysis ........................................................................... 164 
5 
DRUG-SPECIFIC ADVERSE EVENTS AND REPORTING ................................................... 164 
6 
REFERENCES ................................................................................................................ 165 
GANTENERUMAB SCHEDULE OF VISITS: OPEN-LABEL EXTENSION ......................................... 166 
 
 
 


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LIST OF TABLES 
 
Table 1 
Procedures for Asymptomatic ARIA-E ..................................................................... 144 
Table 2 
Procedures for Symptomatic ARIA-E: Any incidence of symptomatic ARIA-E or 
asymptomatic with lesions >2 cm ........................................................................... 145 
Table 3 
Procedures for ARIA-H Microhemorrhage ............................................................... 146 
Table 4 
Procedures for Superficial Siderosis ........................................................................ 146 
Table 5 
DIAN-TU-001 Gantenerumab OLE Titration Safety MRI Schedule ............................ 149 
Table 6 
Gantenerumab - Formulation Dosing Table ............................................................. 151 
 
 


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LIST OF FIGURES 
Figure 1 DIAN-TU-001 Gantenerumab OLE Dose Titration and MRI Monitoring Schedule ..... 136 
Figure 2 Enrollment Diagram: DIAN-TU-001 Gantenerumab Open Label Extension Period ... 152 
Figure 3 Power estimation for different sample sizes and different projected mean 
changes from the OLE baseline to the end of the 3-year OLE. One-sided, one-
sample t-test with type I error of 0.025 ................................................................... 163 
 
 


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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 22 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 highly 
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.  
 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 (Kd ~ 0.5 nM) as determined in vitro.  Specificity was demonstrated for native human Aβ 
plaques on brain sections.  The minimal effective concentration for staining of human Aβ 
plaques was determined to be 10 ng/mL (0.07 nM). 
In functional assays gantenerumab induced cellular phagocytosis of human Aβ 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 
phenotype.  Gantenerumab showed significant Aβ plaque binding up to nine weeks, indicating 


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that there is no requirement for continuous high peripheral levels to achieve a sustained 
binding of gantenerumab to amyloid plaques. 
 Clinical Data  
A summary of the available results of completed clinical studies with gantenerumab is 
presented in this section.  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 participants.  The study 
evaluated safety, tolerability, and pharmacokinetics (PK) of gantenerumab following a single IV 
infusion or subcutaneous (SC) injection.  In this study, participants 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 
(Q4W) 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 
reported for bapineuzumab.  The MRI findings are described further below.  Otherwise, 
gantenerumab was well tolerated in NN19866. 


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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 to 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 Q4W 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 participants.  Participants 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 participants.  
Participants 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. 
BP30042 
A study assessing the safety and tolerability of single ascending doses of SC gantenerumab 
included a total of 38 healthy male participants (32 on gantenerumab and 6 on placebo).  
Participants were randomized to receive single doses of 450 mg, 900 mg or 1500 mg. 
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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 participants.  Participants 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 participants.  The plasma exposure in terms of area 
under the concentration-time curve between time 0 and time infinity (AUCInf) was 
approximately 1.18-fold higher after SC administration of 600 mg gantenerumab G4 compared 
to 600 mg gantenerumab G3, whereas maximum plasma concentrations (Cmax) were similar.  
Gantenerumab produced with either process was generally well tolerated. 
Clinical Pharmacokinetics (PK) 
The PK of gantenerumab after intravenous administration were investigated in White 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). 
 
 
 
lasma 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 
initially included Study WN25203 in participants with prodromal AD, and Study WN28745 in 
participants with mild AD, subsequently converted to open-label extensions; and later 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. 
Further details from each study are summarized below. 
WN25203 
WN25203 was 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 participants 
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, 
participants 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 
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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 Q4W. 
WN25203-PET 
Study WN25203 included 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 
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.  In Study WN28745, 
gantenerumab, at a dose of 105 mg SC Q4W for 6 months followed by 225 mg SC Q4W for up to 
24 months, was safe and well tolerated by patients with mild AD. 
Dosing of Gantenerumab up to 1200 mg Q4W: Open-label Extensions of WN25203 and Study 
WN28745; and Placebo-controlled Period of DIAN-TU-001 Study 
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.  Overall 154 of the 799 patients originally randomized into the study entered the 
WN25203 OLE.  Overall, 230 of 389 patients originally randomized into the study entered the 
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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 to 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 included 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 showed 
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. 
 
 
 
 
 
 
 
 
 
 
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In the WN28745-Tau PET substudy, there was no temporal association between the tau tracer 
administration and AEs. 
In the OLE phase of Studies WN25203 and WN28745, gantenerumab, in doses of up to 1200 mg 
SC Q4W for up to 236 weeks (~4.5 years) for WN25203, and 245 weeks (~4.5 years) for 
WN28745, was safe and well tolerated by patients with AD. 
In the DIAN-TU-001 study, there was no benefit of gantenerumab observed on the primary 
endpoint, the DIAN Multivariate Cognitive Endpoint (DIAN-MCE), or on clinical endpoints 
Clinical Dementia Rating Sum of Boxes (CDR-SB) and Functional Assessment Scale (FAS).  
However, potential cognitive impact was inconclusive given that the asymptomatic placebo 
group showed no cognitive decline, and symptomatic patients had declined substantially before 
reaching target doses.  Gantenerumab significantly reduced brain Aβ deposition, cerebrospinal 
fluid (CSF) total tau, and CSF pT181, and attenuated the increase of neurofilament light chain 
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(NfL).  Aβ Pittsburgh compound B positron emission tomography (PiB-PET) results 
demonstrated significant reduction of Aβ deposition with gantenerumab compared to placebo 
at years 2 and 4. Gantenerumab was safe and well tolerated in doses up to 1200 mg SC Q4W 
(G3).  During the placebo-controlled period of the trial, amyloid-related imaging abnormalities-
cerebral edema (ARIA-E) were observed in 19.2% (10/48) of the gantenerumab group; 
compared to the placebo group, participants in the gantenerumab arm were more likely to 
develop ARIA-E (odds ratio [OR]=9.29, 95% confidence interval [CI]=[1.1, 75.9], p<0.05). ARIA-E 
cases were PiB+ and 60% had cognitive impairment (CDR>0).  ARIA-E cases were mostly 
asymptomatic for lesion associated neurologic change (8/10); if symptoms occurred (2/10), 
they were mild in nature and resolved.  ARIA-E events were managed by temporarily 
withholding the dose and resuming at similar or lower doses, with most reaching the target 
dose (3/10 ARIA-E cases discontinued from the trial, mainly to AD progression).  APOE genotype 
was predictor of ARIA-E.  ARIA-E frequency was 31% in APOE-ɛ4+ and 14% in APOE-ɛ4- (OR=5.0, 
95%; CI [1.0, 30.4], p=0.055).  Seventy (70) percent of the ARIA-E cases occurred at higher doses 
(900 mg or more) and generally after 2 doses of a titration dose.  However, the mean severity 
as measured by Barkhof score was similar regardless of the dose (higher dose=2.8 vs lower 
doses=3.5).  
 
ARIA-E findings were clinically manageable by protocol-defined MRI monitoring and dose 
intervention algorithms.  Clinical symptoms were experienced by a minority of patients with 
ARIA findings on MRI.  If clinical symptoms did occur, they tended to be mild and non-serious, 
and resolved upon dosing suspension.  All serious symptoms that have occurred in patients 
with ARIA-E (4 cases of seizure/epilepsy, 2 cases of stroke-like symptoms, and 1 case of serious 
confusion) resolved following the protocol-mandated dosing intervention and ARIA resolution. 
Immunogenicity and Safety 
 
  
 
 
 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, in WN25203 double-blind period 
 
 
 
No drug-effect on white blood cells or neutrophils was observed.  
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The identified risks of gantenerumab treatment are ARIA of edema/effusion (ARIA-E) and of 
microhemorrhage/hemosiderin deposition (ARIA-H), and injection-site reactions (ISRs) 
associated with SC administration. 
WN29922 and WN39658 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Summary 
Early evidence with anti-amyloid monoclonal antibodies revealed dose-dependent ARIA, and 
effects on clinical and cognitive outcomes with significant amyloid plaque removal (Mintun et 
al., 2021; Swanson et al., 2021).  Evidence from two clinical trials with similar antibodies against 
aggregated Aβ including plaques (i.e., gantenerumab and aducanumab) provide new insights 
into the biological mechanism of aggregated amyloid removal. 
This evidence also indicates that ARIAs are predictable and manageable events.  Gantenerumab 
data also suggest that beneficial effects 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 safety risks that have emerged to date for 
gantenerumab.  Overall, gantenerumab up-titration has been implemented with the objective 
to reduce 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.   
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No other clinical safety liabilities of major relevance have emerged. 
 Dose Selection/Rationale  
1.5.1 Double-Blind Period (1200 mg Q4W, G2 and G3 Formulations) 
The initial dose in the DIAN-TU-001 study double-blind period was 225 mg gantenerumab, 
administered subcutaneously (SC), every 4 weeks (Q4W).  The study was initiated using the 
lyophilized formulation (generation 2 [G2]) and transitioned to the high concentration liquid 
formulation ([HCLF], generation 3 [G3]) as detailed below. 
This dosing regimen was investigated in heterozygous carriers and non-carriers of APOE4 in the 
WN25203 (Scarlet RoAD) trial with an acceptable safety profile.  In WN25203, the dose 
administered to homozygous APOE4 carriers was 105 mg Q4W SC. 
The starting dose of 225 mg of the G2 formulation in the DIAN-TU-001 study, including 
participants homozygous for the APOE4 allele was justified based on the following 
considerations: 
• The DIAN-TU-001 study applied similar MRI monitoring scheme to WN25203 and 
WN28745 with a predefined ARIA related intervention algorithm  
• All new ARIA findings were reviewed by the Project Arm Leader (PAL), Medical Director 
or designee who advised the site on whether a more conservative approach should be 
considered than defined in the ARIA related intervention algorithm (Section 1.14) 
• Participants recruited into the trial were 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) was the 
predominant risk for AD and for amyloid deposition in the DIAN-TU population 
• Given the PET data obtained in the MAD study (Study NN19866) where decreases in the 
amyloid plaque burden were observed, the dosage selected based on systemic overall 
exposure was expected to reduce the plaque burden relative to placebo 
Based on results of a pre-planned futility analyses in the concurrent gantenerumab study 
(WN25203) and similar monoclonal antibody (aducanumab) data emerging at much higher 
doses in sporadic Alzheimer’s disease following approval of Amendment 5, all participants 
initiated up–titration which included transition to the HCLF G3 formulation.  
 
 
 
 
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1.5.2 Open-Label Extension (1500 mg Q2W, G4 Formulation) 
1.5.2.1 
Dose Regimen 
The initial target dose in the OLE period was 
 
 
 
 
 
 
 Unless otherwise stated, 
gantenerumab product used within the OLE study period refers to the G4 formulation. 
The dose will be slowly increased via multiple titration steps similar to that used in the double-
blind period of the trial. Participants will follow the previously established OLE titration 
schedule to reach 
 by receiving 
 doses at each titration step; 
 
 
 and then 
.  After doses at 
, the dosing frequency will 
increase to 
 and participants will receive 
 for 12 weeks, and then the final, 
target dose of 
 thereafter (Figure 1).  The entire dose titration period will take 15 
months.  At some sites, participants may have received 3 or more doses at 
 
before regulatory approval and consenting to Amendment 11 is completed.  Those participants 
will proceed to initiate titration beyond 
 as soon as approvals are in place.   
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. 
1.5.2.2 
PK/PD (Amyloid PET) Model-Based Dose Selection 
Comparison of PET data from DIAD and sporadic AD (sAD) studies indicated that DIAD 
participants with mutations have higher amyloid growth rates and lower amyloid plaque 
removal following administration of gantenerumab than participants in sAD studies who 
received a similar gantenerumab regimen.  Extensive analyses were performed of the double-
blind period data and a combined sAD–DIAD PK/PET model of gantenerumab was developed to 
assess the effect of gantenerumab on amyloid plaque removal (PK/PD Model).  The quantitative 
results suggest that an approximate 3-fold higher dose of gantenerumab is required in DIAD 
mutation carriers compared to sAD to bring most participants below the amyloid threshold of 
positivity (20 centiloids) within 2 years and to fully remove amyloid plaques within 3-4 years. As 
greater amyloid removal is anticipated to increase the likelihood of subsequent improvement in 
cognitive and clinical response, this dose increase was considered necessary in the DIAD 
population.  
 
 double-blind period of the DIAN-TU-001 trial as a higher dose significantly 
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reduced CSF total tau and phospho tau 181 (ptau181), and significantly slowed increases in CSF 
NfL.   
1.5.2.3 
Safety Monitoring 
During the double-blind period of the DIAN-TU-001 trial, which used the same target 
gantenerumab dose as in the sporadic AD trials (Studies WN29922 and WN39658), the safety 
profile of gantenerumab was consistent with trials in sporadic AD.  In DIAN-TU-001, amyloid-
related imaging abnormalities-edema (ARIA-E) were observed in 19.2% (10/52) of the 
gantenerumab group.  Most ARIA-E occurred at doses over 900 mg Q4W. ARIA-E cases were 
mostly asymptomatic (7/10); if symptoms occurred (3/10), they were mild in nature and 
resolved.  Mean severity score measured by Barkhof score was similar regardless of the dose 
(Higher dose=2.8 vs Lower doses=3.5).  APOE genotype was a predictor (OR=5.0, 95%CI=1.0-
30.4) of ARIA-E during the double-blind period with 6 out of 10 ARIA-E cases being APOE-ε4 
carriers. 
MRI Monitoring and Sentinel Cohort 
This titration schedule in the DIAN-TU-001 OLE period will allow for a slow dose escalation over 
a minimum of 15 months with frequent safety MRI scans to monitor and respond to 
radiographic ARIA (Figure 1).  In addition to the titration safety MRI and stable dose MRI 
schedules in Figure 1 and Table 5, participants will be regularly monitored for health changes or 
complaints.   
Further outlined is the planned inclusion of a sentinel cohort for additional MRI monitoring in 
DIAN-TU-001 OLE.  The first 20 participants receiving two doses of 1020 mg Q2W will receive an 
additional safety MRI scan and safety clearance before proceeding with further participant 
exposure to this dose level.  In similar fashion, the first 20 participants receiving two doses of 
1500 mg Q2W will receive an additional MRI with safety clearance before proceeding with 
further participant exposure to this dose level.  No further participants will be eligible to up-
titrate to the 1020 mg Q2W and 1500 mg Q2W dose levels until a safety review of the 
respective sentinel cohort has been completed. 
The DIAN-TU Medical Monitors will review individual MRI changes and ARIA cases following the 
ARIA-Related Interventions outlined in Section 1.14 in addition to quarterly aggregate safety 
data reviews.   
Data Safety Monitoring Board (DSMB) 
At a study-wide level, dosing and safety will be monitored by an experienced DSMB with 
participant-matter experts on ARIA, amyloid removal, and AD to inform about the target dose 
for OLE.  DSMB monitoring will occur on a quarterly basis and will include review of ARIA cases, 
in addition to the sentinel cohort data.   


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 Risks/Benefits 
Participants in this study who receive active study drug have dominantly inherited Alzheimer’s 
disease (DIAD) mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor 
protein (APP) with very high penetrance (near 100%).  AD is a progressive and ultimately fatal 
disease, and no disease-modifying treatment is available to date. 
Plaque removal effect was demonstrated in the prodromal AD 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 DIAD, amyloid deposition is 
present at early asymptomatic stages of the disease when no memory impairment is present 
(Bateman et al., 2012).  In the DIAN-TU-001 study, gantenerumab reduced amyloid plaques in a 
dose-dependent fashion during the double-blind phase, however the 1200 mg Q4W dose did 
not fully remove amyloid plaques as measured by PiB-PET.  Given that prior imaging and 
neuropathological work suggest that pathology accumulates 3-fold faster and to a greater 
extent in DIAD than sporadic AD (Shepherd et al., 2009; Ringman et al, 2016), higher dose and 
longer duration of treatment may be needed to reduce amyloid to an amyloid negative level in 
the DIAD population.  Therefore, during the OLE period we will increase the dose of 
gantenerumab 
to 
 
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The quantitative results suggest that an approximate 3-fold higher dose of gantenerumab is 
required in DIAD mutation carriers compared to sAD to bring the majority of participants below 
the amyloid threshold of positivity (20 centiloids) within 2 years and to fully remove amyloid 
plaques within 3-4 years (Section 1.5.2.2). The amount of amyloid removal is an important goal 
to increase the probability of cognitive improvement and clinical response.  Recent findings 
from the DIAN-TU-001 double-blind period showed that gantenerumab reduced amyloid 
plaques in a dose-dependent fashion.  The effect of gantenerumab on amyloid removal 
assessed by PiB-PET was more pronounced at higher doses (1200 mg gantenerumab [G3 
formulation]).  In addition, the data suggested that higher doses resulted in larger treatment 
effects in downstream biomarkers such as CSF total tau and CSF ptau181 (Salloway et al., 2021). 
Thus, the higher doses to be administered in DIAD during the OLE period (up to 1500 mg Q2W) 
are expected to be more effective on plaque reduction and on downstream biomarkers (i.e., 
decreased CSF measures of tau and neurodegeneration). 
During the DIAN-TU-001 double-blind period, the safety profile of gantenerumab was consistent 
with trials in sporadic Alzheimer’s disease, and no new safety issues were identified.  Adverse 
events reported more frequently (> 20%) with gantenerumab than placebo were injection-site 
reactions, nasopharyngitis, and back pain; however, most AEs were of mild intensity and not 
limiting the maintenance of participants in the long-term treatment trial.  
Amyloid-related imaging abnormalities (ARIAs) events also represent an adverse event of 
concern in the development of immune-therapeutics targeting Aβ in the brain  (Sperling et al., 
2012).  These changes may include micro-hemorrhage (MCH), superficial siderosis (SS), and 
vasogenic edema/effusion (ARIA-E).  During the DIAN-TU-001 placebo-controlled period, ARIA-E 
events were observed in 19.2% (10/52) of the gantenerumab group.  ARIA-E findings were 
mostly asymptomatic (7/10); if symptoms occurred, they were mild in nature (headache, 
vertigo and ear pain) and resolved.  ARIA-E was more frequent during symptomatic stages of 
the disease (6/10, CDR>0), and at the higher doses (8/10, 900mg-1200mg [G3 formulation]).  
The mean time for ARIA-E resolution was 10.4±6.2 weeks.  ARIA-E events did not increase the 
probability of participant discontinuation.  
In the OLE phase of Studies WN25203 and WN28745, gantenerumab G3, in doses of up to 1200 
mg SC Q4W for up to approximately 4.5 years was safe and well tolerated by patients with AD. 
Refer to the IB for more information on the risk/benefit profile of gantenerumab. 
 
 
 
 
 
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Based on the experience with gantenerumab in the double-blind and OLE period, DIAN-TU-001 
will continue with dedicated monitoring and action plans for ARIA during the OLE period.  This 
includes a slow dose titration over 15 months and an ARIA-E risk minimization plan including 
frequent MRI monitoring and reads by independent experts together with an ARIA-based dose 
intervention algorithm, which appears to be effective in preventing clinical sequelae to the 
participants treated with gantenerumab.  In addition, sentinel safety MRI cohorts have been 
added for an initial, early review and safety check at each of the two titration steps at doses 
higher than those previously tested, i.e., 
 
Given results from the GRADUATE studies in early symptomatic sporadic AD, an interim analysis 
is planned to be conducted in this DIAN-TU-001 OLE in order to inform next steps (for details, 
see Section 4.1.4). 
Given the safety results and biomarker effects discussed above, the risk/benefit ratio for 
gantenerumab administration at higher doses in the OLE period remains acceptable.   
 Drug-specific Study Design 
Drug-specific, open-label extension study design features include the use of [11C]PiB-PET as the 
primary 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 ratio (C-SUVR) as biomarker endpoint for DIAN-TU Gantenerumab Arm (Double-
Blind and OLE Periods) 
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 with prodromal  to moderate (sporadic) Alzheimer’s 
disease with the group reaching <20 centiloids by Week 104 (Klein et al., 2019).  Statistically 
significant reductions in [11C]PiB binding were observed in patients treated with gantenerumab 
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as compared to controls in the DIAN-TU-001 double-blind placebo-controlled period (Salloway 
S, 2021). 
 Primary Efficacy Endpoint  
1.9.1 Double-Blind Period 
As detailed in prior protocol versions, the primary efficacy endpoint for the double-blind period 
was the DIAN-MCE which consisted 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. 
1.9.2 Open-Label Extension 
Primary endpoints for the OLE include cerebral amyloid imaging using [11C]PiB-PET as well as 
the safety and tolerability of treatment with gantenerumab at higher doses.   
Additional study endpoints for the gantenerumab OLE will be specified in the gantenerumab-
specific SAP.  The objectives of the OLE are as follows: 
(i) 
To enable participants, who have committed as much as 4 to 7 years to the double-
blind treatment period of the study, to continue or begin to receive gantenerumab, 
which improves critical markers of their progressive disease, following their 
participation in the longest placebo-controlled trial in DIAD;  
(ii) 
To determine if continued treatment with gantenerumab at its target dose can result 
in complete removal of brain amyloid;  
(iii) To investigate which non-amyloid related downstream biological measures (e.g. tau 
and markers of neurodegeneration) can be improved or normalized with complete 
removal of amyloid at different stages of disease;  
(iv) To investigate the relationship of these biological measures with cognitive and clinical 
findings; and  
(v) 
To assess the summation of gantenerumab’s effect on biomarkers during the entire 
double-blind period and open label extension period, including the common close 
portion in which biomarkers were not assessed (i.e., from year 4 to 7). 
 Additional Endpoints and Biomarker Endpoint for Interim Analyses 
Additional 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 gantenerumab-
specific SAP for drug-specific differentiation of endpoint classification based on the respective 
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 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 for the double-blind period and OLE 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 database 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 
1.12.1 Pharmacokinetics (PK) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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The procedures for the collection, handling and shipping of PK and ADA samples are specified in 
the central laboratory manual as well as the Global Manual of Operations supplied to the site 
by the sponsor.  Please refer to the Laboratory Manual for details on blood volume taken for 
pharmacokinetic and ADA assessments.   
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 Drug-specific Safety Concerns 
1.13.1 Amyloid related imaging abnormalities (ARIA) 
ARIA that can occur as either cerebral edema (ARIA-E) or as hemorrhages (ARIA-H), have been 
reported with treatment with gantenerumab (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 areas of edema (ARIA-E) will be monitored at entry and 
throughout the trial.  Any occurrence of ARIA-E will trigger an acute blood (plasma) collection 
and collection every 4 weeks thereafter to monitor biomarker changes until the occurrence 
resolves.  In addition, blood will be collected from all participants approximately every 12 
weeks to identify biomarkers that correlate with, or are predictive of, ARIA-E. Incidence with 
associated risks of ARIA on therapy will be compared to placebo findings.  
A report of new ARIA changes in a participant will trigger a review by the DIAN-TU Medical 
Director or designee, Project Arm Leader (PAL), and site principal investigator.  No further 
dosing will occur until this review is completed.  This review will include contact with the 
participant 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 tables in 
Section 1.14 for 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.   The schedule of visits includes frequent MRI scans to 
assess for ARIA changes.   
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. 
Refer to prior amendments for details regarding the MRI schedule relative to dosing in the 
double-blind period. 
For the OLE Period, all participants will have Safety MRIs performed (Figure 1) at the following 
time points:  
• Titration Period: prior to each up-titration 


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• Once at the target dose of 
 (or highest dose a participant reaches in case 
of safety issues): approximately every  doses (approximately every 
weeks) for the 
first year at that dose; refer to schedule of events for exact timing. 
• The first annual OLE visit will occur at Week 48 after the third dose of 
 to 
obtain the annual/safety MRI prior to subsequent up-titration.  In cases where approval 
and consenting to Amendment 11 does not occur prior to a participant reaching Week 
48, initiation of up-titration should occur once consent has been signed and per 
approved titration and MRI schedule once reviewed by the medical monitoring team. 
The first 20 participants to dose at each of the two additional titration steps beyond 
 
 will have an additional safety MRI after the first two 
doses (sentinel safety cohort) at 
each titration step as follows: 
• 
 
 
   
The DIAN-TU Medical Monitors will perform a safety review of the sentinel cohort data to 
ensure no issues or concerns are detected, and ensure there are no findings that would warrant 
additional scanning of additional participants. 
1.13.2 Injection site reactions 
Injection site reactions after subcutaneous administration have been observed in up to one-
third of participants.  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 majority of events have been mild. 
1.13.3 Neutropenia in the gantenerumab OLE period 
A potential risk of neutropenia with gantenerumab has been observed in a nonclinical mouse 
study, as has been described in the IB, but has not been observed in nonclinical cynomolgus 
monkey study or clinical trials, including at the current human target dose levels (based on a 
total exposure to gantenerumab G3 and G4 product at any dose of approximately 2500 
participants [healthy volunteers or AD patients]).  Therefore, the frequency of chemistry and 
hematology laboratories will be increased from annually after year one (OLE V13) to every 6 
months thereafter. 
The DSMB meeting frequency will be increased from the originally planned every 6 months to 
quarterly. 
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The DIAN-TU Medical Monitors will perform quarterly aggregate review of all safety data (MRI 
findings, AEs, clinical labs, etc.), in addition to review of all MRIs with any change, as is current 
practice as outlined below in Section 1.14. 
 ARIA-Related Interventions Including Dose Changes and Discontinuation 
See main protocol Sections 3.6, 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 
participant will trigger a review by the Medical Director or designee, 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 participant, 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, PAL, and 
Medical Director or designee, at minimum. 
Every 4 weeks until 
resolved 
 
 


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Number of New 
Occurrences1  
Dose Adjustment 
MRI Monitoring 
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 
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, PAL, 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, PAL, 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 


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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, PAL, and Medical Director or designee, 
at minimum. 
Every 4 weeks until 
stable 
>15 new, 
cumulative 
occurrences 
A dosing and safety monitoring plan for the 
participant to be developed by the Site PI, PAL, and 
Medical Director or their designees based on a 
thorough safety review.  If dosing is discontinued, 
the participant 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 
participant 
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. 
 
