A Randomized, Double-blind, Placebo-controlled, Two-cohort, Parallel Group Study to Evaluate the Efficacy of CAD106 and CNP520 in Participants at Risk for the Onset of Clinical Symptoms of Alzheimer's Disease.
Phase: PHASE2
Conditions: Alzheimers Disease
Sponsor: Novartis Pharmaceuticals

  Clinical Development 
CAD106/CNP520 
Clinical Trial Protocol CAPI015A2201J / NCT02565511 
A randomized, double-blind, placebo-controlled, two-
cohort parallel group study to evaluate the efficacy of 
CAD106 and CNP520 in participants at risk for the onset of 
clinical symptoms of Alzheimer’s disease 
Document type: 
Amended Clinical Trial Protocol 
EUDRACT number 
2015‐002715‐15 
Version number 
v06 (Clean) 
Development phase II/III 
Release date: 
7-Jan-2020
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 02-Dec-2013 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 12 
Amendment 6 (xx-Dec-2019) ............................................................................................ 14 
Summary of previous amendments ................................................................................... 16 
Protocol summary ..................................................................................................................... 22 
1 
Introduction ....................................................................................................................... 31 
1.1 
Background ............................................................................................................ 31 
1.2 
Purpose .................................................................................................................. 34 
2 
Study objectives ................................................................................................................. 34 
2.1 
Primary objectives ................................................................................................. 34 
2.2 
Secondary objectives ............................................................................................. 34 
 
 35 
3 
Investigational plan ........................................................................................................... 36 
3.1 
Study design .......................................................................................................... 36 
3.1.1 
Pre-screening Epoch and Genetic Disclosure Follow-up ...................... 38 
3.1.2 
Screening Epoch and Treatment Epoch ................................................ 40 
3.2 
Rationale for study design ..................................................................................... 44 
3.3 
Rationale for dose, regimen, route of administration and duration of treatment ... 47 
3.4 
Rationale for choice of comparator ....................................................................... 50 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 51 
3.6 
Risks and benefits .................................................................................................. 51 
4 
Population .......................................................................................................................... 56 
4.1 
Pre-screening Epoch and Genetic Disclosure Follow-up ...................................... 56 
4.1.1 
Inclusion criteria .................................................................................... 56 
4.1.2 
Exclusion criteria .................................................................................. 57 
4.2 
Screening, Treatment and Follow-up Epochs ........................................................ 57 
4.2.1 
Inclusion criteria .................................................................................... 57 
4.2.2 
Exclusion criteria .................................................................................. 58 
5 
Treatment ........................................................................................................................... 60 
5.1 
Investigational treatment ....................................................................................... 60 
5.1.1 
Cohort I ................................................................................................. 60 
5.1.2 
Cohort II ................................................................................................ 61 

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6.3.1 
Information to be collected on screening failures ................................. 93 
6.3.2 
Demographics/other Baseline characteristics ....................................... 93 
6.3.3 
Assessment of unimpaired cognition at Screening: Diagnostic 
Verification Form .................................................................................. 93 
6.3.4 
Other screening considerations ............................................................. 94 
6.3.5 
Screening extension beyond 12 weeks .................................................. 94 
6.4 
Efficacy .................................................................................................................. 95 
6.4.1 
MCI due to AD or dementia due to AD (MCI/dementia) criteria 
assessment ............................................................................................. 96 
6.4.2 
API Preclinical Composite Cognitive (APCC) battery ......................... 97 
6.4.3 
Repeatable Battery for the Assessment of Neuropsychological 
Status (RBANS) .................................................................................... 98 
6.4.4 
Raven’s Progressive Matrices ............................................................... 99 
 
. 99 
6.4.6 
Mini Mental State Examination (MMSE) ............................................. 99 
6.4.7 
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) ........... 100 
6.4.8 
Everyday Cognition Scale (ECog) ...................................................... 100 
 
 101 
 
 101 
 
 101 
6.4.12 
Appropriateness of efficacy assessments ............................................ 101 
6.5 
Safety and tolerability .......................................................................................... 102 
6.5.1 
Physical (including skin) and neurological examination .................... 102 
6.5.2 
Vital signs............................................................................................ 103 
6.5.3 
Height and weight ............................................................................... 103 
6.5.4 
Laboratory evaluations ........................................................................ 103 
6.5.5 
Electrocardiogram (ECG) ................................................................... 105 
6.5.6 
Safety brain MRI scans ....................................................................... 105 
 
 106 
 
 107 
6.5.9 
Appropriateness of safety measurements ............................................ 109 
6.6 
Other assessments ................................................................................................ 110 
6.6.1 
Immune response (applicable to Cohort I only) .................................. 110 
 
 111 
6.6.3 
Biomarkers .......................................................................................... 112 
7 
Safety monitoring ............................................................................................................ 116 
7.1 
Adverse events ..................................................................................................... 116 

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7.2 
Serious adverse events ......................................................................................... 118 
7.2.1 
Definition of SAE ............................................................................... 118 
7.2.2 
SAE reporting...................................................................................... 119 
7.3 
Liver safety monitoring ....................................................................................... 120 
7.4 
Renal safety monitoring ....................................................................................... 121 
7.5 
Reporting of study treatment errors including misuse/abuse .............................. 122 
7.6 
Pregnancy reporting ............................................................................................. 122 
7.7 
Prospective suicidality assessment ...................................................................... 122 
 
 123 
 
 123 
7.10 
Meningoencephalitis monitoring ......................................................................... 124 
8 
Data review and database management ........................................................................... 124 
8.1 
Site monitoring .................................................................................................... 124 
8.2 
Data collection ..................................................................................................... 124 
8.3 
Database management and quality control .......................................................... 125 
8.4 
Data Monitoring Committee ................................................................................ 126 
8.5 
Progression Adjudication Committee .................................................................. 127 
8.6 
Disclosure Monitoring Advisory Group (DMAG) .............................................. 127 
9 
Data analysis .................................................................................................................... 128 
9.1 
Analysis sets ........................................................................................................ 128 
9.2 
Participant demographics and other baseline characteristics ............................... 129 
9.3 
Treatments ........................................................................................................... 129 
9.4 
Analysis of the primary variable(s) ..................................................................... 129 
9.4.1 
Variable(s) ........................................................................................... 130 
9.4.2 
Statistical model, hypothesis, and method of analysis ........................ 130 
9.4.3 
Handling of missing values/censoring/discontinuations ..................... 132 
9.4.4 
Supportive analyses ............................................................................. 134 
9.5 
Analysis of secondary variables .......................................................................... 136 
9.5.1 
Efficacy variables ................................................................................ 137 
9.5.2 
Safety variables ................................................................................... 138 
9.5.3 
AD-related biomarkers ........................................................................ 140 
9.5.4 
Genetic disclosure impact assessments ............................................... 142 
9.5.5 
Other secondary variables: Abeta-IgG response to CAD106 ............. 142 
9.6 
Interim analyses ................................................................................................... 142 
9.7 
Multiplicity adjustment ........................................................................................ 145 
9.8 
Sample size calculation........................................................................................ 149 