Table 4 
Procedures for Superficial Siderosis 
Number of New 
Occurrences1  
Dose Adjustment 
MRI Monitoring 
1 new occurrence 
of superficial 
siderosis 
Continue dosing at the participant’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, PAL, 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 
participant 
1 Based on new definite ARIA findings (excluding baseline incidences) 
 


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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. 
 Drug-specific Discontinuations or Withdrawal 
Decisions regarding participants who have ARIA AEs will be made based on both imaging and 
clinical factors; decisions will be made by the Medical Director and/or designee following 
discussion between site principal investigator or designated sub-investigator, and the PAL using 
the guidelines outlined above in Tables 1-4. 
If for any reason participants are unable to up-titrate, e.g. safety concerns, appropriate stable 
doses for those participants will be determined by the site investigator along with the PAL, 
Medical Director or designee, as appropriate.   
For participants administered [18F]AV-1451 tau PET tracer who exhibit hypersensitivity to 
[18F]AV-1451 or any of its excipients are to be discontinued from receiving further [18F]AV-1451 
tau PET tracer and are not to have another [18F]AV-1451 dose administered. 
2 STUDY DRUG 
Details regarding use in the open-label extension period are outlined below; refer to prior 
amendments for double-blind period study drug details.  
 Open-Label Extension: Drug Description 
In the open-label extension period (OLE), participants will be dosed with the gantenerumab G4 
formulation.  Gantenerumab (RO4909832) G4 Q4W is a recombinant human anti-Aβ 
monoclonal antibody of the immunoglobulin subclass G1 (IgG1) that binds specifically to 
aggregated Aβ. 
 
 
The gantenerumab drug substance process was optimized during development to increase 
process yields and/or manufacturability, leading to the G1, G2, G3 and G4 processes.  In 
addition to extensive analytical comparability assessments, rat studies have been conducted to 
compare the pharmacokinetics (PK) of G2 versus G1 as well as G4 versus G3.  In addition, all 
these materials have been evaluated with regards to plaque binding in PS2APP transgenic mice.  
Lastly, a relative bioavailability study comparing G3 and G4 gantenerumab (WP40052) has been 
completed.  Currently there is one phase II study, WN29722 (Graduation), and two Phase III 
studies, WN29922 (Graduate 1) and WN39658 (Graduate 2) ongoing, in which gantenerumab 
drug substance G4 is being used. 
Gantenerumab is provided as a sterile, preservative-free high concentration liquid formulation 
 
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 Open-Label Extension: Drug Treatment Regimen 
All participants participating in the OLE will receive gantenerumab produced with the G4 
process.  The pharmacokinetic behavior of the old (G3) and the new (G4) process were 
compared in a relative bioavailability study.  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.  Based on these results, the dosing 
regimen of the Phase III program in sporadic AD (WN29922 and WN39658) has been adjusted 
by a factor of 1.18.  
In DIAN-TU-001, all OLE participants will restart titration, starting at a dose of 
 of drug 
product administered SC approximately every 
 
Participants will initiate up-titration following 3 doses at the 
 level and a safety MRI 
approximately 1 week after the 
dose of 
.  Participants will receive at least 3 doses 
at each titration step, 
 (±  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.  The target maximum dose for all participants is 
. Participants 
will dose escalate/titrate up to 
 receiving at least 3 doses at each titration step.  
After three (3) doses at 
 apart, participants will continue to escalate to 
 
for 6 doses and then to the maximum target dose of 
 
Participants will continue dosing for up to 156 weeks.  The total number of doses may vary by 
participant based on dosing compliance and/or ARIA intervention. 
 
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Table 5 
DIAN-TU-001 Gantenerumab OLE Titration Safety MRI Schedule  
 
a 
OLE safety MRI schedule.  A safety MRI will be scheduled 1 week (± 4 days) after the third dose of each 
 titration step 
 unless otherwise indicated by the ARIA-E and ARIA-H management algorithms 
(Section 1.14).  If an annual visit follows the third 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. 
b 
Sentinel safety cohort.  The first 20 participants to complete the first two doses at 
 and 
 must 
complete a safety MRI after two doses at each dose level as part of the sentinel safety cohort before additional participants 
may dose titrate to that dose level.  Safety MRI data will be reviewed and cleared before additional participants will be 
allowed to up-titrate to each of the higher dose levels. 
c 
A safety MRI will be scheduled 1 week (± 4 days) after the sixth dose of each 
 titration step 
 
 unless otherwise indicated by the ARIA-E and ARIA-H management algorithms (Section 1.14).  If an annual visit 
follows the third 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. 
d  
Once at stable dose of 
, safety MRIs will be scheduled 1 week (± 4 days) after every 12th dose (or 
approximately every 6 months) for the remainder of the trial unless otherwise indicated by the ARIA-E and ARIA-H 
management algorithms (Section 1.14).   
e     The titration schema was designed to reach the target dose of 
; however, the target dose may not be 
achieved as otherwise dictated by ARIA-E and ARIA-H management algorithms (Section 1.14) or more conservative action 
by the site principal investigator/DIAN-TU Medical Monitors.  Once a participant reaches their stable dose (defined as the 
maximum dose the participant will remain at for the duration of the trial) safety MRIs will follow every 12 doses (or 
approximately every 6 months) unless otherwise indicated by the algorithm.   
NOTE: The annual/volumetric MRI assessment can fulfill the safety MRI assessment as long as 
the MRI reading is reviewed prior to dosing at that visit. 
Participants should receive at least  doses at each titration step 
 
 weeks (± 4 days) apart, and  doses at 
 2 weeks (± 3 days) apart, before 
proceeding to the next titration step (Table 5).  The titration schema was designed to reach the 
target dose of 
 administered every 
; however, the target dose may not be 
INITIAL             
DOSE 
•Dose 1: 
•Dose 2: 
•Dose 3: 
•Safety MRIa:                      
1 week after 
 
, 
before increase 
to 
TITRATION 
STEP #1
•Dose 1: 
•Dose 2: 
•Dose 3: 
•Safety MRIa:               
1 week after 3rd  
 dose, 
before increase to 
TITRATION 
STEP #2
•Dose 1: 
•Dose 2: 
•Dose 3: 
•Safety MRIa:               
1 week after 3rd 
 dose, 
before increase to 
TITRATION 
STEP #3
•Dose 1: 
•Dose 2: 
•Dose 3: 
•Safety MRIa: 
During Annual 
Visit (OLE V13, 
Week 48) before 
increasing to 
TITRATION 
STEP #4 
•Q2W, Dose 1: 
•Q2W, Dose 2: 
 
•Safety MRIb for 
Sentinel Cohort
•Q2W, Dose 3: 
•Q2W, Dose 4: 
•Q2W, Dose 5: 
•Q2W, Dose 6: 
•Safety MRIc: 1 
week after 6th 
Q2W dose of 
 before 
increase to 
 
TITRATION 
STEP #5
•Q2W, Dose 1: 
•Q2W, Dose 2: 
•Safety MRIb for 
Sentinel Cohort
•Q2W, Dose 3: 
•Q2W, Dose 4: 
•Q2W, Dose 5: 
•Q2W, Dose 6: 
•Safety MRIc: 1 
week after every 
6th dose of 
 
 for the first 
year at that dose
STABLE             
DOSE 
•
  
•Safety MRId, e: 
One (1) week 
afer approx. 
every 
doses 
(approx every  
 
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achieved as otherwise dictated by the ARIA-E and ARIA-H management algorithms (Section 
1.14) or more conservative action by the site principal investigator/DIAN-TU Medical Monitors. 
Participants consenting to Amendment 11 of this protocol and initiating titration beyond 
 after having received more than 3 doses of 
 may not align with the 
referenced week numbers in Table 5 or the Schedule of Visits and this will be considered 
allowable for this study. 
 Open-Label Extension: Packaging, Preparation and Administration of Drug 
Product 
The drug product formulation consists of a sterile, preservative-free, solution for subcutaneous 
injection in a single-use Type 1 glass vial(s).  The formulation contains
 
 
The drug product should be stored at 2-8°C (36-46°F).  Exposure of the drug product to direct 
sunlight in the vial or disposable syringe should be avoided.  Do not shake and do not freeze vial 
contents.  Gantenerumab must be prepared for dosing under appropriate aseptic conditions.  
After transfer to the syringe, the dose solution should be used immediately, but must be used 
within 2 hours.  If the preparation has taken place in an appropriate laminar flow hood (or 
equivalent), the dose solution in the syringe may be stored for up to 24 hours at 2-8°C (36-46°F) 
prior to administration, including a maximum of 4 hours at room temperature.  All drug product 
solutions should be brought to room temperature prior to administration to minimize 
discomfort during administration.  Refer to the Pharmacy Manual for full storage, vial 
quantities, dose preparation, and administration instructions. 
The investigator or designee is responsible for administering the drug product to the 
participant, verifying that instructions are followed properly, maintaining accurate records of 
drug product dispensing and administration, and returning all unused or used drug product 
supplies to the trial sponsor’s designee or destroyed locally with Sponsor approval.  Drug 
product reconciliation must be completed and documented prior to destruction.  Refer to the 
Pharmacy Manual and Global Manual of Operations for additional details. 
Parenteral drug products should be inspected visually for cloudiness, haziness, and particulates 
prior to administration; partially used vials should NOT be re-used. 
Other parenterally administered medications should not be mixed with the drug product.   
Clinical study materials will be labeled according to the country’s regulatory requirements. 
Site staff preparing and administering the drug product should contact the trial sponsor or 
designee as soon as possible if they have a complaint or problem with the drug product so that 
the situation can be assessed. 
 Open-Label Extension: Blinding of Drug Product 
Drug product administered to participants in the OLE will not be blinded. 
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 Open-Label Extension:  Dispensing of Drug Product 
The drug product for OLE doses of 
 and above will be administered SC with either a 
disposable syringe(s) or syringe infusion pump after withdrawal of the drug product from the 
vial(s).  The amount of the dose will be dependent on where the participant is at in the dose 
titration schedule (Table 6). 
The 
 doses will be manually 
administered with a disposable syringe(s).  The drug product will be administered as 
 
injection(s) for a total of 
mL in the abdominal area.  Refer to the Pharmacy Manual 
for full dose preparation and administration instructions.  The contents of a single syringe 
should be administered within 10 seconds and all administrations (i.e., when the participant 
receives two injections) should be completed within 1 minute. 
Doses of 
 or higher will be administered by syringe infusion pump.  The syringe infusion 
pump is prepared by drawing up the contents of the required number of vials into a 
 
disposable syringe (Table 6).  The drug product is slowly administered subcutaneously over a 
flow rate of 40 mL/hour in the abdomen, alternating location each dosing day.  The infusion 
rate can be slowed if there are signs of intolerance.   
Refer to the Pharmacy Manual for full dose preparation and administration instructions.   
Table 6 
Gantenerumab - Formulation Dosing Table 
Dose (mg) 
Prescribed 
Volume (mL) 
Number of 
Vials Needed1 
Administration Route 
 
 
1 
Disposable Syringe (1 injection) 
 
 
1 
Disposable Syringe (1 injection) 
 
 
2 
Disposable Syringe (2 injections) 
 
 
4 
Syringe Infusion Pump 
 
 
6 
Syringe Infusion Pump 
1 Refers to the number of vials required to be dispensed in order to prepare the appropriate dose due to syringe 
and pump fill administration needs.  Refer to the Pharmacy Manual for full dispensing, preparation, and 
administration instructions. 
Participants will be observed for at least 2 hours after dosing for the first 4 doses.  After the 4th 
injection visit, the observation time may be reduced to at least 1 hour. 
Drug product administration as well as post-injection observation will be done by a qualified 
research nurse who is also equipped with an epinephrine/adrenaline injection. 
Note that all cognitive scales are to be administered before administration of drug product. 
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 Open-Label Extension: Assessing Compliance with Drug Product  
Strict adherence to the planned dose regimen is required.  However, a single missed dose may 
not automatically result in removal from the study.  Site staff or designee will document 
completion of injection on study documents.  Because all dosing is supervised by trained 
healthcare providers, participants who successfully receive at least 70% of a dose (e.g., a 
complete dose not administered due to technical complications) are automatically considered 
compliant with treatment. 
3 STUDY PROCEDURES 
 Enrollment 
Refer to prior protocol amendments for details associated with randomization into the double-
blind period; see details in Section 3.4 of the main protocol. 
After completion of the double-blind period, both the gantenerumab and solanezumab arms 
were analyzed and it was determined that the gantenerumab OLE period would proceed with 
enrollment.  Any participant from either the gantenerumab or solanezumab blinded drug arms 
is eligible to enroll in the OLE period once confirmed as a mutation carrier, and having met the 
continuing eligibility requirements outlined in OLE V1 procedures (Section 3.2.1). Eligible 
participants were able to start treatment in the OLE period after the final analysis of the 
double-blind treatment period had been completed. 
 
Figure 2 
Enrollment Diagram: DIAN-TU-001 Gantenerumab Open Label Extension Period 
 
 Specific Study Visits – Open-Label Extension Treatment Period 
The open-label extension (OLE) period procedures to be completed at each study visit are listed 
below, and provided in the series of tables “Gantenerumab Schedule of Visits: Open-label 
Extension” at the end of this appendix. Refer to prior amendments for the double-blind visit 
schedules.   
The frequency for safety MRIs is provided in Figure 1 and Table 5. 
All information on timing of visits refers to calendar days.  The specific date during the first visit 
(OLE V1) that the first dose of open-label study drug is administered should be used to 
DIAN-TU-001 
Master Protocol 
Platform
Solanezumab 
(n = 71 mutation carriers)
Gantenerumab                    
(n = 73 mutation carriers)
Gantenerumab Open 
Label Extension
COMPLETED


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determine the timing of all subsequent visits.  The dose and treatment regimen are detailed in 
Section 2.2. 
All OLE participants and study sites will be kept blinded to prior drug assignment until the end 
of OLE to protect study integrity. 
Procedural requirements are outlined in Section 6 of the main protocol with the cognitive 
batteries to be used in the gantenerumab OLE period detailed below for reference.  Supporting 
details for all assessments can be found in the Global Manual of Operations and the DIAN-TU 
Cognition Core Procedures Manual for OLE.  
Complete Cognitive Battery (Annual Visits) 
The Complete Cognitive Battery is performed annually at the DIAN-TU site.   
Cognitive measures to be obtained at the OLE V1 and annual visits in the OLE period are 
administered at a DIAN-TU site and include the iPad-administered and conventional cognitive 
tests listed below.  
• iPad-administered Cognitive Testing:  
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 Cogstate Detection Task 
o Cogstate Identification Task 
o Cogstate One Card Learning Test 
o Cogstate One-Back Task 
o Behavioral Pattern Separation Object Task* 
o Memory Complaint Questionnaire (MAC-Q) * 
• Conventional Cognitive Testing:  
o Trailmaking Test parts A & B 
o Wechsler Memory Scale-Revised (WMS-R) Digit Spatial Span Forward and 
Backward 
o Wechsler Adult Intelligence Scale-Revised (WAIS-R) Digit-Symbol Substitution 
Test 
o Raven’s Progressive Matrices (Set A) 
o Category Fluency (Animals & Vegetables) 
o WMS-R Logical Memory/Paragraph Memory (Immediate & Delayed Recall) 
*These tests should not be administered at any visit to participants who had a CDR of 1 at 
their original baseline (V2) visit from the double-blind period. 


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Cognitive Battery Subset (OLE treatment months 6, 18, and 30)  
The Cognitive Battery Subset is performed at the visit associated with approximately 6, 18, and 
30 months and include the iPad-administered and conventional cognitive tests listed below.  
• iPad-administered Cognitive Testing 
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)* 
o Cogstate Detection Task 
o Cogstate Identification Task 
o Cogstate One Card Learning Test 
o Cogstate One-Back Task 
• Conventional Cognitive Testing: 
o Trailmaking Test parts A & B 
o WMS-R Digit Spatial Span Forward and Backward 
o WAIS-R Digit-Symbol Substitution Test 
o WMS-R Logical Memory/Paragraph Memory (Immediate & Delayed Recall) 
*These tests should not be administered at any visit to participants who had a CDR of 1 at 
their original baseline (V2) visit from the double-blind period. 
3.2.1 OLE Visit 1 (baseline/first dose) 
Location: DIAN-TU site. 
Time/Timing:  Approximately a 2 to 3 day visit that is scheduled after the decision is made to 
continue the drug arm in the OLE.  If possible, the study partner should accompany the 
participant to the DIAN-TU site for this visit.  For participants who live near the study site, these 
visit procedures may be scheduled over a longer time period of up to 2 weeks.  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 events 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.   
Procedures: 
• Obtain informed consent.  Participants 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 
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• The following must be confirmed for the participant to be eligible for the OLE:  
(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 
• Vital signs (blood pressure, heart rate, respiratory rate, body temperature), weight and 
height 
• Concomitant medication review 
• Adverse event assessment  
• Administration of C-SSRS 
• 12-lead ECG; the ECG should be performed locally  
• Blood collection for the following: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
o Serum pregnancy test for people of childbearing potential (POCBP) 
o 
; stored plasma and serum 
• 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 
 
 
 
 
 
  
OTE: For each participant, 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 (Section 3.2)  
• 
 
   
 
 
 
  
• 
umbar puncture (LP) should be conducted as close to the participant’s double-blind 
 
 
• Annual MRI (including structural and functional MRI) to be performed on 1st day and 
uploaded immediately to ensure reading obtained prior to approval for dosing.  This 
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MRI includes safety MRI sequences.  ARIA findings on this MRI may affect continued 
eligibility.  MRI should be performed before lumbar puncture, if on the same date. 
• Drug product 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. 
3.2.2 OLE Visits 2-6, 8-9, 11-12, 14-15, 17-19, 21-22, 24-26, 28-29, 31-32, 34-35, and 37-39  
Location: DIAN-TU site or participant’s home or other trial-identified location with the trial-
designated home health nurse. 
 
Timing for Q4W dosing:  Visits as listed below (calculated from day of first dose at OLE Visit 1), 
with a visit window of ± 4 days for Q4W dosing. 
Visit No. 
2 
3 
4 
5 
6 
8 
9 
11 
12 
Week 
4 
8 
12 
16 
20 
28 
32 
40 
44 
 
Timing for Q2W dosing:  Visits as listed below (calculated from day of first dose at OLE Visit 1), 
with a visit window of ± 3 days for Q2W dosing.  Visit references below will remain at the Q4W 
frequency with two time points (weeks) associated with each visit.  All visit procedures should 
be completed at the first time point; the second time point is for dosing and should include 
assessment of vitals, concomitant medications, and AEs as outlined in the Schedule of Visits.  
Visit No. 
14 
15 
17 
18 
19 
21 
Weeks 
52 & 54 
56 & 58 
64 & 66 
68 & 70 
72 & 74 
80 & 82 
 
Visit No. 
22 
24 
25 
26 
28 
29 
Weeks 
84 & 86 
92 & 94 
96 & 98 
100 & 102 
108 & 110 
112 & 114 
 
Visit No. 
31 
32 
34 
35 
37 
Weeks 
120 & 122 
124 & 126 
132 & 134 
136 & 138 
144 & 146 
 
Visit No. 
38 
39 
Weeks 
148 & 150 
152 & 154 
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 POCBP  


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• Drug product dosing and post-dose monitoring/evaluation as specified in Section 2.5 
• Phone call (required for OLE visit 3; not required at all home/off-site visits but direct 
site-participant contact should occur at least once every 3 months throughout the 
study): the DIAN-TU site coordinator calls participant and addresses any concerns, 
discusses scheduling of safety MRI and next visits, and encourages compliance 
3.2.3 OLE Visits 10, 16, 23, 30, and 36 
Location: DIAN-TU site or participant’s home or other trial-identified location with the trial-
designated home health nurse. 
 
Timing for Q4W dosing:  Visit as listed below (calculated from day of first dose at OLE Visit 1), 
with a visit window of ± 4 days for Q4W dosing. 
Visit No. 
10 
Week 
36 
 
Timing for Q2W dosing:  Visits as listed below (calculated from day of first dose at OLE Visit 1), 
with a visit window of ± 3 days for Q2W dosing.  Visit references below will remain at the Q4W 
frequency with two time points (weeks) associated with each visit.  All visit procedures should 
be completed at the first time point; the second time point is for dosing and should include 
assessment of vitals, concomitant medications, and AEs as outlined in the Schedule of Visits.  
Visit No. 
16 
23 
30 
36 
Weeks 
60 & 62 
88 & 90 
116 & 118 
140 & 142 
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 POCBP  
• Blood collection for stored plasma 
• Drug product dosing and post-dose monitoring/evaluation as specified in Section 2.5 
• Phone call (required for OLE visit 3; not required at all home/off-site visits but direct 
site-participant contact should occur at least once every 3 months throughout the 
study): the DIAN-TU site coordinator calls participant and addresses any concerns, 
discusses scheduling of safety MRI and next visits, and encourages compliance. 