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9.9 
Power for analyses of key secondary variables and target engagement of 
CAD106 ............................................................................................................... 152 
9.9.1 
Considerations for CNS activity of CAD106...................................... 153 
9.9.2 
Considerations for CNS activity of CNP520 ...................................... 153 
10 Ethical considerations ...................................................................................................... 153 
10.1 
Regulatory and ethical compliance ...................................................................... 153 
10.2 
Informed consent procedures ............................................................................... 153 
10.3 
Responsibilities of the Investigator and IRB/IEC ............................................... 155 
10.4 
Publication of study protocol and results............................................................. 155 
11 Protocol adherence .......................................................................................................... 155 
12 References ....................................................................................................................... 157 
13 Appendix 1: Clinically notable criteria ........................................................................... 164 
13.1 
Appendix 1.1: Clinically notable SAEs that require discontinuation of 
treatment .............................................................................................................. 164 
13.2 
Appendix 1.2: Other clinically notable findings that require additional 
investigations and may require treatment discontinuation .................................. 167 
13.3 
Appendix 1.3: Clinically notable vital signs ....................................................... 169 
13.4 
Appendix 1.4: Clinically notable ECG and laboratory values ............................ 169 
13.5 
Appendix 1.5: Liver and renal events and laboratory trigger definitions and 
follow-up requirements ........................................................................................ 171 
14 Appendix 2: Recruitment sources ................................................................................... 174 
 175 
16 Appendix 4: Role of study partner and key personnel .................................................... 176 
 
List of tables 
 
 50 
Table 5-1 
Blinding status up to database lock ....................................................... 64 
Table 5-2 
Prohibited treatment .............................................................................. 71 
Table 5-3 
Restricted treatments ............................................................................. 72 
Table 6-1 
Pre-screening Epoch and Genetic Disclosure Follow-up assessment 
schedule ................................................................................................. 79 
Table 6-2 
Screening and Treatment Epoch assessment schedule (Screening – 
Week 52) ............................................................................................... 85 
Table 6-3 
Treatment Epoch assessment schedule (Week 65 - Week 260) ............ 86 
Table 6-4 
Treatment Epoch and Follow-up Epoch assessment schedule 
(Week 273 – End of Study) ................................................................... 87 
Table 6-5 
RBANS version by visit ........................................................................ 99 

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Table 7-1 
SAE and AE capture and documentation ............................................ 116 
Table 7-2 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 122 
Table 9-1 
Schedule of pre-planned Interim analyses .......................................... 142 
Table 9-2 
Local levels up to second level Part I .................................................. 148 
Table 9-3 
Local levels up to second level Part II ................................................ 148 
Table 13-1 
Local reactions requiring Serious adverse event reports ..................... 165 
Table 13-2 
Systemic reactions requiring serious adverse event reports ................ 165 
Table 13-3 
ARIA and actions required by Investigators ....................................... 167 
Table 13-4 
Clinically notable vital signs ............................................................... 169 
Table 13-5 
Abnormal ECG measurements leading to exclusion alerts ................. 169 
Table 13-6 
Abnormal laboratory values leading to participant exclusion ............. 169 
Table 13-7 
Liver event and laboratory trigger definitions .................................... 171 
Table 13-8 
Follow-up requirements for liver events and laboratory triggers ........ 171 
Table 13-9 
Specific renal alert criteria and actions ............................................... 173 
Table 14-1 
Referral source of participants ............................................................ 174 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 37 
Figure 3-2 
Pre-screening Epoch and Genetic Disclosure Follow-up flow chart .... 40 
 
 175 
 

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List of abbreviations 
Aβ  
Amyloid-beta 
AD  
Alzheimer’s Disease 
ADNI  
Alzheimer’s Disease Neuroimaging Initiative 
AE  
Adverse Event 
ALT  
Alanine Aminotransferase 
APCC 
API Preclinical Composite Cognitive (Battery) 
API  
Alzheimer's Prevention Initiative 
APOE  
Apolipoprotein E 
APOE4  
Apolipoprotein E ε4 allele 
APP  
Amyloid Precursor Protein 
ARIA  
Amyloid Related Imaging Abnormalities 
ARIA-E  
Amyloid Related Imaging Abnormality‑edema 
ARIA-H  
Amyloid Related Imaging Abnormality‑hemorrhages 
AST  
Aspartate Aminotransferase 
ATC  
Anatomic Therapeutic Chemical classification  
AUC  
Area Under the Curve 
BACE  
Beta-site-APP Cleaving Enzyme 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte (Federal Institute for Drugs and Medical 
Devices- Germany) 
BUN  
Blood Urea Nitrogen 
BSA  
Body Surface Area 
CAA  
Cerebral Amyloid Angiopathy 
CDR  
Clinical Dementia Rating 
CDR-SOB  
Clinical Dementia Rating Sum of Boxes 
CFR 
US Code of Federal Regulations 
ChEIs  
Cholinesterase-Inhibitors 
CIs  
Confidence Intervals 
CLIA  
Clinical Laboratory Improvements Amendments  
CMO 
Chief Medical Office 
CNAR  
Censoring not at random 
CNS  
Central Nervous System 
CPK  
Creatine Phospho Kinase 
CRF  
Case Report/Record Form (paper or electronic) 
CRO  
Contract Research Organization 
CRP 
C-Reactive Protein 
CSF  
Cerebrospinal Fluid  
(e)C-SSRS  
(electronic) Columbia Suicide Severity Rating Scale 
CYP3A4/2C 
Cytocchrome P450 3A4/2C 
DDI  
Drug-Drug-Interaction 
DMC  
Data Monitoring Committee 
DMAG  
Disclosure Monitoring Advisory Group 
DMI 
(RBANS) Delayed Memory Index 
DNA  
Deoxyribonucleic Acid 
DOA  
Direct Oral Anticoagulant 
DRM  
Dose Regimen Modification 
DTI  
Diffusion Tensor Imaging 

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DVF 
Diagnostic Verification Form 
ECG 
Electrocardiogram 
ECog  
Everyday Cognition Scale  
ECRF  
Electronic Clinical Report Form 
EDC  
Electronic Data Capture 
ELISA 
Enzyme Linked Immunosorbent Assay  
ELISPOT  
Enzyme-Linked ImmunoSpot  
EoS  
End of Study  
FAS  
Full Analysis Set 
FDA 
Food & Drug Administration 
FDG  
Fluorodeoxyglucose 
FLAIR 
Fluid-Attenuated Inversion Recovery 
GCP  
Good Clinical Practice 
GDS  
Geriatric Depression Scale 
GLP  
Good Laboratory Practice 
GRE  
Gradient Echo 
HA  
Health Authorities 
Hb  
Hemoglobin 
HbA1C  
Glycated Hemoglobin 
HBV/HCV  
Hepatitis B virus/Hepatitis C virus 
HIV  
Human Immunodeficiency Virus 
HMs  
Homozygotes for APOE4 
HTs  
Heterozygotes for APOE4 
non-HMs  
non-Homozygotes, i.e. Heterozygotes or non-carriers 
IA  
Interim Analysis 
i.m. 
Intramuscular 
IMI 
(RBANS) Immediate Memory Index 
i.v.  
Intravenous 
IB  
Investigator’s Brochure 
ICF  
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC  
Independent Ethics Committee 
IES  
Impact of Events Scale 
IgG  
Immunoglobulin G 
IGT-AD  
Impact of Genetic Testing for Alzheimer’s Disease 
IPW  
Inverse Probability Weighting  
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology  
LDH  
Lactate Dehydrogenase 
LDR  
Lower Dose Regimen 
LFT  
Liver Function Test 
LLOQ  
Lower Limit of Quantification 
LOAD  
Late Onset Alzheimer’s Disease 
LP 
Lumbar Puncture 
LSM  
Least Square Means 
MAP  
Master Analysis Plan (referring to DMC) 

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MAR  
Missing at Random 
MCI  
Mild Cognitive Impairment 
MedDRA  
Medical Dictionary for Regulatory Activities 
mEOS 
Modified End of Study 
MFAS  
Modified Full Analysis Set 
MHRA  
Medicines and Healthcare products Regulatory Agency 
MMRM 
Mixed Model Repeated Measure 
MMSE 
Mini Mental State Examination 
MNAR 
Missing not at random 
(v)(f)MRI  
(volumetric)(functional)Magnetic Resonance Imaging 
MTD  
Maximum Tolerated Dose 
mTEC 
Modified Treatment Epoch Completion 
NACC 
National Alzheimer’s Coordination Center 
NFL 
Neurofilaments Light-chain 
NIA  
National Institute of Aging 
NOAEL  
No Observed Adverse Effect Level 
NCR(AD)  
National Cell Repository (for Alzheimer Disease) 
NPI-Q 
Neuropsychiatric Inventory Questionnaire 
NR 
see SR/NR 
NYHA 
New York Heart Association 
q.d.  
Quoque die (once each day) 
OC/RDC  
Oracle Clinical/Remote Data Capture  
p.o.  
Oral (per os) 
PAC  
Progression Adjudication Committee  
PBMC 
Peripheral Blood Mononuclear Cells 
PD  
Pharmacodynamic 
PEI  
Paul Ehrlich Institute 
PET  
Positron Emission Tomography 
Pgp  
P-Glycoproteins 
PH  
Proportional Hazards 
PI 
Principal Investigator 
PK  
Pharmacokinetics 
PPW  
Premature Participant Withdrawal 
PRO  
Patient Reported Outcomes 
PS  
Propensity Score 
PT-INR 
Prothrombin Time-International Normalized Ratio 
QOL-AD 
Quality of Life in Alzheimer’s disease 
QTcF 
Fridericia QT Correction Formula 
RAS 
Randomized Analysis Set 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
rCMRgl 
regional Cerebral Metabolic Rate for glucose 
REVEAL 
Risk Evaluation & Education for Alzheimer's Disease  
RNA 
Ribonucleic Acid 
ROI 
Region of Interest  
(e)SAE 
(electronic) Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 

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SD 
Standard Deviation 
SMQ 
Standardized MedDRA Query  
SOC 
System Organ Class 
SR/NR 
Serological Responders/ Serological Non-Responders 
SSRI 
Selective Serotonin Re-uptake Inhibitor  
STAI-AD 
State Trait Anxiety Inventory for AD 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
SUVR 
Standardized Uptake Ratio  
TBL  
Total Bilirubin 
TE 
Target Engagement 
TEC 
Treatment Epoch Completion 
TI 
Therapeutic Index 
Tmax 
Time of maximum concentration 
TSH  
Thyroid Stimulating Hormone 
TTE  
Time-To-Event  
ULN  
Upper Limit of Normality 
USM 
Urgent Safety Measure 
UTE  
Unsatisfactory therapeutic effect  
VAS  
Visual Analogue Scale 
WBC  
White Blood Cells  
WHO  
World Health Organization 
γ-GT  
Gamma-Glutamyl Transferase 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Cohort  
A group of newly enrolled participants treated at a specific dose and regimen 
(i.e. treatment group) at the same time. 
Control drug 
Drug(s) used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug. 
Dose level 
The dose of drug given to the participants (total daily or weekly etc.). 
Enrollment 
Point/time of participants entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol). 
Genetic disclosure 
The participant will be referred to a genetic counselor or such equivalent 
according to the local regulations. The genetic counselor will access the 
individual genotype of the participant and verify the participant’s willingness to 
receive information about their individual genotype. Where appropriate, the 
counselor will proceed with counseling using standardized apolipoprotein E 
(APOE) risk information and talking points across all sites, and disclose the 
genotype. 
Investigational drug 
The drug whose properties are being tested in the study; this definition is 
consistent with US Code of Federal Regulations (CFR) 21 Section 312.3 and 
is synonymous with “investigational new drug” or “investigational medicinal 
product.” 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as 
well 
as 
their 
associated 
treatment 
controls.  
This includes any placebos, any active controls, as well as approved drugs 
used outside of their indication/approved dosage or tested in a fixed 
combination.  
Investigational treatment generally does not include protocol-specified 
concomitant background therapies when these are standard treatments in that 
indication. 
Ligand (also radio 
ligand) 
A radioactive biochemical substance (substance that is radiolabeled) used for 
Positron Emission Tomography (PET) imaging. Also referred to as tracer or 
radiotracer.   
Medication number 
A unique identifier on the label of each investigational drug package. 
Part  
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in patients/participants with 
established disease and in those with newly-diagnosed disease. 
Personal data 
Participant information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. These data include participant 
identifier information, study information and biological samples. 
Protocol 
A written account of all the procedures to be followed in a trial, which describes 
all the administrative, documentation, analytical and clinical processes used in 
the trial. 
Premature 
participant(s) 
withdrawal 
Point/time when a participant exits from the study prior to the planned 
completion of all investigational treatment administration and/or assessments. 
Pre-screening 
Assessments performed prior to disclosure of genotype to the participant.  

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Randomization 
number 
A unique identifier assigned to each randomized participant, corresponding to 
a specific treatment arm assignment. 
Investigational 
drug/ treatment/ 
Study medication 
Any single drug or combination of drugs administered to the participants as 
part of the required study procedures; includes investigational drug(s), active 
drug run-ins or background therapy. Also referred to as Study medication. 
Study/investigation
al treatment 
discontinuation 
Point/time when a participant permanently stops taking study/investigational 
treatment  for any reason; may or may not also be the point/time of premature 
participants withdrawal. 
Study medication 
See Investigational drug/treatment 
Tracer /Radiotracer 
See Ligand 
Participant Number  
A number assigned to each participant who enrolls into the study.  
Variable 
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study. 
Withdrawal of study 
consent (WoC) 
Withdrawal of consent from the study occurs only when the participant does 
not want to participate in the study any longer, and does not allow any further 
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Amendment 6 (7-Jan-2020) 
Amendment rationale 
This amendment documents, for completeness, the changes regarding follow-up of 
participants after early termination of CNP520 according to the Investigator Notifications 
distributed between July and December 2019. 
This amendment also serves the purpose to document the trial termination after Cohort I early 
termination (Investigator letter from 23-Sep-2019). 
The changes related to discontinuation of treatment with CNP520 in Cohort II were already 
formally communicated via an Urgent Safety Measure (USM) dated 11-Jul-2019 and two 
subsequent Follow-up notifications (dated 1-Aug-2019 and 12-Dec-2019) summarized below.  
The USM (11-Jul-2019) was triggered by an unexpected, mild, early worsening that was 
observed in some measures of cognition in the active treatment arms following the assessment 
of unblinded data of CNP520 by the independent Data Monitoring Committee (DMC), during 
a planned data review on 26-June-2019. This finding led the Sponsors to discontinue assessment 
of CNP520 in the two Phase 2/3 studies in the Generation Program in July 2019. Additionally, 
volumetric MRI (whole brain and hippocampal volume) indicated increased volume loss on 
active treatment and greater mean body weight loss was observed at 26 weeks on both doses vs 
control group 
In this communication, randomized participants were instructed to stop the study medication 
immediately (with confirmation of the last dose taken to be documented), and to return to the 
site to complete: 
1. Modified Treatment Epoch Completion (TEC) visit 399.  
• The following assessments were no longer required: MRI, PET and Lumbar Puncture 
for CSF samples. 
2. Modified End of Study visit 401 (mEOS): 
• Timing was changed from 3 month post Treatment Epoch Completion visit to 6 month 
post Treatment Epoch Completion visit: 
• Simplified assessments required at this visit included: AEs and SAEs, RBANS, CDR-
SOB, volumetric MRI (3DT1 sequence only), blood sample for biomarkers. 
The Follow-up #1 (1-Aug-2019) was issued as a clarification to the USM, to recommend that 
the full MRI scan and a lumbar puncture at mTEC visit be conducted as specified in protocol 
v05 in case of early study discontinuation. These assessments were expected to allow evaluation 
of potential markers associated with cognitive decline and/or imaging findings.    
This letter also specified an Interim Telephone Check-in Point, to occur approximately 3 months 
after the mTEC visit. More clarity was provided with a revised Table of Assessments for the 
two visits in scope (mTEC and mEoS). 