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3.2.4 OLE Visit 7 
Location:  DIAN-TU site or participant’s home or other trial-identified location with the trial-
designated home health nurse.   
Timing:  24 weeks ± 4 days from day of first dose at OLE Visit 1.   
Procedures: 
• Cognitive Battery Subset (see Section 3.2)  
• Mini-Mental State Examination (MMSE) 
• 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) 
• Blood collection for the following:  
o 
  
o Stored plasma 
• C-SSRS administration 
• Urine pregnancy testing for POCBP  
• Drug product dosing and post-dose monitoring/evaluation as specified in Section 2.5 
• Phone call (not required at all home/off-site visits but direct site-participant contact 
should occur at least once every 3 months throughout the study): the DIAN-TU site 
coordinator calls participant and addresses any concerns, discusses scheduling of safety 
MRI and next visits, and encourages compliance. 
3.2.5 OLE VISITS 13, 27, and 40 or Early Termination: ANNUAL VISIT AT DIAN-TU SITE  
Location: DIAN-TU site 
Timing:  48 and 104, and 156 weeks ± 7 days (or Early Termination) from day of first dose at OLE 
Visit 1; approximately a 2- to 3-day visit.  The second dose administration for Q2W dosing 
associated with each visit should be completed at weeks 50, 106, and 158 weeks ± 3 days, 
respectively, and will include vitals, concomitant medications, and AEs as outlined in the 
Schedule of Visits.  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 participants 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, and body temperature); weight 
and height  
• Administration of C-SSRS 
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• Blood collection for the following: 
o Clinical laboratory tests (hematology, chemistry, urinalysis) 
o 
 
• Urine pregnancy testing for POCBP 
• 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 
 
 
 
 
 
  
OTE: For each participant, 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 (see Section 3.2) 
• 
 
 
 
 
 
 
• 
umbar Puncture (LP) should be conducted as close to the participant’s double-blind 
 
  
• 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. 
• Drug product dosing and post-dose monitoring/evaluation as specified in Section 2.5 for 
OLE V13 and OLE V27; no drug administration should occur at OLE V40 or an early 
termination visit. 
• Follow-up phone call or brief visit within 24 hours after LP, and no longer than 48 hours 
later, to review any adverse events. 
3.2.6 OLE Visits 20 and 33 
Location:  DIAN-TU site or participant’s home or other trial-identified location with the trial-
designated home health nurse. 
Timing:  76 and 128 weeks ± 3 days from day of first dose at OLE Visit 1.  The second dose 
administration for Q2W dosing associated with each visit should be completed at weeks 78 and 
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130 ± 3 days, respectively, and will include vitals, concomitant medications, and AEs as outlined 
in the Schedule of Visits.    
Procedures: 
• Cognitive Battery Subset (Section 3.2)  
• Mini-Mental State Examination (MMSE) 
• 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) 
• C-SSRS administration 
• Blood collection for the following: 
o Clinical laboratory tests (hematology, chemistry) 
o Stored Plasma 
• Urine pregnancy testing for POCBP 
• Drug product dosing and post-dose monitoring/evaluation as specified in Section 2.5 
• Phone call (not required at all home/off-site visits but direct site-participant contact 
should occur at least once every 3 months throughout the study): the DIAN-TU site 
coordinator calls participant and addresses any concerns, discusses scheduling of safety 
MRI and next visits, and encourages compliance 
 
3.2.7 Safety Follow-up Visit 
Location: DIAN-TU site or participant’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 OLE 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 the main protocol)  
• Clinical laboratory tests (hematology, chemistry, urinalysis at the discretion of the 
investigator) 
• Serum pregnancy testing for POCBP 
3.2.8 Early Termination Visit/Post-treatment Follow-up 
If a participant 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 40.  Procedures may also be eliminated on a case-by-case basis, as determined 
by the sponsor.  Drug-specific testing should also be obtained at early termination visit only if 


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prior to completion of V40 at week 156 (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 participant 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 participant’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 participant’s status changes. 
3.2.9 Safety Magnetic Resonance Imaging MRI 
 
Safety MRIs on 3T scanners will be done primarily to monitor for ARIA.  Safety MRI visits will be 
scheduled over the entire course of the OLE period in addition to the annual MRIs which 
include safety reads. 
Location: Safety MRIs may be done at the DIAN-TU site or, for participants 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 participant’s home. 
Note: Safety MRI timing may be adjusted based on the ARIA-related intervention steps in 
Section 1.14 of this appendix including additional MRIs and dosing adjustments for safety. 
Procedures:  See Section 6.1.16 of the main protocol for more information.  Detailed 
requirements are provided in the MRI Technical Manual. 
3.2.9.1 
Regular Safety MRIs 
Timing:  Annual MRIs in addition to Weeks 9, 21 and 33 weeks ± 4 days from OLE V1 (calculated 
from the day of the first dose) during Q4W dosing; and Weeks 59, 71, 83, 95, and 127 weeks ± 3 
days from OLE V1 (calculated from the day of the first dose) during Q2W dosing as outlined in 
Figure 1 and Table 5 in this appendix.  Sites must ensure that study visits are scheduled so that 
MRIs are uploaded and available for central read at least 5 working days before next 
administration of study product. 
Note: Based on when amendment 11 is approved at each site, some participants may 
commence dose titration above 
 after having more than 3 doses at that dose 
level.  In these cases, the medical monitoring team will review the participant’s current visit 
schedule to identify the timing of the MRIs in the same manner as outlined in the schedule of 
visits however, the exact visit numbers may not align. 
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3.2.9.2 
Sentinel Cohort MRIs 
Timing:  Two additional safety MRIs will be collected for a sentinel cohort of the first 20 
participants receiving doses above 
.  Following the 3rd dose of 
, the 
first 20 participants titrating to 
 and 
 will have an additional safety 
MRI after the first two doses at each titration step, i.e., the first 20 participants receiving two 
doses of 
 two weeks apart, and the first 20 participants receiving two doses of 
 
two weeks apart. 
4 DRUG-SPECIFIC ANALYSIS PLAN 
 OLE Period 
4.1.1 Biomarker Endpoint Statistical Analysis, Power and Sample Size Justification 
The primary endpoint for the OLE period is PiB-PET composite SUVR.  
The null hypothesis for the OLE period is that gantenerumab will not reverse the amyloid 
growth at the end of 3-year OLE compared to the OLE baseline for all participants who enroll 
into OLE: 𝐻𝐻0: 𝜇𝜇≥0, where 𝜇𝜇 is the mean change from the OLE baseline to the end of 3-year 
OLE in PiB-PET SUVR.  The alternative hypothesis is that gantenerumab reverses the amyloid 
growth: 𝐻𝐻𝑎𝑎: 𝜇𝜇< 0.  The change from baseline will be analyzed using mixed model for repeated 
measures (MMRM) with baseline as a covariate in the model. 
4.1.2 Biomarker Endpoint Power Analysis 
Based on DIAN-TU-001 data from the double-blind period, the mean (SD) change from the OLE 
baseline in PiB-PET composite SUVR to the end of the 3-year OLE period with dosing up to 
 
 is projected to be at least -0.473 (0.540) for participants on gantenerumab from the 
beginning of the double-blind period, and participants starting gantenerumab in OLE (having 
been on either active solanezumab or placebo) together. The recruitment goal of OLE is to 
enroll 60 to 90 of the 144 mutation positive participants who participated in the placebo-
control period.  Assuming an annual dropout rate of 5%, at the end of 3-year OLE, there will be 
51 to 77 participants and it will provide over 99% power to detect the projected mean change 
from baseline using a one-sided one-sample t-test with type I error 0.025.  
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4.1.3 Biomarker Endpoint Sample Size Justification 
Figure 3 
Power estimation for different sample sizes and different projected mean 
changes from the OLE baseline to the end of the 3-year OLE. One-sided, one-
sample t-test with type I error of 0.025 
 
Figure 4 demonstrates that even with the least number of enrolled participants (51), there still 
is more than 80% power to detect a reversal in amyloid growth from the OLE baseline as small 
as -0.22 SUVR.  
4.1.4 Interim Analysis 
 
 
 
 
 
  
 
 
 
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 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. 
 
 


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6 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. 
Klein G, Delmar P, et al. (2019). Gantenerumab reduces amyloid-β plaques in patients with 
prodromal to moderate Alzheimer's disease: a PET substudy interim analysis. Alzheimers Res 
Ther 11(1):101. 
Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer's Disease. N Engl J 
Med. 2021 ;384(18):1691-1704. Epub 2021 Mar 13. 
Ostrowitzki S et al.  (2012) Mechanism of amyloid removal in patients with Alzheimer disease 
treated with gantenerumab.  Arch Neurol 69:198-207. 
Ringman, J. M. et al. Neuropathology of autosomal dominant Alzheimer disease in the national 
Alzheimer coordinating center database. J. Neuropathol. Exp. Neurol. 75, 284–290 (2016). 
Salloway S, Farlow M, McDade E, et al; Dominantly Inherited Alzheimer Network–Trials Unit. A 
trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease. Nat Med. 
2021 Jul;27(7):1187-1196. 
Schenk D et al.  (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like 
pathology in the PDAPP mouse.  Nature 400:173-177. 
Shepherd, C., McCann, H. & Halliday, G. M. Variations in the neuropathology of familial 
Alzheimer’s disease. Acta Neuropathologica vol. 118 37–52 (2009). 
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. 
Swanson CJ, Zhang Y, Dhadda S, et al. A randomized, double-blind, phase 2b proof-of-concept 
clinical trial in early Alzheimer's disease with lecanemab, an anti-Aβ protofibril antibody. 
Alzheimers Res Ther. 2021 ;13(1):80. 


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GANTENERUMAB SCHEDULE OF VISITS: OPEN-LABEL EXTENSION 
Gantenerumab Schedule of Visits: Open-label Extension 
PROCEDURE: 
VISIT SITE1,2 
DIAN-TU 
H 
H 
MRI 
H 
H 
H 
MRI 
H 
H 
H 
MRI 
Visit No. 
OLE 
V1 
OLE 
V2 
OLE 
V3 
OSM 1 
OLE 
V4 
OLE 
V5 
OLE 
V6 
OSM 2 
OLE 
V7 
OLE 
V8 
OLE 
V9 
OSM 3 
Timing (weeks)3 
0 
4 
8 
9 
12 
16 
20  
21 
24 
28 
32 
33 
Informed Consent 
X4 
 
 
 
 
 
 
 
 
 
 
 
Verification of Eligibility for OLE5 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Adverse Event Assessment 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Hematology, Chemistry, Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Serum and/or Plasma8 
X 
 
 
 
 
 
 
 
X8 
 
 
 
Pregnancy testing9 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
C-SSRS 
X 
 
 
 
 
 
 
 
X 
 
 
 
Vital Signs10 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Physical/Neurological Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment: Full Battery11 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment: MMSE Only11 
 
 
 
 
 
 
 
 
X 
 
 
 
12-lead ECG12 
X 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Testing13 
X 
 
 
 
 
 
 
 
X 
 
 
 
Annual/Volumetric MRI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Product Administration (mg) 16 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinator Phone Call17 
 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
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Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Final Amendment 13
APPENDIX 3: Gantenerumab 
Version Date: 05 Apr 2023
 
Page 167 of 263 
Gantenerumab Schedule of Visits: Open-label Extension 
PROCEDURE: 
VISIT SITE1,2 
H 
H 
H 
DIAN-
TU 
H 
MRI 
(1st 20) 
H 
H 
H 
H 
MRI 
H 
H 
MRI 
(1st 20) 
H 
H 
Visit No. 
OLE 
V10 
OLE 
V11 
OLE 
V12 
OLE  
V13 
SC1 
MRI19 
OLE 
V14 
OLE 
 V15 
TOSM 
 
OLE 
V16 
SC2  
MRI19 
OLE  
V17 
Timing (weeks)3  
36 
40 
44 
48 
50 
51 
52 
54 
56 
58 
59 
60 
62 
63 
64 
66 
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 
Hematology, Chemistry, Urinalysis 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Serum and/or Plasma8 
X21 
 
 
X 
 
 
 
 
 
 
 
X21 
 
 
 
 
Pregnancy testing9 
X 
X 
X 
X 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
C-SSRS 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs10 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
Physical/Neurological Exam 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment: Full11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Testing13 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Annual/Volumetric MRI 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
3T Safety/Titration MR14 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Product Administration16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinator Phone Call17 
X 
X 
X 
  
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
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Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Final Amendment 13
APPENDIX 3: Gantenerumab 
Version Date: 05 Apr 2023
 
Page 168 of 263 
Gantenerumab Schedule of Visits:  Open-label Extension 
PROCEDURE: 
VISIT SITE1,2 
H 
H 
MRI 
H 
H 
H 
H 
H 
H 
MRI 
H 
H 
H 
H 
H 
H 
Visit No. 
OLE  
V18 
TOSM 
150023 
OLE 
V19 
OLE 
V20 
 OLE 
V21 
TOSM 
120 
OLE 
V22 
OLE 
V23 
OLE 
V24 
Timing (week)3 
68 
70 
71 
72 
74 
76 
78 
80 
82 
83 
84 
86 
88 
90 
92 
94 
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 
Hematology and Chemistry  
 
 
 
 
 
   X18 
 
 
 
 
 
 
 
 
 
 
Stored Plasma8 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
Pregnancy Testing9 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
C-SSRS 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital signs10 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
Clinical Assessment: MMSE Only11 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Cognitive Testing13 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
3T Safety/Titration Safety MRI14 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Drug Product Administration16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinator Phone Call17 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
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Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Final Amendment 13
APPENDIX 3: Gantenerumab 
Version Date: 05 Apr 2023
 
Page 169 of 263 
Gantenerumab Schedule of Visits:  Open-label Extension 
PROCEDURE: 
VISIT SITE1,2 
MRI 
H 
H 
DIAN-TU 
H 
H 
H 
H 
H 
H 
H 
H 
H 
Visit No. 
TOSM  
224 
OLE  
V25 
OLE  
V26 
OLE V27 
OLE 
V28 
OLE 
V29 
OLE 
V30 
OLE  
V31 
Timing (week)3 
95 
96 
98 
100 
102 
104 
106 
108 
110 
112 
114 
116 
118 
120 
122 
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 
Hematology, Chemistry, Urinalysis 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Serum and/or Plasma8 
 
 
 
 
 
X 
 
 
 
 
 
X21 
 
 
 
Pregnancy Testing9 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
C-SSRS 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Vital signs10 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessment: Full11 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Cognitive Testing13 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Annual/Volumetric MRI 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
3T Safety/Titration Safety MR14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Product Administration16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinator Phone Call17 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Final Amendment 13
APPENDIX 3: Gantenerumab 
Version Date: 05 Apr 2023
 
Page 170 of 263 
Gantenerumab Schedule of Visits:  Open-label Extension 
PROCEDURE: 
VISIT SITE1,2 
H 
H 
MRI 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
H 
Visit No. 
OLE 
V32 
TOSM 
325 
OLE 
V33 
OLE 
V34 
OLE 
V35 
OLE 
V36 
OLE 
V37 
OLE 
V38 
Timing (week)3 
124 
126 
127 
128 
130 
132 
134 
136 
138 
140 
142 
144 
146 
148 
150 
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 
Hematology and Chemistry 
 
 
 
   X18 
 
 
 
 
 
 
 
 
 
 
 
Stored Plasma8 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
Pregnancy Testing9 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
C-SSRS 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs10 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Assessment: MMSE Only11 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Cognitive Testing13 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
3T Safety/Titration Safety MRI14 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Product Administration16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinator Phone Call17 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Final Amendment 13
APPENDIX 3: Gantenerumab 
Version Date: 05 Apr 2023
 
Page 171 of 263 
Gantenerumab Schedule of Visits:  Open-label Extension  
PROCEDURE: 
VISIT SITE1,2 
H 
H 
DIAN-TU 
H 
Visit No. 
OLE 
V39 
OLE V40 / Early Termination 
Safety Follow-up Visit 
Timing (week)3 
152 
154 
156 
12 weeks post last dose 
Concomitant Medications 
X 
X 
X 
X 
Adverse Event Assessment 
X 
X 
X 
X 
Hematology, Chemistry, Urinalysis 
 
 
X 
   X22 
 
 
 
 
 
 
 
 
 
 
Stored Serum and Plasma8 
 
 
X 
 
Pregnancy Testing9 
X 
 
X 
X 
C-SSRS 
 
 
X 
 
Vital signs10 
X 
X 
X 
X 
Physical/Neurological Exam 
 
 
X 
 
Clinical Assessment: Full11 
 
 
X 
 
Clinical Assessment: MMSE Only11 
 
 
 
 
Cognitive Testing13 
 
 
X 
 
Annual/Volumetric MRI 
 
 
X 
 
3T Safety/
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Product Administration16 
 
 
 
 
Coordinator Phone Call17 
X 
X 
 
 
OSM = Open-label Safety MRI visits for 3T Safety/Titration Safety 
 
Footnotes: 
1. 
Annual visits will be conducted at the DIAN-TU site (DIAN-TU).  For participants 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 
participant’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. 
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Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Final Amendment 13
APPENDIX 3: Gantenerumab 
Version Date: 05 Apr 2023
 
Page 172 of 263 
2. 
Infusions/injections and safety visits (designated as occurring at home [H]) may occur at the DIAN-TU site or, for participants who live at a distance from the DIAN-TU site, 
these visits may be conducted by a home health nurse at the participant’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. OLE V1 takes approximately 2-3 days to complete. 
4. 
The informed consent form (ICF) for the open-label extension (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. 
Participants must be mutation positive. 
6. 
 
 
 
. 
8. 
For future studies, including future regulatory inquiries or additional monitoring of anti-drug antibodies, other drug-specific tests or ARIA-E. Additional unscheduled blood 
collection may occur to monitor ARIA-E, upon discovery and every 4 weeks following until resolution.  See main protocol Section 6.1.12. 
9. 
Serum pregnancy testing will be performed at OLE V1 and the safety follow-up visit.  Urine pregnancy testing will be performed at all other monthly visits, i.e. every 4 
weeks.  Pregnancy tests will be confirmed as negative prior to Q4W dosing with study drug, or prior to every other dose when dosing Q2W.  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. 
10. 
Blood pressure, heart rate, respiratory rate, and body temperature will be collected at all visits.  Height will be measured at OLE baseline (OLE V1) and annual visits only; 
weight will be measured approximately every 3 months. 
11. 
Clinical assessments: DIAN-TU clinical assessment battery includes: study partner interview and administration of CDR and supplemental CSR-SB; clinician assessment of 
 
 
12. 
Electrocardiogram (ECG) assessment should be performed locally. 
13. 
See Section 3.2 in this appendix and the arm-specific DIAN Trials Unit Cognition Core Procedures Manual for additional details, including visit specific battery information.  
Cognitive testing should be completed as early in the day as possible, and before study drug infusion or injection. 
14. 
A safety MRI will be scheduled 1 week (± 4 days) after the third dose of each 
 titration steps 
, and after 
the sixth dose of the each 
 titration step 
) unless otherwise indicated by the ARIA-E and ARIA-H management algorithms (Section 
1.14).  Once at stable dose (after the annual safety MRI at week 104 (OLE V27) following approximately 22 doses of 
 administered 
), safety MRIs will be 
scheduled 1 week (± 4 days) after every 12th dose (
 unless otherwise indicated by the ARIA-E and ARIA-H management algorithms).  Additional safety MRIs 
may be scheduled to monitor ARIA-E events (Section 1.13.1). 
15. 
 
 
 
16. 
All participants enrolled in OLE for gantenerumab will start at the 
 dose 
 and will up-titrate to 
; then at increased dosing 
frequency of 
 to a target dose of 
.  Participants should receive at least three doses at each Q4W titration step up to 
 4 weeks (± 4 days) 
apart, before proceeding to the next titration step.  Participants should receive six doses of 
 2 weeks (± 3 days) apart before proceeding to the final titration step of 
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Washington University in St. Louis 
Protocol #: DIAN-TU-001
CONFIDENTIAL 
Version: Final Amendment 13
APPENDIX 3: Gantenerumab 
Version Date: 05 Apr 2023
 
Page 173 of 263 
 2 weeks (± 3 days) apart.  The titration schema was designed to reach the target dose of  
 administered every 2 weeks; however, the target dose may not 
be achieved as otherwise dictated ARIA-E and ARIA-H management algorithms (Section 1.14) or more conservative action by the site principal investigator/DIAN-TU Medical 
Monitors.  If needed, the schedule of assessments will be adjusted.  Dosing visits occurring every 2 weeks will be identified/labeled as one visit.  The first portion of the visit 
will include completion of any required visit procedures and dosing; two weeks ± 3 days after, the second dose will be administered. 
17. 
Site study coordinators should call participants either during or within two weeks after OLE V2 and OLE V3.  For OLE V4 and subsequent home visits, coordinator calls can be 
made with less frequency at the discretion of the PI or designee, and/or coordinator, and participant, but should occur at least every 3 months.   
18. 
For OLE V20 and OLE V33, chemistry and hematology are required; no urinalysis is needed.  
19. 
A sentinel cohort of the first 20 participants to titrate beyond 
 every weeks will have an additional safety MRI performed after the first two doses of 
 
administered two weeks apart (Week 51, SC1-MRI) prior to up-titrating to 
; and after the first
 doses of 
 administered two weeks apart (Week 63, 
SC2-MRI).  The DIAN-TU Medical Monitors will review the individual and aggregate data to ensure there are no safety findings warranting more frequent MRI for all 
participants. 
20. 
Any participant not having initiated up-titration at any point should use the MRI label of OSM4 for this safety MRI. 
21. 
For plasma collection only at this visit.  
22. 
Clinical laboratory tests (hematology, chemistry, urinalysis) at the discretion of the investigator. 
23. 
Any participant not having initiated up-titration at any point should use the MRI label of OSM6 for this safety MRI. 
24. 
Any participant not having initiated up-titration at any point should use the MRI label of OSM7 for this safety MRI. 
25. 
Any participant not having initiated up-titration at any point should use the MRI label of OSM8 for this safety MRI. 
 
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SAP_001.pdf: 
 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 1 of 101 
 
 
 
 
Author: 
 
Version Number: 
7 
 
Version Date:  
07Dec2023 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN 
for the Open Label Extension Period for Gantenerumab 
 
DIAN-TU-001 
A Phase II/III Multicenter Randomized, Double-Blind, Placebo-Controlled Platform Trial of 
Potential Disease Modifying Therapies Utilizing Biomarker, Cognitive, and Clinical Endpoints 
in Dominantly Inherited Alzheimer’s Disease 
 
 
 
VERSION NUMBER AND DATE: V7.0, 07 DEC 2023  
 
 
 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 2 of 101 
 
 
 
 
Author: 
 
Version Number: 
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Version Date:  
07Dec2023 
 
 
 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V7.0 (Dated 07Dec2023) for Protocol DIAN-TU-001 
 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis 
Plan, authorizing that the content is acceptable for the reporting of this study. 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 3 of 101 
 
 
 
 
 
 
Version Number: 
7 
 
Version Date:  
07Dec2023 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 4 of 101 
 
 
 
 
Author: 
 
Version Number: 
7 
 
Version Date:  
07Dec2023 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
MODIFICATION HISTORY 
 
Significant Changes from  
Previous Authorized Version 
Not Applicable – First Version 
Incorporate minor updates for efficacy 
parameters and add interim analysis details 
Correct protocol title 
Modified analysis population nomenclature and 
added details for DIAN-OBS selection of data 
for external controls; changed efficacy analyses 
to evaluate asymptomatic and symptomatic 
subjects separately; modified LME analysis to 
consider two slopes when double-blind 
gantenerumab data is included; modified set of 
analyses used to support the interim analysis, 
including identification of primary and 
secondary outcomes; added additional fluid 
biomarker to efficacy; re-ordered efficacy 
parameter presentation 
Changed interim to have CDR Global and CDR 
Sum of Boxes as primary efficacy parameters, 
with primary analysis based on baseline 
asymptomatic subjects; add definition for 
concurrent and non-concurrent  controls; 
updated definition for first and recurrent 
progression; added sensitivity models for 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 5 of 101 
 
 
 
 
Author: 
 
Version Number: 
7 
 
Version Date:  
07Dec2023 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
primary interim parameters based on last post-
baseline PiB-PET and based on concurrent / 
non-concurrent controls; changed MAC-Q and 
Tau PET to use internal controls only due to 
limited data for external controls; added figures 
to interim analysis; reference made to the 
Addendum of the Statistical Analysis Plan 
 
 
 
 
Updated the model used for MTBR243 in 
Section 17, Table B from MMRM to LME; 
added MTBR243 to Section 16.2.3.3. 
 