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The Follow-up #2 (12-Dec-2019) was issued after an unblinded analysis of the available data 
from post-treatment assessments demonstrated reversal of the worsening in key measures of 
cognition after CNP520 treatment discontinuation. The analysis assessed data from visits 
conducted within 1 to 8 weeks after wash-out of CNP520. Treatment-related imbalances were 
still observed for body weight and brain volumes as measured by volumetric MRI. These 
volume changes are interpreted as primarily related to effects of CNP520 on the existing 
amyloid pathology.  
Taking into account the new data on reversibility of cognitive decline after CNP520 
discontinuation, scheduling constraints and burden to participants, the Sponsors concluded that 
cognitive and volumetric MRI assessments were no longer required at the mEoS visits. 
Assessments for adverse events, concomitant medications, eCSSRS and measurement of body 
weight during the mEoS visits remained unchanged. 
Changes to the protocol for Cohort II only: 
This protocol amendment documents the final set of cumulative modifications after the Cohort 
II USM Follow-up #2 notification.  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
• Section 3.1.2.2: specified window for scheduling the mEoS within the 12 weeks following 
the last Treatment Epoch visit. 
• Section 3.5 and 5.4: Additional post-treatment interim analysis after treatment termination  
• Table 6-4: Assessment Schedule for visit 401 is modified accordingly. Two Cohort-
specific tables for the Follow visit 401 are created for clarity. 
• Section 6.2 and footnote 15 to Table 6-4: mEoS visit may be converted to phone call in 
case of logistical constraints. No eCSSRS or body weight to be collected in such case. 
• Section 8.4 and 8.5: Specified responsibility of DMC monitoring of safety and PAC 
adjudication of progression for data obtained for participants on treatment 
No changes will be applied to sections that were superseded by the early trial termination (eg. 
Section 5.5.14 Early Study Termination by the Sponsor, or Section 9 – Data Analysis: All 
changes to analyses related to the early termination of the study will be documented in the 
statistical analysis plan prior to unblinding the study). 
IRBs/IECs 
Only applicable for Cohort II 
This amended protocol will be sent to the Institutional Review Board (IRBs)/Independent 
Ethics Committee (IECs) and Health Authorities as an administrative update for completeness 
of documentation. 

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The changes described above as part of the Urgent Safety Measure (USM) dated 11-Jul-2019 
and Follow-up Notification to Investigators 1-Aug-2019 were required to enhance monitoring 
of participant safety (i.e. necessary to eliminate immediate hazards to the trial subjects ICH 
GCP 3.3.8). The changes described as part of the Follow-up #2 Notification to Investigators 
dated 12-Dec-2019 reduced the monitoring described under USM based on the new unblinded 
data analyses to lessen participants’ burden and should have been implemented prior to 
IRB/IEC approval upon receipt by Investigator of the corresponding Notifications. 
The changes herein described affect the Informed Consent. The Follow-up #2 USM notification 
dated 12-Dec-2019, included Appendix 3 - Information for Study Participants. This information 
was to be shared verbally with ongoing participants that came for their scheduled mEoS visit 
on site (or during the phone contact if applicable) prior to local EC/IRB approval of the revised 
ICF addendum with the appropriate note made in the source documentation.  
Note: No changes were implemented to Cohort I. The Early Termination was performed 
according to protocol. 
 
Summary of previous amendments  
To date, five global amendments and three local amendments to the original protocol have been 
released with their respective rationale described below: 
Amended Protocol v05 (Dec-2018) 
Amended Protocol v04.01DE (Apr-2018) 
Amended Protocol v04 (Nov-2017) 
Amended Protocol v03 (Jun-2017) 
Amended Protocol v02.01DE (Apr-2017) 
Amended Protocol v02.01UK (Mar-2017) 
Amended Protocol v02 (Sep-2016) 
Amended Protocol v01 (Oct-2015) 
 
Amendment 5 (18-Dec-2018) 
Amendment rationale 
This amendment primarily addresses proactive actions required to enhance the ongoing 
monitoring of CNP520. The changes to the protocol are required to reflect the Urgent Safety 
Measure (USM) action plan from 13-Nov-2018.  Other changes to the protocol include 
introduction of a lower dose regimen option, incorporation of changes required by local health 
authorities and clarifications of different administrative aspects of the protocol. 
The USM was triggered by the data disclosed about two other BACE inhibitors indicating an 
increase in neuropsychiatric events and a decline in cognition starting following the first 3 to 6 

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months of treatment. The protocol is therefore amended to include an additional cognitive 
assessment with RBANS, as well as the NPI-Q, at the 3-month visit, 
Results from studies of two other compounds with the same mechanism of action did not 
indicate a decline in cognitive performance or increase in neuropsychiatric events, making it 
difficult to know whether the negative effects reported for some of the other compounds are 
due to BACE inhibition per se or due to other properties of the drugs.  The available data from 
other sponsors indicate that the early effects on cognition were found with doses of BACE 
inhibitors leading to at least 60% reduction of Aβ in CSF. The 50 mg once daily dose of CNP520 
in this study achieves an 86% reduction of CSF Aβ.  
In light of the new data from some other BACE inhibitor compounds, potential lower dose 
regimen options targeting less than 60% reduction of CSF Aβ, are being proposed for the Cohort 
II treatment arm. Such dose regimen modifications could be activated upon DMC 
recommendation after review of CNP520 data and/or in light of new data on either CNP520 or 
other BACE inhibitors.  
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Changes to protocol based on Urgent Safety Measure (USM) dated 13-Nov-2018 
This amendment follows a Letter to Investigators issued on November 13, 2018 and includes 
the changes implemented according to USM plan as required for participant safety monitoring. 
(per ICH GCP 3.3.7; 4.5.4. and European Commission guidance (2010/C 82/01) 3.9) 
• Adding results from other BACE inhibitors (Section 1) 
• Adding RBANS and NPI-Q at the 3-month visit 
• Section 6.4.3:  RBANS Form D to be used for the 3-month visit. 
• Addition of Table 6-5: RBANS version by visit 
• Table 6-2: Update to Assessment Schedule for addition of RBANS and NPI-Q at 
month 3 
Changes to protocol re: Dose Regimen Modification (DRM) 
• Section 3.1: Description of potential Dose Regimen Modification (DRM) in Cohort II 
• Section 3.1.2.2: Addition of DRM for Cohort II if DMC deems current dose of CNP520 50 
mg once daily as unfavorable or decision from Sponsor to activate the DRM. 
• Section 3.3:  Rationale for potential Lower Dose Regimen (LDR) if DRM is activated  
• Table 3-1: New table comparing current CNP520 dose and LDR doses 
• Section 3.5:  Clarification of frequency of DMC meetings and potential for DRM 
• Section 3.6: Clarification on risks and benefits of CNP520 
• Section 5.3: Treatment arms 
• Section 8.4: DMC role in DRM 

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• Section 9:  
• Description of dose regimen and primary treatment arms for final primary analysis 
with or without DRM. 
• DRM added to regular DMC safety evaluation. 
• Discussion of potential impact of DRM on type-1 error rate added. 
• Discussion of potential impact of DRM on power and sample size added. 
Other changes to protocol  
Section 2.2; 2.3, 9.5: Addition of secondary analyses for blood Aβ40, Aβ42 and NFL; additional 
exploratory analyses for APOE genotyping (relationship between CNP520 concentrations 
(plasma and CSF), brain amyloid measurements and concordance between baseline CSF and 
PET results for elevated amyloid criteria 
Section 3.1.1/Figure 3-1: Reduction of Genetic Disclosure follow-up visits for non-HMs, as per 
DMAG recommendation (obtained offline on 14 Aug 2018), endorsed by DMC on 06 Nov 2018 
Section 3.1.2.1: Description on extension of 12-week time frame in screening epoch in case of 
logistical issue. 
Section 4.1 and 4.2: Additional clarification, examples for eligibility criteria (prescreening and 
screening, respectively); specification of numbering to include “a” for prescreening criteria and 
“b” for screening criteria (not in track changes) 
Section 5.1.2: Describing process and documentation to activate the DRM. 
Section 5.1.3, 6.6.3.1: Clarification of PET tracer usage 
Section 5.5.1: Clarification on participant numbering. 
Section 5.5.2: Clarification on dispensing the investigation treatment. 
Section 5.4; 5.5.9: Clarification for re-randomization for participants in case of cohort 
termination. 
Section 5.5.4:  Clarification of number of maximum doses of CAD106. 
Section 5.5.5: Clarification of dose adjustments/interruptions of study treatment (if dose 
changes is warranted by sponsor/DMC) 
Section 5.5.6: New section on Rescue Medication. 
Section 5.5.8, Table 5-2 and Table 5-3: Clarification and additional examples to restricted and 
prohibited treatments, also reformatting to categorize by cohort. 
Section 6.1, 6.3.2, and Table 7-1: Revision and clarification of reporting new condition during 
prescreening or screening as medical history or AE 
Section 6.1.12; 6.3.1: New section on Information to be collected on prescreening failures with 
updated information (removed from Section 6.3.1) 
Table 6-2: Additional of optional Week 7 check in visit (via telephone) 
Section 6.2, Table 6-2: Year 2 amyloid PET change from mandatory to voluntary 

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Section 6.3.3: New section on Diagnostic Verification Form for assessment of unimpaired 
cognition at Screening. 
Section 6.3.4: New section on Other screening considerations 
Section 6.3.5: New section on Screening extension beyond 12 weeks 
Section 6.4.2: Clarification on APCC repeat assessments 
Section 6.5.1: Update on requirements on Health Care Professionals who can perform physical 
and neurological exams.  
Section 6.5.4: Clarification on screening lab tests 
Section 6.5.5: Clarification on ECG  
Section 6.5.4.1: Addition of local measurement of CSF cell count in case of safety concern in 
participant. 
Section 6.6.1.3:  noted Completion of A-beta - and Q-beta-specific T-cell lymphocyte response 
Section 6.6.3.2:  Fluid biomarkers change from voluntary to mandatory 
Section 6.5.8.1. Table 6-2: Dermatologic photographs moved from baseline to screening. 
Section 7.2.1; 7.2.2:  Paper SAE reporting updated to electronic (eSAE).  
Section 7.7: Clarification of use of the short eC-SSRS self-assessment PRO version. 
Section 8.4, 9.6: Ad Hoc meetings for DMC increase frequency as needed.  
Section 9.5.3 and 9.6: Sub-group analysis for AD related biomarkers added in line with 
definition of Stage 1 classification in the Draft FDA guidance. 
Section 10.2: Introduce a re-consent process for participants who progressed to MCI (due to 
AD or other causes) and dementia due to AD after the diagnosis has been confirmed by the 
Progression Adjudication Committee. 
Section 12: Updated references 
Section 13.4: Added table for reference 
Amendment 4.01DE (Apr 2018) 
This amendment is specific to Germany and includes changes required by BfArM and PEI 
(dated 14 February 2018): 
• Clarification that Germany will not be participating in the tau PET substudy and will use 
the locally licensed amyloid ligand, florbetaben. 
These changes will be incorporated in the next global amended protocol version 05 together 
with these DE specific changes. 
Amendment 4 (Nov 2017) 
This amendment includes: 

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• Alignment with recent CNP520 IB update (Edition 4 released 25-Aug-2017) reflecting 
new data from:  
a. GLP embryo-fetal development studies: CNP520 is not genotoxic nor teratogenic, 
therefore, male contraception is no longer required   
b. A pooled concentration-effect analysis of Holter- and 12-lead-ECG QT data from 
Phase 1 and Phase 2a studies: results did not indicate any relevant QT prolongation by 
CNP520, therefore current cardiac monitoring is adequate.  
• Inclusion of tau PET assessments to assess neurofibrillary tangle burden as a secondary 
endpoint (voluntary, only at sites that can access tau tracer and have the required imaging 
capability)  
• A randomization halt to Cohort I is introduced to mitigate the risk that a large number of 
participants are exposed to CAD106 prior to the futility analysis on CNS activity. Recent 
data with immunotherapies indicate that a robust effect on CNS activity should be sought 
to maximize chances that a clinical benefit might emerge following longer treatment. Re-
commencement of randomization will be determined based on the evaluation of the 
futility analysis results by DMC.  
• New Section 7.5: Reporting of study treatment errors including misuse/abuse 
• Additionally, minor administrative changes and clarifying content changes are included, 
such as further details regarding study team roles, role of DMAG for follow-up of non-
HMs, alignment with Study CCNP520A2202J, etc. 
Amendment 3 (Jun 2017) 
This amendment includes: 
• The consolidation of the changes required by the UK Health Authority (MHRA) dated 24 
January 2017 and the German Health Authorities (BfArM and PEI) dated 17 February 
2017.   
• Allowance for PET tracer other than 18F-florbetapir (e.g. 18F-flutemetamol and 18F-
florbetaben) or substitution with Aβ measurement from cerebrospinal fluid (CSF) 
sampling if amyloid PET scan/tracer is unavailable.    
• Prioritization of cohort recruitment for Cohort II defined by 1:4 ratio for Cohort I:Cohort 
II until Cohort II is fully recruited in order to enable a concurrent read-out of Cohort II and 
the parallel study with CNP520 (CCNP520A2202J – Generation Study 2). 
• Additionally, feedback from investigators, other health authorities and ethics committees 
in other countries and updates for consistency with Study CCNP520A2202J are 
incorporated in this global amended protocol version 03. 
Amendment 2.01DE (Apr 2017) 
The current amendment to protocol version 02 addresses the changes required by BfArM and 
PEI dated 17 February 2017. No other changes are included.  
Feedback from investigators, other health authorities and ethics committees in other countries 
have been received in parallel, and will be incorporated in the next global amended protocol 
version 03 together with these Germany specific changes. 

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Amendment 2.01UK (Mar 2017) 
The amendment to protocol version 02 addresses the changes required by MHRA in their Non-
Acceptance letter dated 24Feb2017. No other changes are included. Regulatory Authorities in 
countries where this clinical trial is being performed will be informed of this amended 
v02.01UK as applicable per local requirements. 
These changes will be incorporated in the next global amended protocol version 03 together 
with these UK specific changes. 
Amendment 2 (Sep 2016) 
This amendment addressed the activation of Cohort II (CNP520 and matching placebo). The 
amendment also includes some clarifications of the protocol following feedback from 
investigators, health authorities and ethics committees on the previous version. 
Amendment 1 (Oct 2015) 
This amendment addressed the Special Protocol Assessment comments received from the US 
Food and Drug Administration (FDA) on 18-Sep-2015.  