 
 
 
1. Add a mITT population definition based on 
CDR Global for the final analysis in section 5.3.  
Rationale for this change:  Due to the 
unexpected pandemic, many participants 
were unable to travel to the study site for the 
PET scan, resulting in significant missing 
data, either at baseline or post-baseline. 
Therefore, a mITT population defined based 
on amyloid PET would exclude many 
participants from the final analysis, even 
though they had clinical/cognitive data. To 
maximize the data available for the 
clinical/cognitive analysis, an additional 
mITT population will be defined using CDR 
Global as the endpoint.  
2. Change the external dataset used for the final 
analysis from DF17 to DF16 in section 5.4.1. 
Rationale for this change:  Due to the 
early termination of the OLE study, the final 
analysis, including the data collected after 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 6 of 101 
 
 
 
 
Author: 
 
Version Number: 
7 
 
Version Date:  
07Dec2023 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
the interim analysis, will be conducted 
much earlier than the original timeline. As a 
result, the external dataset DF17, which was 
planned to be used for the final analysis, 
will not be available on time. To avoid 
further delays in the final analysis, the same 
external dataset DF16 will be used for the 
final analysis as well.   
3. Reallocate certain secondary efficacy endpoints 
(initially listed in the no longer present section 
16.2.1.2) as exploratory endpoints (now detailed 
in section 16.3).  
Rationale for this change: The interim 
analysis resulted in the early termination of 
the OLE study without a path for regulatory 
approval. Consequently, several secondary 
efficacy endpoints are not relevant and the 
final Clinical Study Report (CSR) will be 
abbreviated.  
In summary, these modifications do not 
impact any of the pre-specified statistical 
models outlined in this SAP, nor do they 
alter any primary or key secondary 
endpoints. They address challenges 
stemming from the pandemic and the 
premature termination of the OLE study. 
Consequently, they will not compromise the 
overall integrity of the trial.  
4. Update Columbia Suicide Severity Rating Scale 
description and analysis (sections 12, 18.7.1) 
according to CRF. 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 7 of 101 
 
 
 
 
Author: 
 
Version Number: 
7 
 
Version Date:  
07Dec2023 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
TABLE OF CONTENTS 
1. INTRODUCTION ................................................................................................................ 14 
2. STUDY OBJECTIVES ........................................................................................................ 14 
2.1. 
PRIMARY OBJECTIVE ..................................................................................................................................... 14 
2.2. 
SECONDARY OBJECTIVES ............................................................................................................................... 14 
 
 
2.4. 
SAFETY OBJECTIVES ....................................................................................................................................... 16 
3. STUDY DESIGN .................................................................................................................. 16 
3.1. 
GENERAL DESCRIPTION ................................................................................................................................. 16 
3.2. 
SCHEDULE OF EVENTS .................................................................................................................................... 17 
3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL .................................................................................................... 17 
4. PLANNED ANALYSES ...................................................................................................... 18 
4.1. 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................................................... 18 
4.2. 
FINAL ANALYSIS ............................................................................................................................................. 18 
4.3. 
INTERIM ANALYSIS ......................................................................................................................................... 19 
5. ANALYSIS SETS ................................................................................................................. 19 
5.1. 
PROCESS FOR ANALYSIS SET ASSIGNMENT ................................................................................................... 20 
5.2. 
ALL SUBJECTS ENROLLED SET [ENR] .......................................................................................................... 20 
5.3. 
MODIFIED INTENT-TO-TREAT [MITT] .......................................................................................................... 20 
5.4. 
GROUPS OF CONTROLS ................................................................................................................................... 23 
5.4.1. 
EXTERNAL CONTROLS .............................................................................................................................. 23 
5.4.2. 
INTERNAL SET CONTROLS ........................................................................................................................ 26 
5.4.3. 
MAIN SET CONTROLS ............................................................................................................................... 26 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 8 of 101 
 
 
 
 
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Version Number: 
7 
 
Version Date:  
07Dec2023 
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Effective Date: 02Dec2019 
 
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proprietary to 
 Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
5.4.4. 
EXTENDED SET CONTROLS ....................................................................................................................... 26 
5.4.5. 
CONCURRENT CONTROLS ......................................................................................................................... 26 
5.4.6. 
CONTROLS APPLIED TO INDIVIDUAL ANALYSIS POPULATIONS ................................................................ 27 
5.5. 
SAFETY ANALYSIS SET [SAF] ........................................................................................................................ 27 
6. GENERAL CONSIDERATIONS ....................................................................................... 27 
6.1. 
REFERENCE START DATE AND STUDY DAY ................................................................................................... 28 
6.2. 
BASELINE ........................................................................................................................................................ 29 
6.2.1. 
DOUBLE-BLIND BASELINE ....................................................................................................................... 29 
6.2.2. 
OLE BASELINE ......................................................................................................................................... 29 
6.3. 
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA ............................................................ 30 
6.4. 
WINDOWING CONVENTIONS ........................................................................................................................... 30 
6.5. 
STATISTICAL TESTS ........................................................................................................................................ 31 
6.6. 
COMMON CALCULATIONS .............................................................................................................................. 31 
6.7. 
SOFTWARE VERSION ....................................................................................................................................... 31 
7. STATISTICAL CONSIDERATIONS ............................................................................... 31 
7.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES ........................................ 32 
7.2. 
MULTICENTER STUDIES ................................................................................................................................. 33 
7.3. 
MISSING DATA ................................................................................................................................................ 33 
7.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY.................................................................................................... 33 
7.5. 
EXAMINATION OF SUBGROUPS ....................................................................................................................... 34 
8. OUTPUT PRESENTATIONS ............................................................................................ 34 
9. DISPOSITION AND WITHDRAWALS ........................................................................... 34 
9.1. 
DISPOSITION .................................................................................................................................................... 34 
9.2. 
PROTOCOL DEVIATIONS ................................................................................................................................. 35 


 
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10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................... 35 
11. MEDICAL HISTORY ......................................................................................................... 36 
12. COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS)............................... 37 
13. MEDICATIONS ................................................................................................................... 37 
14. SUBSTANCE USAGE ......................................................................................................... 38 
15. STUDY MEDICATION EXPOSURE ................................................................................ 38 
15.1. DERIVATIONS .................................................................................................................................................. 39 
16. EFFICACY OUTCOMES ................................................................................................... 40 
16.1. PRIMARY EFFICACY ....................................................................................................................................... 40 
16.1.1. 
PRIMARY EFFICACY VARIABLE(S) & DERIVATION(S)............................................................................... 40 
16.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) ........................................................... 40 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) ...................................................................... 40 
16.1.4. 
SUPPLEMENTARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) ......................................................... 41 
16.1.4.1. 
Amyloid Removal by Double-Blind Treatment ............................................................................... 41 
16.1.4.2. 
Amyloid Removal by CDR Global Status ....................................................................................... 42 
16.1.4.3. 
Gantenerumab Treatment Effects during the Whole Study Duration (Double-Blind + OLE) ......... 42 
16.1.4.4. 
Proportion of Subjects Converted from Abnormal to Normal ......................................................... 43 
16.1.4.5. 
Evaluate the Association between Amyloid Reduction and Treatment Exposure ........................... 44 
16.2. SECONDARY EFFICACY ................................................................................................................................... 45 
16.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS ............................................................................... 45 
16.2.1.1. 
Key Secondary Efficacy Variables .................................................................................................. 45 
16.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) ...................................................... 46 
16.2.3. 
PRIMARY ANALYSIS OF KEY SECONDARY EFFICACY VARIABLES ............................................................ 47 
16.2.3.1. 
Primary Analysis of CDR-SB .......................................................................................................... 47 
16.2.3.2. 
Primary Analysis of CDR Global .................................................................................................... 48 
16.2.3.3. 
Primary Analysis of OLE Cognitive Composite, FAS, MMSE, Tau-PET SUVR, CSF NfL and 
CSF MTBR243 .................................................................................................................................................... 49 
16.2.3.4. 
Primary Analysis of CSF pTau181 .................................................................................................. 50 
16.2.3.5. 
Primary Analysis of CSF Amyloid Beta1-42/40 ............................................................................. 51 
16.2.4. 
SUPPLEMENTAL ANALYSIS OF KEY SECONDARY EFFICACY VARIABLES .................................................. 51 
16.2.4.1. 
Supplemental Analysis of CDR-SB ................................................................................................. 51 
16.2.4.1.1. 
Subgroup Analysis for CDR SB ................................................................................................. 51 
16.2.4.1.2. 
Cox Proportional Hazards Model for Time to First Disease Progression in CDR SB................ 52 
16.2.4.1.3. 
LME Model for Annual Rate of Change .................................................................................... 53 
16.2.4.1.4. 
Exponential Disease Progression Model .................................................................................... 53 
16.2.4.1.5. 
Logistic Disease Progression Model .......................................................................................... 54 
16.2.4.1.6. 
Longitudinal Logistic Regression Model ................................................................................... 56 
16.2.4.2. 
Supplemental Analysis of the CDR Global ..................................................................................... 57 
16.2.4.3. 
Supplemental Analysis of the OLE Cognitive Composite ............................................................... 58 


 
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16.2.4.4. 
Supplemental Analysis of the CSF Amyloid Beta1-42/40 ............................................................... 58 
16.2.5. 
ANALYSIS OF REMAINING SECONDARY EFFICACY VARIABLES ................................................................ 58 
 
 
16.4. EVALUATION OF THE ASSOCIATION BETWEEN AMYLOID REDUCTION AND CLINICAL/COGNITIVE 
CHANGES ..................................................................................................................................................................... 60 
17. SUBSET OF ANALYSES AT THE INTERIM ................................................................. 61 
18. SAFETY OUTCOMES ........................................................................................................ 69 
18.1. ADVERSE EVENTS ........................................................................................................................................... 69 
18.1.1. 
ALL TEAES .............................................................................................................................................. 70 
18.1.1.1. 
Severity ............................................................................................................................................ 70 
18.1.1.2. 
Relationship to Study Medication .................................................................................................... 70 
18.1.2. 
TEAES LEADING TO TREATMENT TERMINATION ..................................................................................... 71 
18.1.3. 
TEAES LEADING TO STUDY DISCONTINUATION ...................................................................................... 71 
18.1.4. 
SERIOUS ADVERSE EVENTS ...................................................................................................................... 71 
18.1.5. 
INJECTION SITE REACTIONS (ISRS) .......................................................................................................... 72 
18.1.6. 
OTHER CAUSES OF ADVERSE EVENTS ...................................................................................................... 72 
18.2. DEATHS ........................................................................................................................................................... 73 
18.3. SAFETY MRI EVALUATIONS........................................................................................................................... 73 
18.4. LABORATORY EVALUATIONS ......................................................................................................................... 74 
18.4.1. 
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA ........................................... 77 
18.5. ECG EVALUATIONS ........................................................................................................................................ 77 
18.6. VITAL SIGNS .................................................................................................................................................... 78 
18.6.1. 
VITAL SIGNS MARKEDLY ABNORMAL CRITERIA ...................................................................................... 79 
18.7. OTHER SAFETY ASSESSMENTS ....................................................................................................................... 80 
18.7.1. 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) ........................................................................ 80 
18.7.2. 
ANTI-DRUG ANTIBODIES TO GANTENERUMAB ......................................................................................... 80 
19. DATA NOT SUMMARIZED OR PRESENTED .............................................................. 81 
20. REFERENCES ..................................................................................................................... 82 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................. 83 
 OUTPUT CONVENTIONS ................................................................................................................................. 83 


 
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Dates & Times ............................................................................................................................................................ 90 
Spelling Format.......................................................................................................................................................... 90 
Presentation of Treatment Groups .......................................................................................................................... 90 
Presentation of Visits ................................................................................................................................................. 90 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................. 92 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: ....................................................................... 92 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS: ....................................................................................... 94 
APPENDIX 3. THE MEAN AGE AT ONSET FOR EACH MUTATION ........................ 95 
 
 
 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS/TERMS 
Abbreviation/Term 
Definition 
[11C]PiB 
[11C]-Pittsburgh Compound B (PiB) amyloid PET imaging tracer 
AD 
Alzheimer’s Disease 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AO 
Age at onset 
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 
ATC 
Anatomical Therapeutic Chemical 
bpm 
Beats per minute 
CDR 
Clinical Dementia Rating 
CDR-SB 
Clinical Dementia Rating – Sum of Boxes 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
DIAD 
Dominantly inherited Alzheimer’s disease 
DIAN-MCE 
DIAN-Multivariate Cognitive Endpoint 
DIAN-OBS 
DIAN Observational 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ENR 
All Subjects Enrolled Set 
EYO 
Estimated Years to Symptom Onset 
FAS 
Functional Assessment Scale 
FDG-PET 
Fluorodeoxyglucose PET Imaging Tracer 
ICF 
Informed Consent Form 
ISLT 
International Shopping List Test 
ISR 
Injection Site Reaction 
LME 
Linear Mixed Effects 


 
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Abbreviation/Term 
Definition 
MAC-Q 
Memory Complaint Questionnaire 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MMRM 
Mixed-Effects Model for Repeated Measures 
MMSE 
Mini Mental Status Exam 
MRI 
Magnetic Resonance Imaging 
NA 
Not applicable 
NfL 
Neurofilament light chain 
OLE 
Open Label Extension 
PET 
Positron emission tomography 
PT 
Preferred Term 
pTau 
Phosphorylated Tau 
Q2W 
Every 2 weeks 
Q4W 
Every four weeks 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SUVR 
Standardized Uptake Value Ratio 
TEAE 
Treatment Emergent Adverse Events 
WAIS-R 
Wechsler Adult Intelligence Scale - Revised  
WHO 
World Health Organization 
WMS-R 
Wechsler Memory Scale - Revised 
 
 
 


 
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1. INTRODUCTION 
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy, safety and biomarker data for the gantenerumab open label portion of the Protocol 
DIAN-TU-001. It describes the data to be summarized and analyzed, including specifics of the 
statistical analyses to be performed.  
 
This statistical analysis plan (SAP) is based on protocol amendment 12, dated November 10, 
2021. 
 
Details of the analyses presented for the Data Safety Monitoring Board (DSMB) meetings are 
presented in a separate DSMB SAP.  
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective for the final analysis of the Open Label Extension (OLE) is to determine if 
continued treatment with gantenerumab at its target dose can result in continued or complete 
removal of brain amyloid plaque using cerebral amyloid imaging using [11C]-Pittsburgh 
Compound B (PiB) amyloid PET imaging tracer ([11C]PiB) Positron emission tomography 
(PET).  
2.2. SECONDARY OBJECTIVES 
The secondary objectives of the final analysis are as follows: 
● 
The key secondary objective will be to evaluate the efficacy of gantenerumab in 
reducing disease progression and will be assessed for the following key secondary 


 
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efficacy outcome measures. Measures other than Clinical Dementia Rating (CDR) 
scales will be assessed as the annual rate of change and/or assessment of repeated 
measures:  
o CDR - Sum of Boxes (CDR-SB)  
o CDR Global 
o DIAN-TU OLE Cognitive Composite 
o Functional Assessment Scale (FAS) 
o Mini-Mental State Examination (MMSE) 
o Tau PET Binding Partial Volume Corrected Standardized Uptake Value Ratio 
(Tau PET SUVR) 
o Cerebrospinal Fluid (CSF) phosphorylated Tau (pTau)-181 
o Neurofilament Light chain (NfL) in CSF (CSF NfL) 
o  CSF Amyloid Beta1-42/40 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


 
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2.4. SAFETY OBJECTIVES 
This study will assess safety and tolerability of SC gantenerumab up to 1500 mg Q2W in 
individuals at risk for DIAD. 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 this study. 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This SAP refers to the open label period of the trial following a Phase II/III double-blind, 
placebo-controlled study of potential disease modifying therapies in individuals with or at risk 
for dominantly inherited Alzheimer’s disease (AD).  


 
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Document: 
\\quintiles.net\enterprise\apps\sasdata\SASb\SAS\Washington_University\DIAN\SZA59524\Biostatistic
s\Documentation\SAP\CSR\DIANTU001_GantOLE_CSR_SAP_v7_07Dec2023 
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The double-blind period had two arms for each study drug, the active study drug and the blinded 
placebo for that study drug. Subjects were recruited from various sources, i.e., participating 
DIAN-observational (DIAN-OBS) study sites, DIAN-TU-001 trial sites, DIAN-TU-001 partner 
sites, the DIAN Expanded Registry study, and families identified by the sites. Mutation positive 
subjects who signed the informed consent form (ICF), met eligibility requirements and 
completed all baseline evaluations were randomized in a 3:1 ratio to receive either the active 
study drug or placebo for the active study drug. Eligible subjects were offered the opportunity to 
receive active drug for up to 3 years in an open label extension. 
 
Mutation positive subjects who were administered either gantenerumab/placebo to gantenerumab 
or solanezumab/placebo to solanezumab were allowed to participate in the OLE for 
gantenerumab. All subjects participating in the OLE will receive gantenerumab. Dosing and 
titration for the OLE can be found in Section 1.5.2 of Appendix 3 of the protocol. 
3.2. SCHEDULE OF EVENTS 
Schedule of events for the OLE can be found in Appendix 3 of the protocol. 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
Two additional mITT populations, the OLE Gant All Gant exposure mITT and All Gant 
exposure mITT, will be used as supportive analysis populations for selected efficacy parameters, 
noting that linear models for these populations containing double-blind data will allow for the 
use of two slopes, one for double-blind baseline to open-label baseline and the second for open-
label baseline through Year 3 of the open-label period. Parameters for analysis are included in 
this SAP based on OLE primary, secondary and exploratory endpoints and do not reflect all of 
the parameters identified for the analysis of the double-blind period. 


 
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4. PLANNED ANALYSES 
The following analyses will be performed for the gantenerumab OLE for this study: 
● 
Analyses for DSMB meetings 
● 
Interim Analysis 
● 
Final Analysis 
4.1. DATA SAFETY MONITORING BOARD (DSMB)  
A DSMB SAP, describing the methodology and the presentation of, and access to, results will be 
provided by 
 as a separate document. 
4.2. FINAL ANALYSIS  
All final, planned analyses identified in this SAP will be performed by 
 
following Sponsor Authorization of this Statistical Analysis Plan, Database Lock, and Sponsor 
Authorization of Analysis Sets. 
 
Results from selected post hoc exploratory analyses which are not identified in this SAP but are 
deemed relevant to support the planned trial analyses will be documented and reported in the 
clinical study report (CSR); these results will be clearly identified as post hoc.  
 
Exploratory analyses not performed for the study CSR such as exploratory biomarker analysis or 
OLE Baseline comparisons will be described by the Sponsor in a separate document. Analysis of 
pharmacokinetic parameters will be assessed by 
 and will be described in a separate 
document. 


 
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4.3.  INTERIM ANALYSIS 
An interim analysis for selected clinical/cognitive and biomarker endpoints will be conducted 
based on a datacut with all visits conducted through 31 March 2023, at which time it is projected 
that there will be a sufficient number of subjects with data collected at the Year 2 visit. The 
objectives of the interim are to determine if gantenerumab high dose and/or long term treatment 
result in clinical benefit and to determine whether the high dose of gantenerumab results in 
substantially increased amyloid removal compared to the double-blind period. 
 
All visits up to the last visit contributing to interim efficacy assessments, including unscheduled 
visits, will be frozen at the time of the interim. All populations planned for final analysis will 
also be created for the interim, with the exception that external controls identified from DIAN-
OBS may differ due to a different datacut being used for the interim and final analysis. A set of 
subject listings supporting parameters used for the interim analysis from the open-label database 
will be produced. Tables to be produced for the interim will be identified throughout the SAP, 
with analyses of efficacy described in Section 17 with references to the corresponding Section 16 
where applicable.  
 
Analysis of pharmacokinetic parameters will be assessed by
 and will be described in a 
separate document. 
5. ANALYSIS SETS 
Agreement and documentation of mutation positive subjects included/excluded from each 
analysis set will be conducted prior to database lock for the OLE. Treatment groups for all 
analysis sets will be represented as follows and in the given order, noting that “Double-Blind 
Treatment Arm” will be displayed above the individual treatment columns: 


 
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● 
Placebo 
● 
Solanezumab 
● 
Gantenerumab 
● 
Total 
A set of controls will be used for efficacy analysis. The control groups are identified in the 
figures within Section 5.3 and are described within Section 5.4. 
5.1. PROCESS FOR ANALYSIS SET ASSIGNMENT 
● 
Analysis sets will be assigned based on SAP definitions. Subjects excluded from 
each analysis set and reason for exclusion will be prepared for the blind data review 
meeting prior to interim datacut and prior to database lock. 
● 
After the data review meeting, any changes agreed upon during the meeting will be 
incorporated and the analysis sets will be finalized and signed off on by the Sponsor 
prior to the associated data transfer. 
5.2. ALL SUBJECTS ENROLLED SET [ENR] 
The all subjects enrolled (ENR) set will contain all mutation positive subjects who provided 
informed consent for the gantenerumab OLE. 
5.3. MODIFIED INTENT-TO-TREAT [MITT] 
The mITT analysis populations include all enrolled mutation positive subjects who receive any 
treatment post-baseline and have at least one assessment for the analysis primary parameter 
(PiB-PET SUVR for final analysis, CDR Global for both the interim analysis and the final 
analysis) prior to the associated treatment period (as a baseline assessment) and a post-baseline 
assessment. For analysis of clinical/cognitive endpoints or non-PET biomarker endpoints, the 
mITT population identified based on CDR Global should be used.  


 
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There will be three separate mITT populations: 
1. OLE Gant mITT:  Any subjects in the OLE meeting mITT criteria using OLE baseline 
(defined as the last assessment time for the analysis primary parameter prior to the first 
dose of OLE treatment) as the baseline reference point. Refer to figure below where the 
data contributing to the population is highlighted in yellow (and denoted with ‘(Tx)’) for 
the OLE period, regardless of double-blind treatment, with controls (further described in 
Section 5.4) highlighted in green from both placebo double-blind only subjects and 
matched controls from DIAN-OBS. 
 
 
 
2. OLE Gant All Gant exposure mITT:  Any subjects treated with gantenerumab in both the 
DB and OLE who meet mITT criteria using DB baseline as the baseline reference point. 
Refer to figure below where the data contributing to the population is highlighted in 
yellow (and denoted with ‘(Tx)’) for subjects treated with gantenerumab in both DB and 


 
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OLE, with main set controls (further described in Section 5.4) highlighted in green from 
both placebo double-blind only subjects and matched controls from DIAN-OBS, and an 
additional set of extended controls (using DB and OLE baseline values for double-blind 
placebo subjects entering OLE) in a different shade of green to be added to the main set 
controls to form a second set of controls for the population. 
 
 
 
3. All Gant exposure mITT:  Any subjects treated with Gantenerumab in either DB or OLE 
who meet mITT criteria using the baseline associated with the first period of 
Gantenerumab exposure as the baseline reference point. Refer to figure below where the 
data contributing to the population is highlighted in yellow (and denoted with ‘(Tx)’) any 
period of planned gantenerumab treatment, regardless of double-blind treatment, with 
controls (further described in Section 5.4) highlighted in green from both placebo double-


 
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blind only subjects and matched controls from DIAN-OBS. 
 
5.4. GROUPS OF CONTROLS 
To facilitate the analysis, several groups of controls will be defined. It is acknowledged that data 
for the vast majority of subjects in the controls will represent a shorter duration than seen in 
subjects within OLE Gant All Gant exposure mITT. 
5.4.1. EXTERNAL CONTROLS 
External control subjects will be identified by
 and approved by Washington University 
from the associated DIAN-OBS data freeze (DF16 for both the interim analysis and the final 
analysis) based on matched DIAN-TU inclusion/exclusion criteria used to select external 
controls as described in Section 7.2 of the double-blind SAP (including the use of Appendix II 
and Section 12.1.2 in that SAP to calculate EYO), with the exceptions of CDR Global being used 
rather than components of the DIAN-MCE and some variable selections in Table A below 


 
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differing from those used in the double-blind SAP. The exception to the convention is that 
subjects already selected for double-blind period as Eligible DIAN-OBS subjects will be retained 
with the same baseline visit as identified in the double-blind selection. 
 