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• 
To demonstrate the effects of CAD106 and CNP520, vs. respective 
placebo on cognition as measured by changes from Baseline to Month 60 
on the Total Scale score and individual neurocognitive domain index 
scores 
of 
the 
Repeatable 
Battery 
for 
the 
Assessment 
of 
Neuropsychological Status (RBANS). 
• 
To demonstrate the effects of CAD106 and CNP520, vs. respective 
placebo on function as measured by the change from Baseline to Month 60 
in the Everyday Cognition scale (ECog) total scores reported by the 
participant and study partner, respectively. 
• 
To demonstrate the effects of CAD106 and CNP520, vs. respective 
placebo on AD-related biomarkers (amyloid deposition and measures of 
neurodegeneration) as measured by change from Baseline to Months 24 
and 60 in the subset of participants who consent, on: 
o 
Binding of amyloid tracer and Tau tracer obtained using brain positron 
emission tomography (PET) imaging, 
o 
Volumetric MRI measurements, and  
o 
CSF/blood Aβ40, Aβ42, total tau and phospho-tau181 levels and NFL. 
Specific objectives for Cohort I (CAD106 or placebo)  
• To demonstrate the effects of antibody response to CAD106 vs. placebo on 
cognition as measured by the change from Month 6 to Month 60 in the 
APCC test score. 
• To describe amyloid-beta (Aβ)-specific antibody titers and serological 
responder rates over 60 months as measured by peak concentration and 
area under the concentration curve (AUC) of antibody titers and throughout 
the study.  
Specific objectives for Cohort II (CNP520 or placebo) 
• 
To demonstrate the effects of CNP520 vs. placebo on cerebral amyloid 
angiopathy (CAA) as measured by micro-hemorrhages and white matter 
hyper-intensities on MRI 
Study design 
This study protocol has multiple epochs with two informed consents required:  
• 
Pre-screening Epoch and Genetic Disclosure Follow-up (Informed consent 
#1) – also includes an optional genotyping only step (#1A); 
• 
Screening, Treatment and Follow-up Epochs (Informed consent #2). 
The Pre-screening Epoch includes assessments for evaluation of disclosure of 
APOE genotype to participants; the Genetic Disclosure Follow-up includes 
assessment telephone calls for all participants who received disclosure of their 
genotype. 
The Treatment Epoch follows a randomized, double-blind, placebo-controlled, 
two-cohort parallel group design in which participants receive one 
investigational treatment or its matching placebo. Participants will be treated 
for at least 60 months up to a maximum of 96 months, and no longer than when 
the target number of events for the TTE endpoint has been observed and 
confirmed in the respective cohort. Individual participant treatment duration will 
depend on the timing of randomization in the course of the study, i.e. initially 
recruited participants will be treated at least until the last participant in the 
corresponding cohort reaches approximately 60 months of treatment.  
Population 
The Treatment Epoch population will consist of male and female participants 
at risk for the onset of clinical symptoms of AD, based on their APOE4 HM 
genotype and age (60 to 75 years of age, inclusive, at the time of screening). 

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Approximately 1340 participants will be randomized in approximately 145 
centers worldwide across the two cohorts (target of N = 690 in Cohort I 
(recruitment halt after approximately 65 participants are randomized) and N= 
650 in Cohort II) with an allocation ratio of 1:4 for Cohort I to Cohort II until 
completion of recruitment in Cohort II.  
An unbalanced randomization (active: placebo) of 5:3 ratio in Cohort I (430 
CAD106:260 placebo) and 3:2 ratio in Cohort II (390 CNP520:260 placebo) will 
be applied. Randomization will be stratified by age group (60-64 years, 65-75 
years) and region (North America/Other, Europe). 
Inclusion criteria 
Pre-screening Epoch and Genetic Disclosure Follow-up inclusion criteria 
1a. Written informed consent (Informed consent #1) obtained before any 
assessment is performed, including consent to receive disclosure of their 
APOE genotype. 
2a. Male or female, age 60 to 75 years inclusive, at the time of signing Informed 
consent #1(same age restriction also applied at Informed consent #2).  
• 
Once the cap of approximately 20% of total participants in the age 
group 60-64 years (at the time of signature of ICF#2) is met, a 
restriction to this age group will apply. 
Note: the same age limitations of 60-75 years, inclusive is also applied at 
the time of signing Informed consent #2 
3a. Females must be considered post-menopausal and not of child bearing 
potential. Confirmation will be obtained for those who continue on to the 
Screening Epoch. 
4a. Mini-Mental State Examination (MMSE) total score ≥ 24 (can be based on 
documented result obtained in previous 3 months). 
5a. Psychological readiness to receive APOE genotype information based on 
pre-disclosure rating scales, specifically: 
a. Geriatric Depression Scale (GDS short form) total score ≤6.  
If the score is between 7 and 10 (inclusive), the participant can only be 
included based on investigator’s judgment assessing in particular the 
scores  of the questions: 
i. 
Item 3: “Do you feel your life is empty?” 
ii. 
Item 6: “Are you afraid that something bad is going to happen to 
you?” 
iii. 
Item 12: “Do you feel pretty worthless the way you are now?” 
iv. 
Item 14: “Do you feel your situation is hopeless?” 
b. Six Item Subset Inventory of the STAI-AD total score ≤17. 
If the score is 18 or 19, the participant can only be included based on 
the investigator’s judgment.  
6a. Participant is fluent in, and able to read the language in which study 
assessments are administered (e.g. completion of at least 6 years of regular 
schooling or sustained employment). 
7a. Participant’s willingness to have a study partner for the Screening and 
Treatment epoch. 
Screening and Treatment Epoch inclusion criteria 
Participants eligible for inclusion must fulfill all of the following criteria prior to 
randomization: 

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1b. Written informed consent (Informed consent #2) for participation to the 
Screening and Treatment Epochs (Participant must still be between 60-75 
years, inclusive, at the time of signing Informed consent #2; after reaching 
the maximum of 20% in the younger age group of 60-64 years, only those 
65-75 years will be eligible.) 
2b. Continue to meet all eligibility criteria from Pre-screening Epoch and 
Genetic Disclosure Follow-up, as confirmed by the review of the medical 
records by the Investigator, including continued psychological readiness 
for participating in the study as determined by clinical judgment.  
3b. Homozygous APOE4 genotype. 
4b. Cognitively unimpaired as defined by 
At the screening visit, score of 85 or greater on the RBANS delayed 
memory index score AND Clinical Dementia Rating (CDR) global score of 
0 with two exceptions: 
• 
If the RBANS delayed memory index score is between 70 and 84 
(inclusive) AND the global CDR score = 0, the participant may be allowed 
to continue ONLY if the Investigator judges that cognition is unimpaired 
following review of the MCI/dementia criteria. 
• 
If the global CDR score = 0.5 AND the RBANS delayed memory index 
score is 85 or greater, the participant may be allowed to continue ONLY if 
the Investigator judges that cognition is unimpaired following review of the 
MCI/dementia criteria. 
5b. Females must be considered post-menopausal and not of child bearing 
potential, i.e. they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, 
history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal 
ligation at least six weeks before the amyloid PET.  
6b. Study partner, who spends sufficient time with the participant, and agrees 
to participate in the study must have adequate functioning (e.g. intellectual, 
visual, and auditory) and be fluent in, and able to read, the language in 
which study assessments are administered.  
• 
Accompany the participant to all required twice yearly visits  
• 
Meet the definition of a “study partner” as described in Appendix 4 
Exclusion criteria 
Pre-screening Epoch and Genetic Disclosure Follow-up exclusion 
criteria 
1a. Any disability that may prevent the participant from completing all study 
requirements (e.g., blindness or deafness that is not appropriate for age, 
severe language difficulty, etc.).  

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2a. Current medical or neurological condition that might impact cognition or 
performance on cognitive assessments e.g., MCI, dementia, Huntington’s 
disease, Parkinson’s disease, Lyme disease, syphilis, schizophrenia, 
bipolar disorder, active major depression, attention-deficit / hyperactivity 
disorder (ADD / ADHD),  multiple sclerosis (MS), amyotrophic lateral 
sclerosis (ALS), active seizure disorder, history of traumatic brain injury 
with loss of consciousness and ongoing residual transient or permanent 
neurological 
signs/symptoms 
including 
cognitive 
deficits, 
and/or 
associated with skull fracture, alcohol/drug abuse or dependence currently, 
or dependence within the last two years.  
3a. Advanced, severe progressive or unstable disease that may interfere with 
the safety, tolerability and study assessments, or put the participant at 
special risk, e.g. active hepatitis or Human Immunodeficiency Virus (HIV) 
infection (based on a positive lab result for HBV/HCV and/or HIV, to be 
performed during screening if not available from the last 12 months), 
severe renal impairment, severe hepatic impairment, uncontrolled or 
significant cardiac disease including recent (within six months) myocardial 
infarction, congestive heart failure (New York Heart Association [NYHA] 
functional class III-IV), unstable angina, or long QT syndrome. 
4a. History of malignancy of any organ system, treated or untreated, within the 
past 60 months, regardless of whether there is evidence of local recurrence 
or metastases. However, localized nonmalignant tumors not requiring 
systemic chemo- or radio-therapy, localized basal or squamous cell 
carcinoma of the skin, in-situ cervical cancer, localized vulvar carcinoma 
and localized prostate carcinoma with no progression over the past two 
years are permitted. 
5a. History of hypersensitivity to any of the investigational drugs or their 
excipients/adjuvant, or to drugs of similar chemical classes. 
6a. Indication for or current treatment with Cholinesterase Inhibitors (ChEIs) 
and/or another AD treatment (e.g. memantine). 
7a. Contraindication or intolerance to MRI or PET investigations (with 
fluorinated radioligands). 
Screening and Treatment Epoch exclusion criteria 
Participants fulfilling any of the following criteria prior to randomization will be 
excluded.  
Participants who fulfill one or more exclusion criteria due to a temporary 
condition, or the use of treatment requiring a specific time window prior to 
randomization, can be re-screened at a later stage: 
1b. Brain MRI results from the central reading showing findings unrelated to 
AD that, in the opinion of the Investigator, might be a leading cause of 
future cognitive decline, might pose a risk to the participant, or might 
confound MRI assessment for safety monitoring (e.g. extensive white 
matter lesions (score of 3 on the Wahlund’s scale in 2 or more bilateral 
brain regions), recent stroke, recent cerebrovascular disease evidenced 
by more than one lacunar infarct ≤ 20 mm or any single infarct > 20 mm, 
evidence of cerebral contusion, encephalomalacia, aneurysms, vascular 
malformation, subdural hematoma or space-occupying lesions).  
For Cohort I (CAD106) only, in addition, evidence of Amyloid Related 
Imaging Abnormality‑hemorrhages (ARIA-H) as demonstrated by: 
• 
More than four cerebral microhemorrhages (defined as diameter ≤ 
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• 
Single area of superficial siderosis of the central nervous system 
(CNS) or evidence of a prior cerebral macrohemorrhage (> 10 mm 
diameter) 
2b. Score “yes” on item four or item five of the Suicidal Ideation Section of the 
eC-SSRS if this ideation occurred in the past six months, or “yes” on any 
item of the Suicidal Behavior Section, except for the “Non-Suicidal Self-
Injurious Behavior” (item is included in the Suicidal Behavior Section) if this 
behavior occurred in the past two years prior to screening. 
3b. A positive drug screen at Screening, if, in the Investigator’s opinion, this is 
due to drug abuse or dependence. Participants with a positive drug screen 
not believed to be related to drug abuse or dependence (e.g. presence of 
prescription drugs in urine without evidence of prescription drug abuse), 
can be re-screened once. 
4b. Significantly abnormal laboratory results at Screening as described in 
Appendix 1.4 or meeting the exclusionary alert values as specified in the 
Laboratory Manual. If, in the opinion of the Investigator, an abnormal 
finding is the result of a temporary condition, the laboratory test can be 
repeated once.  
5b. Clinically significant “active” infection which has not resolved within two 
weeks prior to initial dosing. In that particular case, delayed randomization 
may be considered. 
6b. Current significant ECG findings as reported by central reader that are 
assessed as clinically significant by the investigator  (e.g. sustained 
ventricular tachycardia, significant second or third degree atrioventricular 
block without a pacemaker, long QT syndrome or clinically meaningful 
prolonged QT interval). QTc interval > 500ms is exclusionary. 
7b. Use of other investigational drugs prior to screening until: 
• 
Blood concentration has returned to Baseline or below Serological 
responder threshold for antibodies induced by active immunotherapy; 
or 
• 
Within 30 days or 5 half-lives, whichever is the longest for monoclonal 
antibodies or small molecules e.g., Beta-site-APP Cleaving Enzyme -
1 (BACE-1) inhibitors. 
8b. Treatment  
• 
In the four weeks prior to randomization with any drug or treatment 
known for their potential to cause major organ system toxicity, i.e. 
drugs that may require periodic safety monitoring of a specific organ 
or body fluid (examples include, but are not limited to, clozapine, 
cancer 
medical 
treatments 
like 
tamoxifen, 
systemic 
immunosuppressive drugs like methotrexate and interferon, or other 
immunosuppressive biological medicines for rheumatic diseases or 
multiple sclerosis).  
• 
In the four weeks prior to randomization and/or current treatment with 
any CNS active drug(s) with exceptions  described in Table 5-3. 
• 
For Cohort I (CAD106) only: Treatment with warfarin or other 
coumarin derivatives, or with a combination of acetylsalicylic acid and 
an anti-platelet agent (e.g. clopidogrel) within seven days (or five half-
lives, whichever is longer) prior to randomization, or current indication 
for chronic treatment with a direct anti-coagulant  
• 
For Cohort II (CNP520) only: Current chronic treatment (>3 months) 
with (see Table 5-2)  

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• 
strong cytochrome P450 3A4 (CYP3A4) inducers or strong 
CYP3A4 inhibitors;  
• 
or drugs with a narrow therapeutic index known to be primarily 
metabolized by CYP2C or 3A isoenzymes, and sensitive Pgp 
substrates 
9b. Violations of concomitant medication restrictions as described in Table 5-
3. 
10b. 
Donation or loss of 400 mL or more of blood within 8 weeks prior to 
screening lab tests or lumbar puncture, if applicable. 
11b. 
Previous or planned Nuclear Medicine Radiology exposure that will 
exceed the acceptable dosimetry exposure in the country, when adding the 
scheduled study PET scans or allergy to low doses of fluorinated 
radioligands.  
12b. 
For Cohort II (CNP520) only: Participants with clinically relevant 
depigmenting or hypopigmenting conditions (e.g. albinism, vitiligo) or 
active / history of chronic urticaria in the past year. 
13b. 
For Cohort I (CAD106) only: Participants with previous organ 
transplantation or stem cell transplantation 
 