 
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Table A: 
DIAN-TU-001 Exclusion Criteria Specified in Protocol Amendment 10 That Can 
Be Validated Using Information from the DIAN-OBS Database 
DIAN-TU-001 
Exclusion 
Criteria 
Corresponding DIAN-OBS  
Available Information 
DIAN-OBS 
Data Source 
Variable Names in 
DIAN-OBS  
(the values to remove) 
4.2.3 
Subjects with recent health history of 
stroke, cerebral hemorrhage or transient 
ischemic attack. 
UDS Form A5  
Subject Health History  
(Item 2a/2b) 
CBSTROKE (1) 
CBTIA (1) 
Eligibility Baseline 
MCH (5+) 
4.2.4 
Subjects with alcohol or drug 
dependence sufficient to meet DSM-IV 
criteria currently or within the past 1 
year. 
UDS Form A5 Subject 
Health History  
(Item 7a,7c) 
ALCOHOL (1) 
ABUSOTHR (1) 
4.2.6, 7, 8, 9, 10 
Subjects with recent myocardial 
ischemic events, congestive heart failure 
or major cardiovascular procedures 
including angioplasty / 
endarterectomy/stent, cardiac bypass 
procedure, pacemaker 
UDS Form A5  
Subject Health History 
(Item 1a,1c,1d,1e,1f) 
CVANGIO (1) 
CVBYPASS (1) 
CVCHF (1) 
CVHATT (1)  
CVPACE (1) 
4.2.3, 11 
Subjects with active atrial fibrillation or 
in treatment with anticoagulation 
 
UDS Form A4  
Subject Medications 
 
UDS Form A5  
Subject Health History 
(Item 1b) 
DRUGID              
(d00210 
d00022) 
 
CVAFIB (1) 
4.2.18 
Subjects with clinically significant 
deficiency in B12 (recent diagnosis or in 
active treatment) 
 
UDS Form 
Neurological Exam 
(Item 8, 9) 
 
UDS Form A5  
Subject Health History 
(Item 5d) 
NXSENSOR (2) and 
NXTENDON (2) and 
B12DEF (1) 
 


 
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When subjects meet the criteria above (per the respective DIAN-OBS data freeze corresponding 
to the analysis) to be included in the DIAN-TU-001 primary analysis, selected secondary, and 
selected sensitivity analyses, only their data from the point of eligibility and thereafter will be 
included. 
5.4.2. INTERNAL SET CONTROLS 
The internal set controls are defined as the placebo data from the double-blind period among 
subjects who did not enter the open-label extension. 
5.4.3. MAIN SET CONTROLS 
The main set controls are defined as the external controls plus the internal set controls. 
5.4.4. EXTENDED SET CONTROLS 
The extended set controls are defined as the main set controls plus the double-blind baseline and 
OLE baseline values for subjects treated with placebo during the double-blind period who 
entered the OLE. This set will be an additional set used with the OLE Gant All Gant exposure 
mITT to add further long-term follow-up given that the two timepoints will differ by over four 
years for subjects added to this control group. 
5.4.5. CONCURRENT CONTROLS 
Subjects in any control group will be identified as either concurrent or non-concurrent controls.  
The concurrent set of controls are defined as the internal set controls (including those in the 
extended set controls where applicable) and the external set controls where the point of eligibility 
occurs on or after the first dose of double-blind treatment in DIAN-TU-001.  Based on this 
convention, the subject’s baseline visit for internal set controls or point of eligibility for external 


 
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set controls will have occurred within the period during which DIAN-TU-001 subjects were 
treated (including the gap period between double-blind and open-label treatment).   
5.4.6. CONTROLS APPLIED TO INDIVIDUAL ANALYSIS POPULATIONS 
Controls will be applied to the three mITT populations as follows, with the exception that Mixed 
Model for Repeated Measures (MMRM) analyses will be assessed against the internal set 
controls (when any controls are used) and parameters which are not assessed within DIAN-OBS 
will be assessed against the internal set controls: 
● 
OLE Gant mITT:  Evaluated against main set controls 
● 
OLE Gant All Gant exposure mITT:  Evaluated against main set controls (as 
primary set of controls) and also against extended set controls (as supportive set of 
controls) 
● 
All Gant exposure mITT:  Evaluated against main set controls 
5.5. SAFETY ANALYSIS SET [SAF] 
The safety analysis population includes all subjects who have consented to participate and have 
received at least one dose of study drug in the gantenerumab OLE period.  
6. GENERAL CONSIDERATIONS 
All statistical analyses and summary information are to be generated according to this SAP. Any 
deviations from this SAP will be documented in the CSR. 
 
For continuous variables, descriptive statistics such as the number of subjects (n), mean, standard 
deviation (SD) or standard error (SE), minimum, median, and maximum values will be reported. 
Lower and upper quartiles will be presented for select efficacy summaries. For categorical 


 
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variables, frequencies and percentages will be displayed. Subject data collected in the electronic 
case report form (eCRF) and other data sources will be presented in listings. 
6.1. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day 
of assessments and events.  
 
Reference start date is defined as the day of the first dose of OLE study medication (where Day 1 
is the day of the first dose of study medication) and will appear in every listing where an 
assessment date or event date appears.  
 
If the date of the event is on or after the reference date, then:  
 
Study Day = (date of event – reference date) + 1. 
 
If the date of the event is prior to the reference date, then:  
 
Study Day = (date of event – reference date). 
 
In the situation where the event date is partial or missing, Study Day and any corresponding 
durations will appear partial or missing in the listings. 
 
Similar variables will be created where needed for analysis based on using a reference start date 
as the day of first double-blind treatment. Study day will also be created for all controls where 
the reference date corresponds to the date of the visit to be used as the analysis baseline. 


 
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6.2. BASELINE 
6.2.1. DOUBLE-BLIND BASELINE 
Double-blind baseline is defined as the latest non-missing DIAN-TU-001 measurement taken 
prior to the double-blind study drug administration and will be consistent with the value 
identified as baseline during the double-blind analysis. Select imaging measures identified as 
failing after locking of the double-blind database a quality control during collection will be 
excluded from contributing to baseline.  
6.2.2. OLE BASELINE 
OLE Baseline is defined as the latest non-missing DIAN-TU-001 measurement taken prior to 
OLE study drug administration, using data from the OLE database where applicable. OLE 
baseline for specific assessments are as follows:  
● 
OLE baseline for CDR Global and CDR-SB will be defined as the latest non-
missing measurement prior to OLE study drug administration. 
● 
For blood pressure, OLE baseline will further be defined as the latest time prior to 
OLE study drug administration where both systolic and diastolic blood pressure 
measurements are available. 
● 
For laboratory assessments, OLE baseline will be defined as the values at Visit 1 of 
the OLE. 
● 
OLE baseline measurements for height and weight will be derived from the values 
at Visit 1. 
 
OLE Baseline will not be defined for subjects who never took the study drug. For assessments 
collected without a time measurement on the date of the first dose, the assessment can contribute 


 
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to OLE baseline if it was scheduled per protocol to take place prior to dosing. 
Baseline for DIAN-OBS will be defined based on the first visit in which the subject met criteria 
as described in Section 5.4, noting that this visit will be identified at the time the subject is 
identified to contribute to the external controls. 
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION 
DATA 
Summaries by visit will be based on the visit windows described in Section 6.4. Early 
discontinuation assessments of efficacy will be included at the annual visit when it occurs +/- 6 
months relative to the visit, except in cases where a scheduled visit was conducted for the 
corresponding annual visit. Unscheduled visits that are not captured by analysis visit windowing 
will not contribute to by-visit analyses.  
 
Listings will include scheduled, unscheduled, retest and early discontinuation data. 
6.4. WINDOWING CONVENTIONS  
Analysis visit windows will be applied based on the planned frequency of collection outlined in 
the protocol. Planned visit dates will be calculated from the date of the first OLE dose at V1 
(Week 0). For data collected yearly, visit windows will begin 182 days prior to the planned visit 
date and end 182 days after the planned visit date. For data collected semi-annually, visit 
windows will begin 91 days prior to the planned visit date and end 91 days after the planned visit 
date. Safety/titration MRI’s and measurements collected more frequently than a semi-annual 
basis (e.g., vital signs) will be summarized based on the nominal visit. If multiple measurements 
fall within the same visit window, the value closest to the planned visit timepoint per the 
protocol schedule of events will contribute to by-visit summaries, with the later visit to be used 


 
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in the case of a tie. 
6.5. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be 
two-sided, unless otherwise specified in the description of the analyses. 
6.6. COMMON CALCULATIONS 
Scores for CDR Global and CDR-SB will be reported based on the value entered in the database 
and will not be recalculated. 
 
For quantitative measurements, change from baseline will be calculated as post-baseline 
assessment - baseline assessment. If either the baseline or post-baseline value is missing, the 
observation will not be included in the change from baseline summary. 
EYO equals a subject’s age at the clinical assessment minus this subject’s estimated age at onset 
(AO). The details of the estimated AO are provided in the double-blind period SAP, Section 12.1.2, 
noting that Appendix III of this SAP will be used for analysis rather than the Appendix II in the 
double-blind SAP. CRF visit date will be used for the calculation of EYO to ensure a constant 
value across all tests within a visit.  
6.7. SOFTWARE VERSION 
All analyses, summary tables, figures, and data listings will be generated with SAS® version 9.4 
or higher, or R, or with analysis code that has been appropriately validated. 
7. STATISTICAL CONSIDERATIONS 


 
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7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates and factors are used in the analyses. For details of their inclusion in the 
models, see the specific analysis section. 
• 
Double-blind baseline CDR Global  
o CDR=0 (asymptomatic) 
o CDR>0 (symptomatic) 
• 
OLE baseline CDR Global  
o CDR=0 (asymptomatic) 
o CDR>0 (symptomatic) 
• 
Double-blind baseline PiB-PET SUVR  
o PiB-PET SUVR <= 1.25 
o PiB-PET SUVR > 1.25 
• 
OLE baseline PiB-PET SUVR  
o PiB-PET SUVR <= 1.25 
o PiB-PET SUVR > 1.25 
• 
Time since OLE baseline (in years; continuous) 
• 
Time since double-blind baseline (in years; continuous) 
• 
Double-blind baseline EYO (in years; continuous) 
• 
OLE baseline EYO (in years; continuous) 
• 
Post-baseline EYO (in years; continuous) 
For external controls, baseline values will be identified as the last measurement at or prior to the 
first visit for the subject to be identified as contributing to the external controls. 


 
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7.2. MULTICENTER STUDIES 
This platform study is conducted in three regions, USA/Australia/Canada, Europe, and the rest of 
the world. This study is being conducted at approximately 30 global sites. The homogeneity of 
treatment effects across investigational sites will be investigated using descriptive statistics. 
 
When specified, statistical analysis will be adjusted for geographic region. Geographic region 
will be categorized as follows: 
Geographic Region 
Country 
United States/Canada/Australia 
United States, Canada and Australia 
Europe 
France, Spain, United Kingdom, as well as 
any European countries available from 
external controls.  
Rest of World 
The rest of world besides the above 2 
regions, based on countries applicable to 
external controls. 
7.3. MISSING DATA 
There will be no imputation of missing data. Handling of missing data for specific efficacy 
endpoints is detailed in Sections 16.1.2 and 16.2.2. 
7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
There will be no adjustments for multiplicity or multiple comparisons for the open label analysis 
as the study was powered based on the double-blind analysis.  


 
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7.5. EXAMINATION OF SUBGROUPS 
Subgroup analysis will be conducted as described within Section 16 for the primary variables, 
(key) secondary variables, and exploratory variables.  
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
 
The templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures, and listings to be provided by 
 
 
9. DISPOSITION AND WITHDRAWALS 
All mutation positive subjects who provide informed consent for the Gantenerumab OLE will be 
accounted for in this study period.  
9.1. DISPOSITION 
Subject disposition and withdrawals and study region will be presented for the ENR set, and 
presented separately by baseline asymptomatic and symptomatic status for the OLE Gant mITT 
population. In addition, visit attendance will be listed and summarized for each scheduled visit. 
Reasons for end of study and end of treatment will be presented in a listing. An additional listing 
will include subjects who did not meet one or more eligibility criteria. 
 
Summaries for disposition will be presented for the interim analysis and will also identify the 
number of subjects who are active in the study as of the interim analysis datacut. 


 
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9.2. PROTOCOL DEVIATIONS 
A summary will be provided to identify subjects who had important protocol violation(s) and a 
list will be provided for important protocol violation(s). The identification of the important 
protocol violation(s) will be discussed at the data review meeting prior to final database lock.  
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for each mITT population 
(along with their associated controls) and the SAF. No statistical testing will be carried out for 
demographic or other baseline characteristics. The univariate summary statistics, n, mean (SD), 
median, minimum and maximum will be calculated for the continuous variables. The following 
demographic and other baseline characteristics will be reported, where values will be presented 
as collected prior to double-blind treatment if the value was not collected in the open label 
database:  
• 
Age (years) - calculated relative to date of consent for the OLE, based on date of 
birth as collected in the double-blind period 
• 
Sex 
• 
Race (where subjects can contribute to multiple race categories) 
• 
Ethnicity 
• 
OLE Baseline CDR Global 
• 
OLE Baseline CDR-SB (summarized both as a continuous value and an ordinal 
value) 
• 
OLE Baseline EYO 
• 
Years of Education 


 
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• 
OLE Baseline Height 
• 
OLE Baseline Weight 
 
For the OLE Gant All Gant exposure mITT and All Gant exposure mITT populations, values for 
the double-blind period baseline for age, CDR Global, CDR-SB, EYO, height and weight will 
also be presented for subjects in the population who were randomized to gantenerumab during 
the double-blind period. 
 
Demographic data will also be presented in a listing. 
 
Demographic data will be summarized for the interim analysis for each mITT population and 
associated controls. 
11. MEDICAL HISTORY 
Updated Medical History information collected in the OLE eCRF will be listed for the SAF, and 
select family history as collected prior to the double-blind period will be summarized  
• 
Medical History will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and Preferred Term (PT). The version 
will be established and documented prior to lock of the data and will be identified 
within footnotes. 
• 
Family AD History as indicated by symptoms, history or diagnosis will be 
summarized by descriptive statistics and listed for the OLE Gant mITT and the 
SAF. Mutation gene types (PSEN1, PSEN2, and APP), APOE4 status (as 
positive/negative, as number of copies (0, 1, or 2), and by allele combinations), 
number and percentage of blood grandparents and parents, siblings, and children 
in a family with dementia will also be tabulated. 


 
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12. COLUMBIA – SUICIDE SEVERITY RATING SCALE (C-SSRS) 
The OLE baseline C-SSRS score, as obtained using the Since Last Visit version of the form, will 
be summarized using descriptive statistics by severity rating scale for each category of Suicidal 
Ideation, Intensity of Ideation, and Suicidal Behavior for the SAF. C-SSRS scores will also be 
listed.  
13. MEDICATIONS 
Medications defined as concomitant medications (as identified below) will be presented for the 
SAF and coded using the World Health Organization (WHO) dictionary. The version will be 
established and documented prior to lock of the data and will be identified within footnotes. 
Medications will be classified and summarized by anatomical therapeutic chemical (ATC) drug 
class and by the WHO drug preferred name. Subjects who report use of more than one 
medication or multiple uses of the same medication will be counted once per medication code 
and once for all drugs taken within an ATC drug class. 
 
Concomitant medications will also be summarized based on the number of subjects with changes 
to AD medication between the first and last dose of OLE treatment. The number of subjects will 
be presented along with the incidence of AD medications by WHO drug preferred name. 
 
If the medication start date is missing or partial, the date will be compared as far as possible with 
the date of first dose of the OLE study drug. Medications will be assumed to be concomitant 
unless there is clear evidence (through comparison of partial dates and/or collected assessment of 
whether the medication started prior to the first dose of the study drug) suggesting the 
medication started prior to the first dose of study medication. 


 
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● 
‘Prior’ medications are medications which have a start date prior to the first dose of 
OLE study drug and will include those medications which were identified as 
ongoing at the end of double-blind and re-entered onto an Ongoing Concomitant 
Medication page of the OLE eCRF form. 
● 
‘Concomitant’ medications are all medications which have a start date on or after 
the date of the first dose of OLE study drug. 
All medications captured in the OLE eCRF concomitant medications form will be listed, ordered 
within subject by the medication start date. The listing will display the recorded term from the 
CRF and, adjacent to that, the preferred name that appears in the tables. 
14. SUBSTANCE USAGE 
Substance usage history was not re-assessed after double-blind baseline and will not be included 
in any OLE listings.  
15. STUDY MEDICATION EXPOSURE 
Duration of treatment in the OLE will be summarized as both total days and total weeks per 
subject and will be presented using the descriptive statistics including mean (SD), 25th percentile, 
median, 75th percentile, min and max for the SAF. Similarly, duration of total gantenerumab 
exposure spanning the double-blind and OLE periods, duration of gantenerumab exposure at the 
highest dose in the OLE and duration of gantenerumab exposure at the highest dose in either the 
double-blind or OLE period will be summarized.  
 
The total number of administered doses (including both fully and partially administered) for each 
subject will be summarized overall and by dose levels using descriptive statistics. The 
cumulative OLE dose exposure will be summarized. A listing of OLE study drug administration 


 
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will be presented. In addition, percent compliance will be summarized during the OLE. 
 
Study medication exposure will be summarized for the interim analysis. 
15.1. DERIVATIONS 
Duration of treatment from OLE baseline (days) = date of last OLE dose – date of first OLE dose 
+1 
 
Total duration of treatment with gantenerumab from double-blind baseline (days) = (date of last 
double-blind dose – date of first double-blind dose) + (date of last OLE dose – date of first OLE 
dose) +1 
 
Duration of treatment of gantenerumab at the highest OLE dose received (days) = date of last 
OLE dose – date of first OLE dose at the same dose level +1 
 
Duration of treatment of gantenerumab at the highest dose received (days) = date of last dose at 
the highest level in either the OLE or double-blind periods – date of first dose at the same dose 
level +1 
 
Percent compliance in the OLE = (number of OLE doses/ number of planned OLE dosing visits 
prior to treatment discontinuation) x 100, where the number of OLE doses combines dosing at 
the visit and the preceding Q2W dosing timepoint, where applicable, as a single dose 
 
Cumulative OLE dose of gantenerumab = sum of all OLE doses, based upon the planned dose 
for any dose administered. 


 
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16. EFFICACY OUTCOMES  
16.1. PRIMARY EFFICACY 
16.1.1. 
PRIMARY EFFICACY VARIABLE(S) & DERIVATION(S) 
The primary efficacy variable is the change in amount of amyloid deposition as measured by 
[11C]PiB-PET. The composite PiB partial volume corrected 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 for amyloid 
deposition. Corresponding analyses based on conversion of SUVR to centiloid will be performed 
by Washington University.  
16.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
There will be no missing data imputation for the primary efficacy variable. 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary objective for the OLE is to determine if treatment with gantenerumab at its target 
dose can result in removal of brain amyloid plaque using cerebral amyloid imaging using 
[11C]PiB-PET. 
 
The primary efficacy analysis will be performed for the OLE Gant mITT without the use of 
controls in the model. A Mixed-Effects MMRM analysis will be used to test if the change from 
the OLE baseline to the end of OLE in PiB-PET SUVR is significantly less than 0 for the OLE 
Gant mITT population. The MMRM will include the OLE baseline PiB-PET SUVR and visit 
(treated as categorical) as the fixed effects. An unstructured variance-covariance matrix will be 


 
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used to model the within-subject errors among the repeated measures. If the unstructured 
covariance structure matrix results in a lack of convergence, the following covariance structures 
will be assumed in sequence: heterogeneous Toeplitz, heterogeneous autoregressive, 
heterogeneous compound symmetry, and compound symmetry. The corresponding p-value and 
the 95% confidence interval for the estimated least squares mean change at each visit will be 
presented. If the upper bound of the 95% CI at the year 3 OLE visit is less than 0, it is concluded 
gantenerumab significantly removes amyloid plaque at year 3. In the case that a structured 
variance-covariance matrix is used to enable the model to converge, the "sandwich" estimator of 
the variance-covariance matrix will be employed by using the “empirical” option in the proc 
mixed procedure. P-values for within-subject change resulting from a one-sample t-test using 
least squares mean estimates and associated standard errors will be presented. 
 
Descriptive statistics including number of observations, mean, SD, median, minimum, and 
maximum will be provided by visit. P-values for within-subject change resulting from a one-
sample t-test using least squares mean estimates and associated standard errors will be presented. 
In addition, a listing of the primary endpoint will be presented.  
 
Figures of model estimated mean over time or spaghetti plots of individual data over time/EYO 
color-coded by treatment arms and doses will be presented as deemed necessary by Washington 
University team and may be included in CSR as needed.  
16.1.4. 
SUPPLEMENTARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
16.1.4.1. 
Amyloid Removal by Double-Blind Treatment 
An MMRM analysis similar to the one described in Section 16.1.3 will be re-run to compare the 
change during the double-blind period in amyloid PET for participants on gantenerumab (only 


 
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their data in the double-blind period will be included) with the change from the OLE baseline for 
participants (only their data in the OLE period will be included) on solanezumab or placebo in 
the double-blind period using an MMRM model. 
16.1.4.2. 
Amyloid Removal by CDR Global Status 
The analysis described in Section 16.1.3 will be re-run with the OLE baseline CDR Global (in 
categories of baseline CDR=0 and baseline CDR >0) as a covariate to estimate the treatment 
effect for the subgroup Figures of model estimated mean over time or spaghetti plots of 
individual data over time/EYO (CDR=0 vs CDR >0) will be presented as deemed necessary by 
Washington University team and may be included in CSR as needed. 
16.1.4.3. 
Gantenerumab Treatment Effects during the Whole Study Duration 
(Double-Blind + OLE) 
To evaluate the treatment effect of gantenerumab during the whole study duration, the change from 
the double-blind baseline for subjects in the All Gant exposure mITT and for subject in the OLE 
Gant All Gant exposure mITT will be calculated for each post double-blind baseline visit and will 
be analyzed using the MMRM model (without controls) described in Section 16.1.3. The MMRM 
model will include the double-blind baseline value, the double-blind treatment arm (gantenerumab, 
solanezumab, placebo) as applicable per analysis population, visit, and the interaction between the 
double-blind treatment arm and visit as the fixed effects. The visit variable will be considered as 
categorical with the following categories: visit 1 (the ~1-year visit in the double-blind period), visit 
2 (the ~2-year visit in the double-blind period), visit 3 (the ~4-year visit in the double-blind period), 
visit 4 (the OLE baseline visit), visit 5 (the ~1-year OLE visit), visit 6 (the ~2-year OLE visit), 
visit 7 (the ~3-year OLE visit). Subjects on gantenerumab or placebo during the double-blind 
period will contribute to all visits. Subjects on solanezumab during the double-blind period will 
not contribute to post-baseline values within the double-blind period. An unstructured variance-


 
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covariance matrix will be used to model the within-subject errors among the repeated measures. If 
the unstructured covariance structure matrix results in a lack of convergence, the following 
covariance structures will be assumed in sequence: heterogeneous Toeplitz, heterogeneous 
autoregressive, heterogeneous compound symmetry, and compound symmetry. In the case that a 
structured variance-covariance matrix is used to enable the model to converge, the "sandwich" 
estimator of the variance-covariance matrix will be employed by using the “empirical” option in 
the proc mixed procedure.  
 
The corresponding p-value for the difference from no change from baseline and the 95% 
confidence interval for the estimated least squares mean change at each visit will be presented. 
 
The model described above will also be analyzed with the addition of the double-blind baseline 
CDR status (CDR=0 vs CDR >0) as a covariate, the two-way interactions of CDR status and the 
double-blind baseline PiB-PET SUVR, CDR status and treatment arm, and CDR status and visit, 
and the three-way interaction of CDR status, treatment arm and visit. If the model fails to 
converge, the model will be removed.  
 
Figures of model estimated mean over time by the double-blind treatment arms or spaghetti plots 
of individual data over time/EYO by the double-blind treatment arms will be presented as 
deemed necessary by Washington University team and may be included in CSR as needed. 
16.1.4.4. 
Proportion of Subjects Converted from Abnormal to Normal 
To evaluate whether gantenerumab can decrease the accumulated amyloid plaque from abnormal 
level to normal level, the threshold of 1.25 will be used to define normal level vs abnormal level 
at the OLE baseline and at each post-baseline visit. A PiB-PET SUVR >1.25 is considered 
abnormal while a PiB-PET SUVR ≤1.25 is considered normal. A shift from OLE baseline to 


 
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each post-baseline visit, where missing values are replaced using last observation carried forward 
(allowing the baseline value to also be carried forward), and to the last post-baseline OLE 
measurement will be provided along with a corresponding Fisher’s exact test. A supportive 
analysis of shifts at each post-baseline visit without carrying forward values will also be 
provided. This analysis will be conducted for the OLE Gant mITT population. 
16.1.4.5. 
Evaluate the Association between Amyloid Reduction and Treatment 
Exposure 
The total treatment exposure at each visit, defined as the cumulative OLE dose prior to the start 
of the associated visit, will be calculated for each subject. Linear mixed effects model will be 
used to estimate the association between amyloid reduction and the treatment exposure.  
The change from baseline in PiB-PET SUVR will be the dependent variable and the total 
treatment exposure at each visit and the baseline PiB-PET SUVR will be independent variable.  
Random effects in intercept and total treatment exposure will be included in the model to 
account the correlation among the repeated measures. This analysis will be applied to the OLE 
Gant mITT population and will also be run with baseline covariates such as disease status 
(asymptomatic vs symptomatic) and EYO. When the disease status is included in the model, the 
interaction between disease status and total treatment exposure will also be included so that the 
treatment effect will be evaluated separately for each disease status.  
 
Figures of individual amyloid removal vs individual total dose exposure will be presented as 
deemed necessary by Washington University team and may be included in CSR as needed. If the 
plot demonstrates a non-linear relationship, an ad-hoc non-linear mixed effects model will be 
used to estimate this non-linear relationship.  
 
Figures of model estimated mean over time by high dose and low dose or spaghetti plots of 


 
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individual data over time/EYO by high dose and low dose will be presented as deemed necessary 
by Washington University team and may be included in CSR as needed. 
16.2. SECONDARY EFFICACY 
For details of the collection methods for each test please refer to the protocol. For each 
secondary efficacy variable, the direction of benefit with effective drug is listed below. These 
may be calculated as change from baseline or difference between drug vs. control. 
16.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. 
Key Secondary Efficacy Variables 
● 
Clinical Dementia Rating – Sum of Boxes (CDR-SB): Higher scores indicate worse 
performance.  
● 
CDR Global: Higher scores indicate worse performance.  
● 
DIAN-TU OLE Cognitive Composite (OLE Cognitive Composite) 
Based on the four components, the DIAN-TU-001 OLE Cognitive Composite will be calculated 
using the following formula: 𝑌= (0.25) 𝑀−𝑚𝑒𝑎𝑛
𝑆𝐷
+ (0.25) 𝑊−𝑚𝑒𝑎𝑛
𝑆𝐷
+ (0.25) 𝐴−𝑚𝑒𝑎𝑛
𝑆𝐷
+ (0.25) 𝐷−𝑚𝑒𝑎𝑛
𝑆𝐷
 , 
where, D represents the WMS-R Digit Span Backward Recall, A represents the Category 
Fluency (Animals) value, W represents the Wechsler Adult Intelligence Scale Digit Symbol 
Substitution Test value, and M represents the Mini Mental State Examination value. The mean 
(SD) for each of the four parameters will be calculated using the double-blind baseline data of 
the mutation positive subjects in the DIAN-TU-001 trial. Lower scores of each component 
indicate worse performance. 
● 
Functional Assessment Scale (FAS): Higher scores indicate worse performance. 
● 
Mini-Mental State Examination (MMSE): Lower scores indicate worse 


 
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performance. 
● 
Tau PET Binding Partial Volume Corrected Standardized Uptake Value Ratio - 
Parietal Composite (Tau PET SUVR): The summary region is the average SUVR 
values for the postcentral gyrus, supramarginal gyrus, superior parietal cortex, 
inferior parietal cortex, precuneus, posterior cingulate, and isthmus cingulate 
regions. Expected to decrease with effective drug. 
● 
CSF pTau181: Expected to decrease with effective drug.  
● 
CSF NfL: Expected to decrease with effective drug.  
● 
CSF Amyloid Beta1-42/40: Expected to increase with effective drug 
16.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
Missing values in the clinical or cognitive assessments (such as MMSE, FAS etc.) are expected 
to be rare. If at any given visit, the number of missing items within a questionnaire is less than 
30% of the total number of items, then the score for this component at this visit will be 
calculated as the sum of the non-missing items multiplied by the ratio of the total number of 
items to the number of the non-missing items (Doody, 2014). If the number of missing items is 
equal to or greater than 30%, then the score at this visit is considered missing (Doody, 2014). 
 
If at any given visit, where all four components of the OLE Cognitive Composite are intended to 
be measured and one of the four components has missing scores, meaning less than 30% of the 
total components as described above, then the OLE Cognitive Composite will be calculated 
using only the other three components and with the method described in SAP Section 16.2.1.1. 
But the composite will be weighed by 1/3 instead of 0.25. If two or more components have 
missing scores, then the composite will be considered missing as well.  
 


 
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If at any given visit, only some of the four components are intended to be measured instead of 
all, then the composite score will not be calculated and will not be used in the analysis for these 
visits. 
 
Values captured within the FAS as ‘not applicable (e.g., never did)’ (NA) will be treated as 
missing. 
16.2.3. 
PRIMARY ANALYSIS OF KEY SECONDARY EFFICACY VARIABLES 
16.2.3.1. 
Primary Analysis of CDR-SB 
The primary analysis will be on the All Gant Exposure mITT, with other baseline covariates 
(such as baseline EYO) defined in the same way as baseline for the associated population. The 
recurrent progression is defined as any progression which is either the first increase in CDR-SB 
above baseline or any progression above the highest preceding post-baseline value identified as a 
progression, where progression above the preceding value must be observed at two consecutive 
measurements unless the progression occurs at the last measurement. Subjects without a 
progression event at their last measurement will be censored at the time of that measurement. 
The time-to-event is the time elapse between the two visits where the recurrent progression is 
observed, or the time since the baseline assessment for the first progression. Subjects can 
contribute multiple records to the analysis (i.e., once for each progression and potentially for 
censoring at the time of last measurement).  The same definition will be applied to all controls as 
defined in Section 5.4. The Cox proportional hazards model employing the Andersen-Gill 
method (Prentice RL, 1981) with robust variance estimator will be used to compare the hazards 
of recurrent progression in CDR-SB between population and all controls. The model will include 
treatment group and baseline EYO as the fixed effects. Should the model produce a two-sided p-
value less than 0.10, a sensitivity analysis will be conducted using the shared frailty method (add 
reference). 


 
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Analyses will be conducted separately for baseline asymptomatic and symptomatic subjects. 
 
The same analysis will be applied to the OLE Gant mITT population and the OLE Gant All Gant 
exposure mITT populations, along with all controls. The analysis will also be conducted for each 
of the three mITT populations based on the baseline asymptomatic and symptomatic subjects 
presented separately. A Kaplan-Meier figure will be generated for baseline asymptomatic 
subjects for all three mITT populations and associated controls. 
 
The spaghetti plots of individual data will be presented over time since baseline and over EYO 
for both the OLE Gant All Gant exposure mITT population and for all controls. These figures, 
including those described for CDR-SB in Section 3 of the Addendum to the Statistical Analysis 
Plan created by Washington University prior to the interim analysis, will be generated by 
Washington University team and may be included in CSR as needed. 
16.2.3.2. 
Primary Analysis of CDR Global 
The primary analysis will be on the All Gant Exposure mITT, with all the other baseline 
covariates (such as baseline EYO) defined in the same way as baseline for the associated 
population. The time to the first disease progression is defined as the time from the baseline to 
the first visit where CDR Global is greater than CDR Global baseline value, where a progression 
is considered an increase above baseline observed at two consecutive measurements unless the 
progression occurs at the last measurement. Subject without progression will be censored at their 
last measurement. 
 
The Cox proportional hazards model will be applied to compare the hazards of disease 
progression in CDR Global between each of the three mITT population separately and all 


 
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controls. The models will include the treatment group (specifically gantenerumab and controls) 
and baseline EYO as the fixed effects.  
 
Analyses will be conducted separately for baseline asymptomatic and symptomatic subjects. A 
Kaplan-Meier figure will be generated for baseline asymptomatic subjects for all three mITT 
populations and associated controls. 
 
Spaghetti plot of EYO for each participant will be presented for each of the three mITT 
populations. Lines and data points will be coded by different color/symbol for different CDR 
groups (without progression, with progression) and doses. This figure will be generated by 
Washington University team. 
16.2.3.3. 
Primary Analysis of OLE Cognitive Composite, FAS, MMSE, Tau-PET 
SUVR, CSF NfL and CSF MTBR243 
The annual disease progression between the OLE Gant mITT population and all controls (with 
the exception of internal controls only for Tau-PET SUVR) will be compared using a linear 
mixed effects (LME) model. CSF NfL will be log transformed for the analysis. The LME model 
will include time since baseline (in years: treated as continuous), treatment group (the OLE Gant 
mITT and all control), interaction between the treatment group and time, and random intercepts 
and slopes for each subject as the random effects. The unstructured covariance will be used to 
model the covariance between random intercepts and random slopes and will be modelled 
separately for baseline asymptomatic and symptomatic subjects.  
 
The same analysis will also be applied to the OLE Gant All Gant exposure mITT population and 
the All Gant exposure mITT populations, along with all controls. This model will be tested using 
linear splines, which fits two slopes with one prior to the OLE baseline and one after the OLE 


 
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baseline (the linear splines have a node at the OLE baseline) to account for the different dosing 
regimens in the DIAN-TU-001 gantenerumab exposure population; for the pooled controls, only 
one slope will be fitted since no treatment was administered at any point in time. The analysis 
will also be conducted for each population based on the baseline asymptomatic and symptomatic 
subjects presented separately. 
 
Figures of model estimated mean over time by treatment arms or spaghetti plots of individual 
data over time/EYO by treatment arms will be presented as deemed necessary by Washington 
University team and may be included in CSR as needed. The plots will also be presented 
separately for baseline asymptomatic and symptomatic subjects at the OLE baseline.  
16.2.3.4. 
Primary Analysis of CSF pTau181 
To evaluate whether gantenerumab will continue to reduce the CSF pTau181 from OLE baseline, 
MMRM (without controls) will be used to test if the change from the OLE baseline to the end of 
OLE in CSF pTau181 is significantly less than 0 for the OLE Gant mITT population. The 
MMRM will include the OLE baseline CSF pTau181 and visit (treated as categorical) as the 
fixed effects. An unstructured variance-covariance matrix will be used to model the within-
subject errors among the repeated measures. If the unstructured covariance structure matrix 
results in a lack of convergence, the following covariance structures will be assumed in 
sequence: heterogeneous Toeplitz, heterogeneous autoregressive, heterogeneous compound 
symmetry, and compound symmetry. The corresponding p-value and the 95% confidence 
interval for the estimated least squares mean change at each visit will be presented. If the upper 
bound of the 95% CI at the year 3 OLE visit is less than 0, it is concluded gantenerumab 
significantly remove amyloid plaque at year 3. 
 


 
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Figures of model estimated mean over time by treatment arms or spaghetti plots of individual 
data over time/EYO by treatment arms will be presented as deemed necessary by Washington 
University team and may be included in CSR as needed. The plots will also be presented 
separately for baseline asymptomatic and symptomatic subjects at the OLE baseline.  
16.2.3.5. 
Primary Analysis of CSF Amyloid Beta1-42/40 
To evaluate if treatment with gantenerumab increases CSF Amyloid Beta1-42/40, the MMRM as 
described in Section 16.2.3.4 will be applied for the OLE Gant mITT and the MMRM as 
described in Section 16.1.4.3 will be applied for the All Gant exposure mITT, with both 
asymptomatic and symptomatic subjects included within the same model. 
16.2.4. 
SUPPLEMENTAL ANALYSIS OF KEY SECONDARY EFFICACY VARIABLES 
16.2.4.1. 
Supplemental Analysis of CDR-SB  
16.2.4.1.1. 
Subgroup Analysis for CDR SB 
Each subject in the All Gant exposure mITT population and all controls will be categorized into 
3 groups by comparing the baseline and the last available PiB SUVR values to 1.25: (1) Amyloid 
normal group (both the baseline and the last available PiB SUVR values <1.25); (2) Amyloid 
abnormal to normal group (the baseline PiB SUVR value>=1.25 and the last available PiB 
SUVR value <1.25); (3) The rest (not in groups (1) and (2)). The model described in Section 
16.2.3.1 will be applied to the All Gant exposure mITT population and all controls to compare 
the hazard of progression in CDR SB among these 6 subgroups (i.e., 3 groups above assessed 
within baseline asymptomatic/symptomatic status). 
 
A separate analysis will identify DIAN-TU-001 subjects as either PiB-PET SUVR normal or 
abnormal based upon the last post-baseline measurement for the subject.  The model described in 


 
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Section 16.2.3.1 will be applied to the asymptomatic subjects in the All Gant exposure mITT 
population where treatment groups are replaced with the three groups of PiB-PET SUVR normal, 
PiB-PET SUVR abnormal, and external controls, with the normal and abnormal groups being 
compared to the external controls and to each other.  The model will also be run with factors of 
the number of post-baseline PiB-PET normal values (as a continuous measure to replace the 
normal/abnormal status) and the interaction of that variable with the treatment groups. 
 
The model described in Section 16.2.3.1 will be applied to the asymptomatic subjects in the All 
Gant exposure mITT population where treatment groups are replaced with the three groups of 
gantenerumab exposure, concurrent controls, and non-concurrent controls, with the 
gantenerumab exposure being compared to both sets of controls.   
 
Figures of model estimated mean over time by treatment arms or spaghetti plots of individual 
data over time/EYO by treatment arms will be presented as deemed necessary by Washington 
University team and may be included in CSR as needed. The plots will also be presented 
separately for baseline asymptomatic and symptomatic subjects at the OLE baseline. 
16.2.4.1.2. 
Cox Proportional Hazards Model for Time to First Disease 
Progression in CDR SB 
The analysis models in Section 16.2.3.2 (Cox proportional hazards model) will be applied to 
CDR SB. The same analysis will be repeated for the OLE Gant mITT population with 4 
treatment groups (subjects on gantenerumab in the double-blind period, subjects on solanezumab 
in the double-blind period, subjects on placebo in the double-blind period, and all control) and 
will be repeated for the six subgroups defined in the first paragraph in Section 16.2.4.1.1. The 
same analysis may also be conducted for subgroups defined in the second paragraph in Section 
16.2.4.1.1. 


 
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16.2.4.1.3. 
LME Model for Annual Rate of Change 
The annual disease progression between each mITT population and all controls will be compared 
using an LME model for each key secondary efficacy variable. The same model described in 
Section 16.2.3.3 will be used. Separate analyses of baseline asymptomatic and symptomatic 
subjects will also be made to determine if treatment before symptom onset is different from after 
symptom onset.  
 
The same analysis will also be conducted for the six subgroups defined in the first paragraph in 
Section 16.2.4.1.1.  
16.2.4.1.4. 
Exponential Disease Progression Model 
The exponential disease progression model with EYO as the continuous time variable as 
presented below will be applied to CDR-SB. The model will be used to estimate the slowing of 
disease progression in the OLE Gant mITT population compared to all controls. Because the 
baseline values of the OLE Gant mITT population were obtained before the treatment, these 
values will be counted into all controls for estimating the disease progression over EYO.  
Briefly, the model can be described as: 
𝑌𝑖𝑗𝑘= (𝛽+ 𝜇𝑖) + 𝛾1𝑘∗𝑒
(𝐸𝑌𝑂𝑖𝑗+𝛿𝑖
𝛾2𝑘
)
+ 𝜀𝑖𝑗𝑘 
Where, 𝑦𝑖𝑗𝑘 denotes the assessment for subject 𝑖 at visit EYO 𝑗 in treatment arm 𝑘= 1, 2; 
treatment is a categorical variable with two categories: subjects the OLE Gant mITT population 
(only post OLE baseline data), and subjects in all controls (data in this category include: baseline 
data of the OLE Gant mITT population and data of all controls); 𝛽 is the mean of the healthy 
period (e.g. EYO <=-15) and is assumed to be the same for all arms; 𝛾1𝑘 is the mean decline 


 
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from the healthy period to symptom onset (e.g. EYO=0); 𝐼 is the indicator function with 
𝐼(𝑘= 2) = 1;  𝜇𝑖 and 𝛿𝑖 are the subject-level random effects and are assumed to follow a 
bivariate normal distribution; 𝜀𝑖𝑗𝑘 is the within- subject error and is assumed to follow a normal 
distribution 𝑁(0, 𝜎2); and 𝛾2𝑘 represents the scale parameter of the treatment and all control 
group.  
The null hypothesis is: γ21 = γ22;  
and the alternative is: 𝛾21 ≠𝛾22. 
The same analysis will also be applied to the OLE Gant mITT population and the OLE Gant All 
Gant exposure mITT populations, along with all controls. The analysis will also be conducted for 
each population based on the baseline asymptomatic and symptomatic subjects presented 
separately. 
 
The spaghetti plots of individual will be presented over time since baseline and over EYO for 
both the OLE Gant mITT population and all controls.  
 
Figures of model estimated mean over EYO by treatment arms or spaghetti plots of individual 
data over EYO by treatment arms will be presented as deemed necessary by Washington 
University team and may be included in CSR as needed. 
 
The same analysis will also be conducted for the six subgroups defined in the first paragraph in 
Section 16.2.4.1.1.  
16.2.4.1.5. 
Logistic Disease Progression Model  
The logistic disease progression model with EYO as the continuous time variable as presented 


 
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below will be applied to the CDR-SB. The model will be used to estimate the slowing of disease 
progression in the OLE Gant mITT population compared to all controls. Because the baseline 
values of the OLE Gant mITT population were obtained before the treatment, these values will 
be counted into all controls for estimating the disease progression over EYO.  
 
Briefly, the model can be described as: 
𝑌𝑖𝑗𝑘= (𝛽+ 𝜇𝑖) +
𝛾1
1 + 𝑒
(−
(𝐸𝑌𝑂𝑖𝑗+𝛿𝑖)−𝛾3𝑘
𝛾2𝑘
)
+ 𝜀𝑖𝑗𝑘, 
where, 𝑦𝑖𝑗𝑘 denotes the assessment for subject 𝑖 at visit 𝑗 in treatment arm 𝑘= 1, 2; treatment is 
a categorical variable with two categories: subjects the OLE Gant mITT population , and 
subjects in all controls; 𝛽 is the mean of the healthy period (e.g. EYO <=-15) and is assumed to 
be the same for all groups; 𝛾1 is the mean decline from the healthy stage to the disease stage (e.g. 
EYO>=0) and is assumed to be the same for all groups; 𝛾3𝑘 is the EYO point where the disease 
progressed to the middle point between the healthy stage and the disease stage; 𝛾2𝑘 is the scale 
parameter indicating the spread of the disease progression curve; 𝜀𝑖𝑗𝑘 is the within-subject error 
and is assumed to follow a normal distribution 𝑁(0, 𝜎2); 𝜇𝑖 and 𝛿𝑖 are the individual level 
random effects to account for the correlation among the repeated measures and use an 
unstructured covariance matrix. The main assumption of this model is that after accounting for 
the between subject difference though the random effects, the disease progression from EYO to 
EYO is the same for both cross-sectional data (from different subjects) and longitudinal data 
(repeated measurements of the same individual). 
 
The treatment effect will be estimated by comparing the EYO points where the disease 
progressed to the middle point between the healthy period (𝛽) and the disease period (𝛽+ 𝛾1). 
The null hypothesis is: 𝛾31 = 𝛾32;  


 
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and the alternative is: 𝛾31 ≠𝛾32. 
The model will be used to estimate the slowing of disease progression in the OLE Gant mITT 
population compared to all controls.  
If the model fails to converge, the random effect (𝛿𝑖) in EYO will be removed.  
 
The model will also be used to compare OLE Gant mITT population and the OLE Gant All Gant 
exposure mITT populations, along with all controls.  
 
Figures of model estimated mean over time by treatment arms or spaghetti plots of individual 
data over time/EYO by treatment arms will be presented as deemed necessary by Washington 
University team and may be included in CSR as needed. 
 
The same analysis will also be conducted for the six subgroups defined in the first paragraph in 
Section 16.2.4.1.1.  
 
16.2.4.1.6. 
Longitudinal Logistic Regression Model 
 
For subjects in the All Gant exposure mITT, at each post-baseline visit including all the OLE 
visits, the CDR-SB value will be compared to that of the previous visit (rather than compared to 
highest value of previous visits), if the value of the later visit is larger than the previous one, the 
disease progression status is defined as 1; otherwise, the disease progression status is defined as 
0. The same definition will be applied to all controls. Longitudinal logistic regression model will 
be applied to compare the odds of disease progression in CDR-SB between the All Gant 
exposure mITT and all controls. The model will include treatment group, time since baseline 
(continuous), interaction between the treatment group and time, and baseline EYO as the fixed 


 
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effects, and a subject-level random intercept will also be included to account for the within-
subjects correlation among the disease progression status. 
 
Baseline CDR status will also be included in the model along with the three-way interaction 
between time, treatment group, and CDR status to determine if treatment before symptom onset 
is different from after symptom onset. 
16.2.4.2. 
Supplemental Analysis of the CDR Global 
The analysis models described in Section 16.2.3.1 (Cox proportional recurrent event hazard 
model) and in Section 16.2.4.1.5 (Logistic disease progression model) will also be applied to 
CDR Global for both asymptomatic and symptomatic subjects together.  Models described in 
Section 16.2.3.1 (Cox proportional recurrent event model) will also be applied separately for 
baseline asymptomatic and symptomatic subjects in each of the three mITT populations and all 
controls, with Kaplan-Meier figures presented for asymptomatic subjects.  
 
Each subject in the OLE Gant All Gant Exposure mITT population and all controls will be 
categorized into 3 groups as defined in the first paragraph in Section 16.2.4.1.1. The model 
described in Section 16.2.3.1 (Cox proportional recurrent event hazard model) and in Section 
16.2.3.2 (Cox proportional hazard model) will be applied to the OLE Gant All Gant Exposure 
mITT population and all controls to compare the hazard of progression in CDR Global among 
the 3 subgroups.  
 
Each subject in the All Gant Exposure mITT population and external controls will be categorized 
as described in the second  and third paragraphs in Section 16.2.4.1.1, with the analysis being 
applied to the primary parameter for CDR Global described in Section 16.2.3.2 (Cox 
proportional hazards model). 


 
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16.2.4.3. 
Supplemental Analysis of the OLE Cognitive Composite 
The supplemental analysis of the OLE Cognitive Composite will follow the logistic disease 
progression model in Section 16.2.4.1.5 and the exponential disease progression model as 
described in Section 16.2.4.1.4. 
16.2.4.4. 
Supplemental Analysis of the CSF Amyloid Beta1-42/40 
The supplemental analysis of the CSF Amyloid Beta1-42/40 will follow the logistic disease 
progression model in Section 16.2.4.1.5 for the OLE Gant mITT and All Gant exposure mITT 
populations. 
16.2.5. 
ANALYSIS OF REMAINING SECONDARY EFFICACY VARIABLES 
The analyses for secondary clinical and cognitive tests will follow the LME model for the annual 
rate of change as described in Section 16.2.3.3, with ISLT and MAC-Q compared to internal 
controls only. Additionally for ISLT and MAC-Q, the OLE Gant mITT population will be 
evaluated to compare the annual rate of change among 3 groups: gantenerumab in the double-
blind period, solanezumab in the double-blind period, and placebo in the double-blind period 
with the double-blind baseline as the baseline. The same analysis will be re-run with the double-
blind baseline as the baseline and the OLE baseline as the first post-baseline visit, and the time 
variable will be the time since the double-blind baseline. 
 
The analysis for remaining secondary fluid and imaging biomarkers will follow the analysis of 
the key biomarkers as described in Section 16.2.3.3 (the LME models). Fluid biomarker will also 
be assessed using the same MMRM models as described in Section 16.2.3.5. 
 
For all these analyses, figures of model estimated mean over time by treatment arms or spaghetti 
plots of individual data over time/EYO by treatment arms will be presented as deemed necessary 


 
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by Washington University team and may be included in CSR as needed. 
  
 
 
 
 
  
 
 
 
 
 
. 
 
 
. 
 
 
 
 
 
. 
 
. 
 
  
 
 
 


 
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16.4. EVALUATION OF THE ASSOCIATION BETWEEN AMYLOID 
REDUCTION AND CLINICAL/COGNITIVE CHANGES 
To evaluate if amyloid reduction is associated with clinical/cognitive benefits, the following 
analysis will be conducted. 
 
1. The correlation between the change in PiB-PET SUVR and the change in clinical/cognitive 


 
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endpoints of CDR SB and OLE Cognitive Composite will be evaluated using Spearman 
correlation. This correlation will be evaluated using the annual rate of change and the change 
from baseline to the end of OLE, respectively. The correlation will also be estimated for the 
subjects on double-blind gantenerumab treated group vs combined double-blind placebo and 
double-blind solanezumab treated group, or for subgroups defined below in item #2 (Amyloid 
normal group, Amyloid abnormal to normal group, and the rest). This analysis will be applied to 
the Gant OLE mITT and All Gant exposure mITT, respectively. Additionally, all controls will 
also be included to evaluate the correlation without any treatment.  
 
2. Each subject will be categorized into 3 groups as defined in the first paragraph in Section 
16.2.4.1.1. The LME model will be applied to the All Gant exposure mITT population and all 
controls to compare the annual rate of change among the 3 subgroups for key secondary efficacy 
variables. 
 
Baseline PiB PET SUVR and baseline EYO will be included as covariates in these analyses 
when evaluating the correlation of the annual rate of change.  
 
For all these analyses, figures of model estimated mean over time by treatment arms or spaghetti 
plots of individual data over time/EYO by treatment arms will be presented as deemed necessary 
by Washington University team and may be included in CSR as needed. 
17. SUBSET OF ANALYSES AT THE INTERIM 
The two objectives of the interim analysis are to determine if gantenerumab OLE treatment 
results in clinical benefit and determine the extent of amyloid removal compared to the double-
blind period.  The primary analyses for the interim will be the primary analysis of CDR Global 


 
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(in Section 16.2.3.2) and CDR-SB (in Section 16.2.3.1) applied to subjects who are 
asymptomatic at baseline for the All Gant Exposure mITT and main set controls. 
The following subset of analyses will be conducted separately for baseline asymptomatic and 
baseline symptomatic subjects, except where noted for select imaging and fluid biomarker 
analyses, at the interim analysis and additional exploratory analyses will be conducted as needed, 
noting that focus will be on Year 2 findings in the absence of Year 3 findings, with any 
imputation for Year 3 excluded. These analyses will be conducted for the each of the three mITT 
populations and controls as specified for each model, unless the associated section describes the 
analysis as being conducted on select mITT populations, noting that when multiple models are 
described within a section, only the first one will be conducted for the interim unless otherwise 
specified. By-visit descriptive statistics during OLE will be displayed, overall and by OLE 
baseline symptomatic status, for each associated parameter, including each component of the 
OLE cognitive composite. 
 
 


 
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Table B: 
Interim Analysis Models  
Endpoint 
Analysis Tier and Statistical 
Method 
Objective 
CDR Global 
Primary:  
16.2.3.2: Cox proportional 
hazards time to first progression 
To evaluate whether the treatment 
delays the disease progression 
Sensitivity:  16.2.4.2 (third 
paragraph):  post-baseline PiB-
PET SUVR normal 
To evaluate whether normal / 
abnormal amyloid levels are 
associated with lower risk of first 
progression (delay of disease 
progression) in CDR Global 
compared to all controls 
Sensitivity:  16.2.4.1.1 (third 
paragraph):  comparison to 
concurrent and non-concurrent 
controls 
To evaluate whether the treatment 
delays the disease progression in 
CDR Global compared to the 
concurrent and non-concurrent 
controls 
CDR-SB 
Primary: 16.2.3.1:  Cox recurrent 
event proportional hazards model 
To evaluate whether the treatment is 
associated with lower risk of recurrent 
progression (delay of disease 
progression) in CDR-SB compared to 
all controls 


 
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Endpoint 
Analysis Tier and Statistical 
Method 
Objective 
Secondary: 
16.2.3.3: LME model  
To evaluate whether the treatment 
will slow down annual rate of change 
of CDR-SB compared to all controls 
Sensitivity:  16.2.4.1.1 (both 
analyses in second paragraph):  
post-baseline PiB-PET SUVR 
normal 
To evaluate whether normal / 
abnormal amyloid levels are 
associated with lower risk of recurrent 
progression (delay of disease 
progression) in CDR-SB compared to 
all controls 
Sensitivity:  16.2.4.1.1 (third 
paragraph):  comparison to 
concurrent and non-concurrent 
controls 
To evaluate whether the treatment is 
associated with lower risk of recurrent 
progression (delay of disease 
progression) in CDR-SB compared to 
the concurrent and non-concurrent 
controls 
OLE Cognitive 
Composite 
Secondary: 
16.2.3.3: LME model 
To evaluate whether the treatment 
will slow down annual rate of change 
of OLE Cognitive Composite 
compared to all controls 


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Endpoint 
Analysis Tier and Statistical 
Method 
Objective 
FAS 
Secondary:  
16.2.3.3: LME model 
To evaluate whether the treatment 
will slow down annual rate of change 
of FAS compared to all controls 
MMSE 
Secondary:  
16.2.3.3: LME model 
To evaluate whether the treatment 
will slow down annual rate of change 
of MMSE compared to all controls 
Amyloid PET 
SUVR 
Secondary: 
16.1.3: MMRM (asymptomatic 
and symptomatic combined) 
To evaluate whether gantenerumab 
can stop or reverse amyloid plaque 
growth during the OLE period for all 
participants  
Secondary: 
16.1.4.1: MMRM (asymptomatic 
and symptomatic combined) 
To compare the gantenerumab 
treatment effect during OLE period 
by the double-blind treatment 
(gantenerumab, combination of 
solanezumab and placebo)  
Secondary: 
16.1.4.2: MMRM 
To evaluate whether gantenerumab 
can stop or reverse amyloid plaque 
growth during the OLE period for 
asymptomatic and symptomatic 
separately 


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Endpoint 
Analysis Tier and Statistical 
Method 
Objective 
Secondary: 
16.1.4.3: MMRM 
To evaluate the treatment effect of 
gantenerumab in reducing or 
reversing amyloid plaque growth 
during the whole study duration for 
all participants treated with 
gantenerumab in double-blind, overall 
and for asymptomatic and 
symptomatic separately 
Secondary: 
16.1.4.4:  Fisher’s exact test 
To evaluate whether treatment with 
gantenerumab is associated with a 
shift from baseline abnormal to post-
baseline normal 
MAC-Q 
Secondary: 
16.2.3.3: LME model 
To evaluate whether the treatment 
will slow down annual rate of change 
of MAC-Q compared to internal 
controls 
Tau PET SUVR 
Secondary: 
16.2.3.3: LME 
To evaluate whether gantenerumab 
can reverse the annual rate of amyloid 
plaque growth compared to internal 
controls 


 
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Endpoint 
Analysis Tier and Statistical 
Method 
Objective 
FDG-PET SUVR 
Secondary: 
16.2.3.3: LME 
To evaluate whether gantenerumab 
can reverse the annual rate of amyloid 
plaque growth compared to all 
controls 
CSF Amyloid 
Beta1-42/40 
Secondary: 
16.2.3.5: MMRM (asymptomatic 
and symptomatic combined) 
To evaluate whether the treatment 
will show an increase from baseline 
in CSF Amyloid Beta 42/40 
CSF Total Tau 
Secondary: 
16.2.3.5: MMRM (asymptomatic 
and symptomatic combined) 
To evaluate whether the treatment 
will show a decrease from baseline in 
CSF Total Tau 
CSF pTau217 
Secondary: 
16.2.3.5: MMRM (asymptomatic 
and symptomatic combined) 
To evaluate whether the treatment 
will show a decrease from baseline in 
CSF ptau217 
CSF MTBR243 
Secondary: 
16.2.3.3: LME model 
To evaluate whether the treatment 
will slow down annual rate of change 
of MTBR243 compared to all controls 
 


 
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Kaplan-Meier figures will be created for asymptomatic subjects for each of the three mITT 
populations and associated controls for both the CDR Global time to first progression and CDR-
SB time to recurrent progression.  Figures of model estimated mean over time by treatment arms 
with spaghetti plots of individual data over time of CDR-SB will be provided for asymptomatic 
subjects for each of the three mITT populations. 
 
The following biomarkers are considered the most relevant to the mechanism of action of 
gantenerumab: Tau PET SUVR, CSF pTau217 and CSF MTBR243.  Analyses using LME and 
MMRM of additional CSF biomarkers, additional clinical/cognitive parameters, and select 
plasma biomarkers which are not listed in Table B will be assessed as exploratory analyses by 
Washington University, with planned analyses to be described in the Addendum of the Statistical 
Analysis Plan written and signed prior to the availability of data to Washington University, and 
associated items will not be run by
 for the interim analysis. Analyses of 
CDR-SB described in Sections 16.2.4.1.4 (exponential disease progression model), 16.2.4.1.5 
(logistic disease progression model), and 16.2.4.1.6 (longitudinal logistic regression model) may 
also be assessed as exploratory analyses by Washington University and will not be run by 
 
for the interim analysis. Any exploratory analyses, including those planned as noted 
above, will be included in any reports written to summarize the interim analysis only when 
considered relevant and will be identified as exploratory analyses.


 
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Version Date:  
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Effective Date: 02Dec2019 
 
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proprietary to 
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18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the SAF.  
 
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified with the relevant section.  
18.1. ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA SOC and PT. The version will be 
established and documented prior to lock of the data and will be identified within footnotes.  
 
An AE is defined as any untoward medical occurrence in a clinical trial subject, regardless of 
whether it is considered to be drug related. AEs will be recorded and assessed as to whether they 
are TEAEs. TEAEs are defined as events that first occur or worsen (increase in severity) after the 
first dose of the OLE study drug. The onset date/time of an AE will be compared to the date/time 
of first dose of the OLE study drug to determine if the AE is treatment emergent or not. If the AE 
onset date is missing or partial, the date will be compared as far as possible with the date of first 
dose of the OLE study drug. AEs will be assumed to be treatment-emergent unless there is clear 
evidence (through comparison of partial dates and/or collected assessment of whether the AE 
started prior to the first dose of the study drug) suggesting the AE started prior to the first dose of 
OLE study medication. 
 
An overall summary of TEAEs will be presented with the number and percentage of subjects 
having a TEAE, number of TEAEs by severity, number of subjects with a TEAE by highest 
severity, a TEAE related to study treatment, an injection site reaction TEAE, a serious TEAE, a 


 
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TEAE leading to treatment discontinuation, a TEAE leading to study discontinuation, and an AE 
with an outcome of death. An overall summary of TEAEs will also be presented by dose level.  
 
Subjects experiencing more than one TEAE by SOC and PT will only be counted once at the 
preferred terminology level in AE frequency tables, but each unique TEAE will be included in 
the total number of TEAEs (where provided) for each SOC and PT. The overall summary for 
SOC and PT will be presented overall. A separate table summary will also be reported by dose 
level. 
 
In summaries presented by SOC and PT, SOC will be sorted by alphabetical order within SOC, 
then PT.  
 
A listing will include TEAEs and Non-TEAEs. Events ongoing from the double-blind period and 
events reported in the open label period will be listed separately 
18.1.1. 
ALL TEAES 
18.1.1.1. 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first 
dose of OLE study medication with a missing severity will be classified as severe.  
18.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “Definite”, “Probable/Likely”, 
“Possible”, “Unlikely”, “Definitely Not” (decreasing severity of relationship). A “related” TEAE 
is defined as a TEAE with a relationship to study medication as “Definite”, “Probable/Likely” or 


 
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“Possible” to study medication. TEAEs with a missing relationship to study medication will be 
regarded as related to study medication. If a subject reports the same AE more than once within 
that SOC/ PT, the AE with the worst case relationship to study medication will be used in the 
corresponding relationship summaries.  
18.1.2. 
TEAES LEADING TO TREATMENT TERMINATION 
TEAEs that lead to treatment termination will be presented by a listing. TEAEs leading to 
treatment termination are those which are recorded as “Drug Withdrawal” for action taken with 
study treatment on the OLE AE page of the eCRF. The subject’s ID number, the TEAE that 
caused treatment termination, and date of withdrawal will be included in the listing. 
18.1.3. 
TEAES LEADING TO STUDY DISCONTINUATION 
TEAEs that lead to study discontinuation will be presented by a listing and are determined using 
the question “Did the AE cause the subject to discontinue from the study?” on the OLE AE page 
of the eCRF. The subject’s ID number, the TEAE that caused the study discontinuation, and date 
of discontinuation will be included in the listing. 
18.1.4. 
SERIOUS ADVERSE EVENTS 
An SAE is any AE which meets any of the following criteria: 
● 
Death of subject 
● 
Life-threatening 
● 
Inpatient hospitalization or prolongation of existing hospitalization 
● 
Persistent or significant disability/incapacity 
● 
Important medical event requiring medical or surgical intervention to prevent 


 
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serious outcome 
● 
Congenital anomaly/birth defect 
● 
Suspected Hy’s Law Case 
● 
Other (otherwise medically significant) 
The SAE will be presented by a listing. The subject’s ID number, SOC, PT and verbatim term 
and SAE onset/stop date will be included in the listing. Treatment Emergent SAEs will be 
summarized by SOC and PT.  
18.1.5. 
INJECTION SITE REACTIONS (ISRS) 
Injection site reactions related to study treatment will be recorded as injection site reactions on 
the AE CRF page, with signs and symptoms (e.g., swelling, redness) collected separately. The 
signs and symptoms associated with ISRs will be coded in the same manner as other AEs and 
will be summarized separately from other events, with summaries by SOC and PT consistent 
with the overall summary of AEs. 
18.1.6. 
OTHER CAUSES OF ADVERSE EVENTS 
The other causes of AEs include: 
● 
AE involving the injection/infusion site 
● 
AE occurring due to administration of PIB 
● 
AE occurring due to administration of FDG 
● 
AE occurring due to administration of [18 F] AV-1451 Tau PET 
The relationship of an AE to these causal factors will be presented in the same manner as 
described for relationship to study drug. The other causes of AEs will be summarized by cause 
and by relationship.  


 
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18.2. DEATHS 
A listing of all deaths will be provided. 
18.3. SAFETY MRI EVALUATIONS 
The number and percentage of subjects with MRI scan (including annual, safety, and dose 
titration MRIs) conducted will be summarized by visit for each type of MRI finding during the 
OLE. Summaries will also display the number of subjects with a new finding and those with any 
post-baseline finding for each type of MRI finding. 
 
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. MRI 
scans will be analyzed for ARIA changes at the Mayo Clinic Aging and Dementia Imaging 
Laboratory. The number of microhemorrhages (ARIA-H, including both hemorrhages and 
hemosiderin deposits) and size of areas of edema (ARIA-E) will be monitored at entry and 
throughout the trial. 
 
Frequencies and percentages of ARIA-E will be summarized by dose (all doses), by visit, and for 
the highest post-baseline value. Frequency and percentage of ARIA-H will be summarized by 
dose separately for ARIA-H Microhemorrhages and ARIA-H Superficial Siderosis, with 
summarizes separated for those associated with ARIA-E and those which are not. The number of 
ARIA-H and ARIA-E will be categorized (1, 2 to 4, 5+, or no presence). The size of ARIA-E, 
where present, will be summarized using mean (SD) by visit. A summary of time to ARIA-E 
resolution will be presented. ARIA-E resolution corresponds to the first MRI following a new 
post-baseline ARIA-E finding where no definite findings are observed and is calculated as the 
date of the MRI with no findings – the date of the MRI with AREA-E +1 day. If a subject has 


 
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PROTOCOL DIAN-TU-001 
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more than one ARIA-E that resolves, the largest duration per subject will be used for the 
summary of time to ARIA-E resolution. A listing of all ARIA-E findings will be produced for all 
subjects who have an incidence of ARIA-E at any assessment. The listing will include the 
number of definite findings for ARIA-E, the size of ARIA-E, the number of days since treatment 
start, the current active drug dose, and the number of days since start of the current active drug 
dose. In addition, the frequencies and percentages of the following findings will be summarized 
in separate tables by visit and for the highest post-baseline value: 
● 
Large cortical infarctions 
● 
Small cortical infarctions 
● 
Subcortical infarctions 
● 
Acute ischemia infarctions 
● 
Other findings (frequencies and percentages only, including for individual sub-
categories) 
MRI findings will be listed. Details for other findings will be listed separately for all subject with 
other MRI findings at any assessment. The listing will include number of definite other findings, 
a description of the other findings, number of days since treatment start, current active dose and 
the number of days since start of the current active dose. 
18.4. LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for hematology, 
chemistry and urinalysis. Presentation of results for drug-specific laboratory parameters including 
gantenerumab levels and anti-gantenerumab antibodies are described in Section 18.7.2. A list of 
expected laboratory assessment visits can be found in the protocol Appendix 3, Section 3.2. Table 
C identifies the laboratory parameters and order of parameters to be included in table summaries.  


 
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PROTOCOL DIAN-TU-001 
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Table C: 
Laboratory Parameters 
Chemistry 
Hematology 
Urinalysis 
ALT (SGPT) 
Basophils 
Bilirubin 
AST (SGOT) 
Basophils % 
Blood 
Albumin-QT 
Eosinophils 
Clarity 
Alkaline Phosphatase-QT 
Eosinophils % 
Color 
Calcium (EDTA) 
Hematocrit 
Glucose 
Cholesterol (High 
Performance) 
Hemoglobin 
Ketones 
Creat Cir, Cockroft & Gault 
Lymphocytes 
Leukocyte Esterase 
Creatinine Kinase 
Lymphocytes (%) 
Nitrate 
Creatinine (Rate Blanked) 
MCH 
Protein 
Direct Bilirubin 
MCHC 
Specific Gravity 
GGT 
MCV 
Urobilinogen 
LDH 
Monocytes 
pH 
Magnesium 
Monocytes (%) 
 
Phosphorus 
Neutrophils 
 
Serum Chloride 
Neutrophils (%) 
 


 
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Chemistry 
Hematology 
Urinalysis 
Serum Glucose 
Platelets 
 
Serum Potassium 
RBC 
 
Serum Sodium 
WBC 
 
Serum Uric Acid 
 
 
Total Bilirubin 
 
 
Total Protein 
 
 
Triglycerides 
 
 
Urea Nitrogen 
 
 
 
Presentations will use SI Units. Clinical laboratory parameters will be summarized descriptively 
at each measurement time. Mean and mean change from baseline values will be presented at 
each study visit for continuous parameters. Change from baseline will be calculated as post-
baseline assessment - baseline assessment. If either the baseline or post-baseline value is 
missing, the observation will not be included in the change from baseline summary. If a 
laboratory parameter has a value “< x”, where x is a numerical number, then the value “x/2” will 
be assigned to the parameter. If a laboratory parameter has a value “> x”, then the value “1.1x”. 
will be assigned to the parameter. 
 


 
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The following summaries will be provided for laboratory data: 
● 
Observed values and change from baseline by visit for Chemistry, Hematology and 
Urinalysis (quantitative measurements) 
● 
Observed values for categorical Urinalysis measurements 
● 
Shifts from OLE baseline to annual post-baseline visit for Chemistry, Hematology 
and Urinalysis 
● 
Shifts from OLE baseline to markedly abnormal value for Chemistry and 
Hematology 
● 
Listing of subjects with markedly abnormal results for Chemistry, Hematology and 
Urinalysis 
● 
Listing of all observed values for Chemistry, Hematology and Urinalysis 
18.4.1. LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA 
For each visit, laboratory results will be classified as low (L), normal (N), and high (H) 
according to the laboratory-supplied normal range. The shift from baseline will be presented for 
each annual post-baseline visit. 
 
A laboratory value is considered Critically High or Critically Low if it exceeds a pre-defined 
threshold as set by the laboratory vendor. All values for a parameter will be listed for a subject 
when at least one value for that parameter is identified as Critically High or Critically Low by 
the laboratory vendor. 
18.5. ECG EVALUATIONS 
ECG evaluations are not scheduled after the OLE Baseline measurement. Therefore, no table 
summaries of ECG findings will be produced for the OLE. Any data collected during the OLE 


 
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will be included in a listing of ECG findings sorted by subject, visit and parameter. Potential 
parameters to be included in the listing if collected include: 
● 
PR Interval (msec) 
● 
QRS Interval (msec) 
● 
QTcF Interval (msec) [derived] 
● 
QTcB Interval (msec) [derived] 
● 
HR (bpm) 
● 
Overall assessment of ECG (Investigator’s judgment): 
o Normal 
o Abnormal, Not Clinically Significant (ANCS) 
o Abnormal, Clinically Significant (ACS) 
18.6. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
● 
Systolic Blood Pressure (mmHg) 
● 
Diastolic Blood Pressure (mmHg) 
● 
Heart Rate (bpm) 
● 
Respiratory Rate (breaths/min) 
● 
Temperature (⁰C) 
● 
Weight (kg) 
● 
Height (cm) 


 
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The following summaries will be provided for vital signs data: 
● 
Observed values and change from baseline by visit (blood pressure, heart rate, 
respiratory rate and temperature) 
● 
Incidence of post-baseline markedly abnormal values (blood pressure, heart rate, 
respiratory rate and temperature) 
● 
Observed values and change from baseline by visit for Weight 
● 
Observed values for Height 
● 
A listing of all vital sign data will be presented for the OLE.  
18.6.1. 
VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance with 
the following predefined markedly abnormal criteria in Table D. 
Table D:   
Post-Baseline Markedly Abnormal Vital Sign Criteria 
Variable 
Unit 
Low 
High 
Systolic 
Blood 
Pressure 
mmHg 
≤ 90 mmHg AND  
decrease from baseline 
≤ 20 mmHg 
≥ 180 mmHg AND 
increase from baseline 
≥ 20 mmHg 
Diastolic 
Blood 
Pressure 
mmHg 
≤ 50 mmHg AND 
decrease from ≤ 15 mmHg 
≥ 105 mmHg AND 
increase from baseline 
≥ 15 mmHg 


 
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Variable 
Unit 
Low 
High 
Heart rate 
bpm 
≤ 50 bpm AND 
decrease from baseline ≤ 15 
bpm 
≥ 120 bpm AND 
increase from baseline 
≥ 15 bpm 
Body 
temperature 
˚C 
NA 
≥ 38.3 ˚C AND 
increase from baseline ≥ 0.8 ˚C 
18.7. OTHER SAFETY ASSESSMENTS 
18.7.1. 
COLUMBIA SUICIDE SEVERITY RATING SCALE (C-SSRS) 
C-SSRS score observed at any post-baseline assessment will be summarized using descriptive 
statistics for categories of Suicidal Ideation, Suicidal Behavior, as well as for the individual 
questions associated with each category. Treatment-emergence of suicidal ideation and suicidal 
behavior during OLE will also be summarized. Responses for each of the 12 corresponding 
questions will also be listed.  
18.7.2. 
ANTI-DRUG ANTIBODIES TO GANTENERUMAB 
Frequencies and percent of Anti-Drug Antibodies (ADA) to Gantenerumab will be summarized 
for evaluable subjects at baseline prior to first gantenerumab exposure (in either double-blind or 
open-label period) by positive/negative status and post baseline by the following categories:  
● 
Treatment-emergent ADAs 
o Treatment-induced ADAs- defined as a subject with a negative or missing 
baseline ADA result and at least one positive post-baseline ADA result. 


 
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o Treatment-enhanced ADAs- defined as a subject with a positive ADA result at 
baseline who has one or more post-baseline titer results that are >2.5-fold greater 
than the baseline titer result. 
● 
No treatment-emergent ADAs 
o Negative ADAs 
o Treatment Unaffected ADAs- defined as a subject with a positive ADA result at 
baseline and where all post-baseline titer results are less than or equal to the 
baseline result. 
All ADA results will be listed by subject, visit, specimen type and parameter. For subjects with a 
treatment emergent positive ADA, all adverse events will be listed with along with results from 
the most recent ADA and the most recent positive ADA.  
19. DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 
● 
Comments 
● 
Physical Examination 
● 
Pregnancy Report 
● 
Volumetric MRI, fluid biomarkers, PET scan data, clinical efficacy parameters, and 
cognitive efficacy parameters which are not included in Section 16.  
These domains and/or variables will not be summarized or presented, but will be available in the 
clinical study database, SDTM and/or ADaM datasets. 


 
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20. REFERENCES  
Diggle PJ, H. P.-Y. (2002). Analysis of Longitudinal Data, 2nd ed. New York: Oxford University 
Press. 
Doody, R. (2014). Phase 3 trials of solanezumab for mind-to-moderate Alzheimer's disease. New 
England Journal of Medicine, 370, 311-321. 
Prentice RL, W. B. (1981). On the regression analysis of multivariate failure time data. Biometrika, 
68, 373-379. 
 
 


 
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PROTOCOL DIAN-TU-001 
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
1. ABBREVIATIONS 
RTF  Rich text file format 
2. INTRODUCTION 
This document applies to standards used for outputting tables, listings and figures. It is intended 
to provide specifications to guide the statistician or statistical programmer in setting up 
specifications for programming tables, listings and figures. These standards should be used in the 
absence of customer specific standards. 
3. OUTPUT FILE NAMING CONVENTIONS 
File names should only consist of uppercase letters, digits (0 to 9) and underscores. A period 
should only be used to indicate a separator between the file name and the extension. No spaces, 
other special characters or punctuation marks are permitted. 
 
As far as possible, output files should be in RTF format, although .DOC files are also permitted. 
 
The program, program log and output file name should reflect the type and number of the 
statistical output. If this is not possible, then the output name should be at least as descriptive as 
possible. A prefix can be used to distinguish between a Table, Listing and Figure document (‘T’ 
for table, ‘L’ for listing and ‘F’ for figure). If there is only 1 digit in the number of the table, 
listing or figure in the place where 2 digits are possible, a leading zero should be added in the file 
name to make sorting consistent with the sequence (e.g., T14_3_01_1.RTF). 


 
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4. PAPER SIZE, ORIENTATION AND MARGINS 
The size of paper will be Letter. 
The page orientation will be landscape. 
Margins should provide at least 1 inch (2.54 centimeters) of white space all around the page, 
regardless of the paper size. 
The number of columns per page (linesize) should be 134 for Letter. 
The number of rows per page (pagesize) should be 51 for Letter. 
5. FONTS 
The font type ‘Courier New’ should be used as a default for tables and listings, with a font size 
of 8. The font color should be black. No bolding, underlining, italics or subscripting should be 
permitted. Super-scripts should be avoided. Single spacing should be used for all text. 
6. HEADER INFORMATION 
Headers should be defined as follows: 
● 
On the left side of the header, the following will represent the top three lines: 
o Washington University 
o Protocol DIAN-TU-001 
o Gantenerumab OLE, [delivery name as either Dry Run or Final] 
● 
On the right side of the header, the following will represent the top two lines, with 
the third line being blank: 
o Confidential 
o Page X of Y (where Y is the total number of pages for the output) 


 
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● 
The header values as shown above should be placed at the top of the page (same 
place on each page) 
● 
A blank line should appear between the header and the output title. 
● 
The output identification number and title should appear, centered, in the next set of 
rows. 
● 
The output population should appear, centered, below title row(s). The population 
should be spelled out in full. 
● 
The following row should be a continuous row of underscores (‘_’) (the number of 
underscores should equal the linesize). 
● 
Mixed case should be used for titles. 
● 
The output titles should be designed so that they are arranged consistently through 
all outputs. For example, content (e.g., Vital Signs) followed by metric (e.g., 
Change from Baseline) e.g., Vital Signs – Change from Baseline. 
● 
Titles should not contain quotation marks or footnote references. 
● 
The column headings should be underlined with a row of underscores (‘_’) 
● 
Column headings spanning more than one column should be underlined and have 
underscores on either side of the title and should be centered. 
● 
Column headings containing numbers should be centered. 
● 
In general, the population count should appear in the column header in the form 
“(N=XXX)”. 
● 
“Statistic” should be the column header over n, Mean, SE, n (%) etc. 
● 
As a rule, all columns should have column headings. 


 
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7. TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
● 
The first row in the body of the table or listing should be blank. 
● 
The left-hand column should start in column 1. No indenting or centering of the 
output should occur. 
● 
Rounding should be done with the SAS function ROUND. 
● 
Numbers in tables should be rounded, not truncated. 
● 
Alphanumeric output should be left aligned. 
● 
Numbers should be decimal point aligned. 
● 
Whole numbers should be right aligned. 
● 
Text values should be left aligned. 
● 
The first letter of a text entry should be capitalized. 
● 
Listings of adverse events, concomitant medications, injection site reactions etc. 
should be sorted in chronological order, with earliest event or medication coming 
first. 
● 
The treatment column order should be Placebo, Solanezumab, Gantenerumab, Total, 
with all columns other than Total having a value of Double-Blind Treatment Arm 
that is a merged field over the treatment group names. 
● 
If possible, include 100% frequencies in the table shell, so that it is clear what the 
denominator is for percentage calculations. 
● 
All listing outputs should be sorted (preferably by Subject Number) and will not 
reference double-blind treatment. 
● 
Do not use superscripts and subscripts. 
● 
Exponentiation will be expressed using a double asterisk, i.e., mm3 will be written 
as mm**3. 


 
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● 
The width of the entire output should match the linesize. 
Univariate Statistics: 
● 
Statistics should be presented in the same order across tables (i.e., n, Mean, SD, 
Median, Minimum, Maximum). 
● 
Table statistics should line up under the N part of the (N=XXX) in the table header. 
All decimal points should line up. If the minimum and maximum are output on one 
line as Minimum, Maximum then the comma should line up with the decimal point. 
● 
If the original data has N decimal places, then the summary statistics should have 
the following decimal places: 
Minimum and maximum: N 
Mean and median: N + 1 
SD or SE: N + 2 
Frequencies and percentages (n and %): 
● 
Percent values should be reported inside parentheses, with one space between the 
count and the left parenthesis of the percentage. Parentheses should be justified to 
accept a maximum of 100 as a value and padded with blank space if the percent is 
less than 100. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
 
 
● 
Percentages will be reported to no decimal places, except percents <100% but 
>99.5% will be presented as ‘>99%’ (e.g., 99.6% is presented as >99%); and 
percents < 0.5% will be presented as ‘<1%’ (e.g., 0.4% is presented as <1%). 


 
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Rounding will be applied after the <1% and >99% rule, noting that due to the small 
number of subjects this rule is only expected to be applicable for summaries of total 
number of administered doses by dose level. 
e.g., ( <1%) 
( 6.8%) 
(>99%) 
 
● 
Where counts are zero, no percentage will be displayed. 
Spacing: 
● 
There must be a minimum of 1 blank space between columns (preferably 2). 
Denominators: 
● 
If a different count other than the population count is used for a denominator (within 
the table) to calculate percentages, there should be a row in the table that identifies 
that number “n”. 
● 
Alternatively, a footnote should be included in each table with percentages to 
indicate the denominator for percentages. 
Missing values 
● 
A “0” should be used to indicate a zero frequency. 
● 
A blank will be used to indicate missing data in a subject listing. 
8. FOOTNOTE INFORMATION 
Footers should be defined as follows: 
● 
A continuous line of underscores (‘_’) will follow the body of the table or listing 
prior to any footnotes at the bottom of the page. 
● 
Table footnotes should be defined using compute statements in the proc report and 


 
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should appear directly after the body of the table. 
● 
The program path (starting with sponsor) and name should appear as footnote 1 at 
the bottom of the page and be left aligned, while the date/time stamp should appear 
right aligned on the same line. 
● 
Footnotes should be left-aligned. 
● 
Footnotes should be in sentence case. 
● 
Only “typewriter” symbols are permitted – e.g., “*”, “$”, “#”, “@”, “&” and “+”. 
● 
The choice of footnote symbols should be consistent. E.g., if you have the footnote 
“# indicates last observation carried forward” for one table, the same symbol and 
footnote should indicate LOCF for all tables. 
● 
If text wraps across more than one line (for a note), the first letter for all lines of text 
after the first one will be indented to align beneath the first letter of the text in the 
first line. 
Ordering of footnotes should be as follows: 
 
1.) Symbols 
2.) Abbreviations and definitions 
3.) Formulae 
4.) Specific notes 
● 
Common notes from table to table should appear in the same order. 
● 
The symbols should appear in the same order as what they are defined in the table or 
listing, from left to right. 
9. PROGRAMMING INSTRUCTION 
Programming instructions must appear in blue font at the end of each table or listing shell. 


 
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Programming instructions, where necessary, should follow the table or listing shells in blue font, 
beginning with the words “Programming Note” followed by a colon. These include notes on the 
output, reminders of how to handle missing values, repeat shells for similar tables etc. 
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US. 
PRESENTATION OF TREATMENT GROUPS 
For tables, treatment groups will be represented as follows and in the given order, noting that 
“Double-Blind Treatment Arm” will be displayed above the individual treatment columns: 
● 
Placebo  
● 
Solanezumab 
● 
Gantenerumab 
● 
Total 
PRESENTATION OF VISITS 
For outputs, OLE visits will be represented as follows and in that order (Note: refer to protocol 
for full list of OLE visits), noting that listings will display visits (including unscheduled visit) in 
date order: 


 
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Long Name (default) 
Short Name  
Baseline (OLE Visit 1) 
BL (V1) 
Week 4 (OLE Visit 2) 
W4 (V2) 
Week 8 (OLE Visit 3) 
W8 (V3) 
… 
… 
Week 48/52 (OLE Visit 14) 
*Note: due to a protocol amendment, 
assessments for year 1 occurring at either 
week 48 or week 52 will be displayed with 
the format above 
W52 (V14) 
… 
… 
Week 156 (Visit 40) 
W156 (V40) 
Early Termination 
ET 
Safety MRI 1 (120 mg) 
OSM1 
… 
… 
Safety MRI 11 (stable dose 5 MRI)  
OSM11 
 
Summaries and/or models including external and/or double-blind data may display timepoints 
based on the anticipated duration from treatment start or observational period start, such as 
Month 6 or Year 1, rather than using visit identifiers.  
 


 
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Missing dates will not be imputed. Note that conventions below will not be applied to items 
which are on CRF pages to capture ongoing events/medications from the double-blind period, as 
all such records will be considered as starting prior to OLE. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known/Partial
/ Missing 
If start date < OLE study med start date, then not 
TEAE 
If start date > study med start date, then TEAE 
 
If start date = study med start date with AE start 
time present and < med start time, then not TEAE 
If start date = study med start date with AE start 
time present and >= med start time, then TEAE 
 
If start date = study med start date with AE start 
time missing and AE noted as starting prior to 
OLE treatment, then not TEAE 
If start date = study med start date with AE start 
time missing and AE noted as not starting prior to 
OLE treatment, then TEAE 
 
 
 


 
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START DATE 
STOP DATE 
ACTION 
Partial, but known 
components show that it 
cannot be on or after 
study med start date 
Known/Partial
/ Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study OLE med 
start date 
OR Missing 
Known 
If stop date < OLE study med start date, then not 
TEAE 
If stop date >= OLE study med start date, then 
TEAE 
 
Partial, could 
be on or after 
OLE study 
med start date 
OR Missing 
Assumed TEAE 
 
 
 


 
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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START 
DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < OLE study med start date, assign as prior  
If start date >= OLE study med start date, assign as 
concomitant  
 
 
 
Partial, could 
be on or after 
OLE study 
med start 
date OR 
Missing 
Known 
If stop date < OLE study med start date, assign as prior 
If stop date >= study med start date, assign as 
concomitant 
 
 
Partial, could be 
on or after OLE 
study med start 
date OR Missing 
Assign as concomitant  
 
 
 


 
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PROTOCOL DIAN-TU-001 
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APPENDIX 3. THE MEAN AGE AT ONSET FOR EACH MUTATION 
If a subject’s mutation type is listed below, the mean mutation AO is used to define the subject 
EYO.  If the mutation type is not listed, the estimated AO is set to the subjects’ parental AO. If, 
in addition, the parental AO is unavailable, the estimated AO is set to the subjects’ secondary 
degree relatives’ AO. 
Table E: 
The Mean Mutation Ago at Onset 
Gene 
Mutation 
Mean Mutation AO 
Standard Error (SE) 
# of Available AO 
APP 
Ala692Gly 
45.8 
1.8 
5 
APP 
Asp678As
n 
58.8 
0.7 
3 
APP 
Asp678His 
52.6 
1 
17 
APP 
Glu693Gly 
57 
1 
3 
APP 
Ile716Phe 
34.7 
1.8 
7 
APP 
Ile716Thr 
37 
0 
2 
APP 
Ile716Val 
56.3 
3.2 
7 
APP 
Leu723Arg 
46 
1.1 
4 
APP 
Leu723Pro 
42 
2 
2 
APP 
Lys724Asn 
53.5 
1.5 
2 
APP 
Thr714Ala 
53.6 
1.4 
19 
APP 
Thr714Ile 
36.5 
1.5 
4 
APP 
Val715Ala 
49.4 
1.7 
7 
APP 
Val715Met 
47.8 
3.7 
5 
APP 
Val717Gly 
50 
2.7 
5 
APP 
Val717Ile 
50.2 
0.7 
136 
APP 
Val717Leu 
45.8 
0.9 
41 
APP 
Val717Phe 
43.6 
1.2 
19 
PSEN1 Ala231Val 
56 
1.8 
7 
PSEN1 Ala246Glu 
50.1 
1.2 
15 
PSEN1 Ala260Gly 
53.5 
2.2 
13 
PSEN1 Ala260Val 
34 
1.2 
5 


 
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Gene 
Mutation 
Mean Mutation AO 
Standard Error (SE) 
# of Available AO 
PSEN1 Ala275Val 
46.5 
1 
8 
PSEN1 Ala285Val 
46.5 
0.5 
2 
PSEN1 Ala396Thr 
52.5 
8.8 
4 
PSEN1 Ala426Pro 
43.8 
1.1 
19 
PSEN1 Ala431Glu 
40.4 
0.4 
97 
PSEN1 Ala431Val 
44  
1 
PSEN1 Ala434Thr 
41  
1 
PSEN1 Ala79Val 
60.1 
1.3 
52 
PSEN1 Arg269Gly 
48.3 
0.7 
3 
PSEN1 Arg269His 
58.3 
1.8 
18 
PSEN1 Arg278Ile 
52.6 
1.3 
7 
PSEN1 Arg278Lys 
44.7 
2 
3 
PSEN1 Arg278Ser 
39  
1 
PSEN1 
Asn135As
p 
35.2 
0.4 
12 
PSEN1 Asn135Ser 
34.3 
0.8 
10 
PSEN1 Asn135Tyr 
36.2 
2.8 
4 
PSEN1 Cys410Tyr 
46.9 
1.1 
18 
PSEN1 Cys92Ser 
55.5 
3 
6 
PSEN1 Gln222His 
39.8 
1.7 
4 
PSEN1 Gln223Arg 
34.8 
1.5 
4 
PSEN1 Glu120Asp 
45.9 
1.4 
14 
PSEN1 Glu120Asp 
45.9 
1.4 
14 
PSEN1 Glu120Asp 
45.9 
1.4 
14 
PSEN1 Glu120Gly 
37 
1.3 
5 
PSEN1 Glu120Lys 
39  
3 
PSEN1 Glu123Lys 
59 
3 
2 
PSEN1 Glu184Asp 
42.3 
0.9 
18 
PSEN1 Glu184Gly 
49.2 
4.2 
6 
PSEN1 Glu273Lys 
47.5 
1.5 
2 
PSEN1 Glu280Ala 
38.6 
2.4 
6 
PSEN1 Glu280Gly 
44.1 
2.2 
13 
PSEN1 Glu280Lys 
56.4 
2.4 
5 


 
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Gene 
Mutation 
Mean Mutation AO 
Standard Error (SE) 
# of Available AO 
PSEN1 Gly206Ala 
54.6 
1.1 
75 
PSEN1 Gly206Asp 
37.3 
1.3 
8 
PSEN1 Gly206Ser 
37.3 
1.5 
3 
PSEN1 Gly206Val 
50.6  
5 
PSEN1 Gly209Arg 
52.1 
2 
7 
PSEN1 Gly209Glu 
49.3 
1.6 
10 
PSEN1 Gly209Val 
41.2 
0.9 
21 
PSEN1 Gly217Arg 
45 
0.6 
18 
PSEN1 Gly266Ser 
39.3 
1.9 
4 
PSEN1 Gly378Glu 
36.5 
1.7 
6 
PSEN1 Gly378Val 
42.4 
0.9 
5 
PSEN1 Gly384Ala 
34.8 
1.4 
5 
PSEN1 Gly394Val 
43.5 
0.6 
4 
PSEN1 His163Arg 
45.7 
0.5 
63 
PSEN1 His163Tyr 
54.2 
1.7 
18 
PSEN1 His214Asn 
51.5 
2.2 
4 
PSEN1 His214Asp 
55  
1 
PSEN1 His214Tyr 
54 
4 
2 
PSEN1 Ile143Met 
48.2 
2.2 
6 
PSEN1 Ile143Phe 
53.4 
1.2 
8 
PSEN1 Ile143Thr 
31.6 
1 
7 
PSEN1 Ile143Val 
51 
2.1 
3 
PSEN1 Ile168del 
44 
1 
2 
PSEN1 Ile202Phe 
52 
2 
5 
PSEN1 Ile213Leu 
43.4 
3.1 
5 
PSEN1 Ile213Phe 
33  
1 
PSEN1 Ile213Thr 
50 
0.6 
3 
PSEN1 Ile229Phe 
39 
2.9 
3 
PSEN1 Ile238Met 
57.7 
2.4 
9 
PSEN1 Ile249Leu 
55.4 
1 
7 
PSEN1 Ile416Thr 
49.7 
2.3 
12 
PSEN1 Ile439Ser 
55  
1 
PSEN1 Leu113Gln 
33  
1 


 
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Gene 
Mutation 
Mean Mutation AO 
Standard Error (SE) 
# of Available AO 
PSEN1 Leu113Pro 
42.2 
2.1 
5 
PSEN1 Leu153Val 
35.6 
0.5 
9 
PSEN1 Leu166Arg 
38 
6 
2 
PSEN1 Leu171Pro 
42.3 
0.2 
3 
PSEN1 Leu173Phe 
43.2 
2.3 
5 
PSEN1 Leu174Arg 
48.7 
1.6 
7 
PSEN1 Leu174Met 
57.6 
2 
16 
PSEN1 Leu219Pro 
50 
2.1 
9 
PSEN1 Leu226Arg 
48.1 
1 
7 
PSEN1 Leu235Pro 
32.3 
0.9 
6 
PSEN1 Leu235Val 
47.7 
1.2 
15 
PSEN1 Leu250Ser 
51.1 
3.5 
10 
PSEN1 Leu250Val 
50.5 
0.5 
2 
PSEN1 Leu262Phe 
53.3 
4.3 
10 
PSEN1 Leu271Val 
49.8 
1.8 
11 
PSEN1 Leu282Arg 
43.8 
3.4 
4 
PSEN1 Leu282Phe 
51 
2 
2 
PSEN1 Leu282Val 
46.5 
2.5 
4 
PSEN1 Leu286Pro 
39.5 
0.8 
8 
PSEN1 Leu286Val 
45.7 
0.9 
34 
PSEN1 Leu381Val 
43.5 
7.4 
4 
PSEN1 Leu392Pro 
36 
0 
3 
PSEN1 Leu392Val 
43.2 
1 
5 
PSEN1 Leu424Arg 
30.5 
0.5 
2 
PSEN1 Leu424His 
39 
0 
2 
PSEN1 Leu85Pro 
25.5 
2.5 
2 
PSEN1 Lys239Asn 
56.7 
3.1 
9 
PSEN1 Met139Ile 
35.8 
0.5 
12 
PSEN1 Met139Thr 
49.5  
2 
PSEN1 Met139Val 
39.9 
0.8 
24 
PSEN1 Met146Ile 
43.4 
1.1 
29 
PSEN1 Met146Leu 
39 
0.8 
29 
PSEN1 Met146Val 
40.1 
0.7 
7 


 
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Gene 
Mutation 
Mean Mutation AO 
Standard Error (SE) 
# of Available AO 
PSEN1 Met233Leu 
39.1 
1.4 
14 
PSEN1 Met233Thr 
33 
1.3 
7 
PSEN1 Met233Val 
26.3 
1 
7 
PSEN1 Met84Val 
54.7 
1.6 
13 
PSEN1 Phe105Leu 
51.2 
4 
5 
PSEN1 Phe105Ser 
50.1 
0.6 
5 
PSEN1 Phe175Leu 
54.7 
4.2 
10 
PSEN1 Phe176Val 
57 
3.5 
3 
PSEN1 Phe177Ser 
30.3 
0.3 
11 
PSEN1 Phe283Leu 
45.3 
1.5 
6 
PSEN1 Phe386Ile 
49.9 
2.2 
7 
PSEN1 Phe386Leu 
45 
2.5 
8 
PSEN1 Phe386Ser 
33.7 
0.3 
3 
PSEN1 Pro117Ala 
35.8 
2.4 
10 
PSEN1 Pro117Arg 
36.3 
0.6 
6 
PSEN1 Pro117Leu 
30.6 
1.2 
9 
PSEN1 Pro117Ser 
31 
1.2 
3 
PSEN1 Pro264Leu 
48.5 
0.9 
38 
PSEN1 Pro267Leu 
53.5 
1.7 
5 
PSEN1 Pro284Leu 
32  
1 
PSEN1 Pro436Gln 
27.5  
2 
PSEN1 Pro436Ser 
47 
3 
2 
PSEN1 Pro88Leu 
44  
2 
PSEN1 Ser169Leu 
31 
0.8 
10 
PSEN1 Ser169Pro 
33.3 
0.9 
4 
PSEN1 Ser170Phe 
29.5 
1.2 
13 
PSEN1 Ser178Pro 
41.2 
1.7 
5 
PSEN1 Ser212Tyr 
45.6 
2 
9 
PSEN1 Ser230Asn 
57.2 
0.7 
6 
PSEN1 Ser290Cys 
40.8 
0.7 
22 
PSEN1 Thr116Asn 
37.4 
0.7 
7 
PSEN1 Thr116Ile 
41.3 
1.8 
12 
PSEN1 Thr119Ile 
59.9 
3.3 
15 


 
Washington University in St. Louis 
PROTOCOL DIAN-TU-001 
(Gantenerumab OLE) 
 
Statistical Analysis Plan 
Page 100 of 101 
 
 
 
 
Author: 
 
Version Number: 
7 
 
Version Date:  
07Dec2023 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 
 All rights reserved. The contents of this document are confidential and 
proprietary to 
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Gene 
Mutation 
Mean Mutation AO 
Standard Error (SE) 
# of Available AO 
PSEN1 Thr147Ile 
25.8 
1.3 
2 
PSEN1 Thr245Pro 
42.6 
1 
5 
PSEN1 Thr291Pro 
33  
1 
PSEN1 Trp165Cys 
50 
2.9 
3 
PSEN1 Trp165Gly 
36 
1.2 
4 
PSEN1 Tyr115Cys 
45.1 
1.7 
17 
PSEN1 Tyr115His 
36.1 
1.8 
4 
PSEN1 Tyr154Asn 
37  
1 
PSEN1 Tyr256Ser 
27.5 
2.5 
2 
PSEN1 Tyr288His 
45.7 
1.7 
4 
PSEN1 Val261Ile 
41.8 
6.2 
2 
PSEN1 Val261Leu 
40.3 
0.3 
3 
PSEN1 Val261Phe 
34 
1.2 
3 
PSEN1 Val272Ala 
31.6 
1.5 
9 
PSEN1 Val89Leu 
44.8 
2.5 
5 
PSEN1 Val96Phe 
42.5 
1.9 
4 
PSEN2 Asn141Ile 
53.7 
0.6 
40 
PSEN2 Met239Ile 
50.2 
2.3 
12 
PSEN2 Met239Val 
63.1 
6.1 
8 
PSEN2 Thr122Pro 
46.8 
0.9 
5 
APP 
Ala713Thr 
65.4 
2.4 
17 
PSEN2 Arg71Trp 
53 
 
1 
 
* Note:  For mutations where the fourth character is a ‘0’, a corresponding mutation value that excludes 
that ‘0’ will be assigned the same Mean Mutation AO.