Exclusion criteria for participation in lumbar puncture: 
14b. 
Contraindication to lumbar puncture, e.g. low platelet count, abnormal 
prothrombin time international normalized ratio (PT-INR), history of lumbar-
spinal surgery (with the exception of microdiscectomy or laminectomy over 
one level), signs or symptoms of intracranial pressure, spinal deformities 
or other spinal conditions that in the judgment of the Investigator would 
preclude a lumbar puncture. 
No additional exclusions may be applied by the Investigator, in order to 
ensure that the study population will be representative of all eligible 
participants. 
Investigational and 
reference therapy 
Cohort I (CAD106 and placebo): 
Arm #1: CAD106 450 µg + Alum 450 µg given i.m.  
Arm #2: Placebo to CAD106 + Alum 450 µg given i.m.  
Participants will be given intramuscular (i.m.) injections at Weeks 1, 7, 13 and 
quarterly i.m. injections (every 13 weeks) thereafter, until the last injection 3 
months prior to completion of the Treatment Epoch. 
Cohort II (CNP520 and placebo): 
Arm #3: CNP520 50 mg capsule for once daily administration (p.o.) 
administration; or CNP520 LDR   
Arm #4:  Placebo to CNP520 50 mg capsule for one daily (p.o.) administration; 
or placebo to CNP520 LDR 
Participants will be dispensed medication supplies for 3-month treatment with 
CNP520  or matching placebo for  oral intake for the duration of the Treatment 
Epoch. 
Efficacy 
assessments 
• 
MCI due to AD or dementia due to AD (MCI/dementia) (diagnostic 
verification form)  

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1 
Introduction 
1.1 
Background 
Alzheimer’s disease (AD) is one of the most prevalent neurological disorders worldwide and 
the most common and debilitating age-related condition, causing progressive amnesia, 
dementia, and ultimately global cognitive failure and death. Currently, the only 
pharmacological therapies available are symptomatic drugs such as cholinesterase 
inhibitors (ChEIs) or other drugs used to control the secondary behavioral symptoms of AD.  
Investigational treatments targeting the AD pathogenic cascade include those intended to 
interfere with the production, accumulation, or toxic sequelae of amyloid-beta (Aβ) species 
(Kramp and Herrling, 2011). Strategies that target decreasing Aβ by: (1) enhancing the amyloid 
clearance with an active or passive immunotherapy against Aβ; (2) decreasing production 
through inhibition of Beta-site-APP cleaving enzyme-1 (BACE-1, an enzyme involved in the 
processing of the amyloid precursor protein [APP]), are of potential therapeutic value. 
Based on animal data and limited benefits in recent clinical trials targeting dementia stages of 
the disease, there is a growing belief that the Aβ-lowering therapies might be most effective in 
preventing or slowing the progression of AD in the preclinical stages. This approach allows 
participants to be treated before, or in the very earliest stages of, symptoms and disease onset, 
prior to plateau of fibrillary Aβ, extensive appearance of tau (neurofibrillary) pathology and 
irreversible synaptic or neuronal loss. 
In this context, and under the umbrella of the Alzheimer’s Prevention Initiative (API) (API: a 
public-private partnership) intended to help the field accelerate the evaluation of investigational 
prevention therapies (Reiman et al 2011), this study, CAPI015A2201J (also referred to as 
Generation Study 1), will provide an opportunity to evaluate the effects of two amyloid targeted 
therapies (CAD106 and CNP520) in cognitively normal people who, on the basis of their age 
and genetic background (apolipoprotein E ε4 allele homozygotes [APOE4 HMs]), are at the 
highest imminent risk of developing symptoms of AD. 
In this clinical trial, the identification of APOE4 HMs is employed as a prognostic enrichment 
strategy to select individuals with a greater likelihood of having substantial worsening in 
cognition, in a reasonable timeframe, that can be practically assessed within the setting of a 
clinical trial. APOE4 HMs are estimated to represent about 2 to 3% of the general population 
and are at much higher risk of developing symptoms of late–onset AD (LOAD) than people 
with other APOE genotypes, with a mean age of 68 years at onset (Corder et al 1993). 
Previously published estimates of lifetime risk of developing dementia due to AD by age 85 
were 51 to 68% and 23 to 35% for APOE4 HMs and heterozygotes (HTs), respectively (Genin 
et al 2011). Risk estimates communicated in the Risk Evaluation and Education for Alzheimer’s 
Disease (REVEAL) study, based on cross-sectional or case-control data, are 51 to 68% in 
APOE4 HMs and 22 to 52% in APOE4 HTs, (the risk of developing MCI due to AD was not 
separately estimated.). In preparation for this study, standardized risk information for the target 
population based on APOE4 genotype was compiled by independent researchers (Qian et al 
2017). Risk estimates for developing MCI or dementia due to AD by age 85 were determined 
for each APOE genotype using data from four prospective cohort studies. The resulting estimate 
for the Generation Study 1 participants (60 to 75 years old) of the corresponding risk by 85 is 

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30 to 55% for HMs (E4/E4). This risk estimates will be used during the genetic disclosure 
session (Qian et al 2017). 
It is proposed that APOE4 HM status enhances the risk for AD by affecting Aβ clearance, 
aggregation, and deposition (Liu et al 2013).  
Based on current knowledge, the results might be generalized and applicable to preclinical AD 
beyond APOE4 HMs, since amyloid-targeted therapies are expected to reduce and/or prevent 
amyloid plaque accumulation, independent of the multiple potential causes of amyloid 
deposition in late-onset AD. 
Trial outcomes and designs need to be established for pre-symptomatic stages of AD. 
Traditional measures of cognitive changes developed for studies in mild cognitive impairment 
(MCI) or dementia due to AD are of limited value due to the psychometric properties of the 
tests (e.g. ceiling effects). This study will employ two primary outcomes: time to diagnosis of 
MCI due to AD and/or dementia due to AD, and the API preclinical composite cognitive (APCC) 
test battery. The APCC battery was developed as a sensitive tool to detect and track cognitive 
decline in individuals at risk to progress to the clinical stages of LOAD (Langbaum et al 2014). 
Although data are available for AD biomarkers in longitudinal cohorts, understanding of the 
extent to which treatment biomarker effects could predict clinical benefit is limited. By 
assessing different biomarkers of AD pathology, this study aims to address this question. 
Lastly, the psychological and behavioral impact of disclosure of APOE genotype has been 
studied only in restricted settings (Green et al 2009, Roberts et al 2011). This study will improve 
our understanding of the impact of disclosing APOE4 HM genotype status and associated risk 
information to older adults, who are at more imminent risk of AD. Furthermore, by 
incorporating innovative models for delivery of genetic services for risk disclosure, the study 
will provide data on these delivery modalities for genetic education and counseling and will be 
essential in expanding the reach of and access to genetic counseling services, given the limited 
number of trained providers in this discipline (Patrick-Miller et al 2014). 
CAD106 
CAD106 is a second-generation active Aβ immunotherapy which comprises multiple copies of 
the Aβ1–6 peptide coupled to a carrier containing 180 copies of bacteriophage Qβ coat protein. 
CAD106 effectively induced Aβ antibodies in animal models, without activating an Aβ-specific 
T-cell response. Aβ antibodies were shown to reduce amyloid accumulation by enhancing 
amyloid clearance in multiple transgenic mouse models, with a stronger effect when 
administered in the early stages. Chronic toxicology studies in rabbits, transgenic mice, and 
Cynomolgus monkeys, using adjuvanted (aluminum hydroxide or MF59) and non-adjuvanted 
CAD106, supported progressing to trials in humans. 

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Clinical data generated so far includes a total of four double-blind, placebo-controlled clinical 
studies in Alzheimer patients and two open-label extension studies. Across all studies in 206 
predominantly mild AD patients, CAD106 showed a favorable safety and tolerability profile. 
CAD106 was not associated with meningoencephalitis, symptomatic amyloid-related imaging 
abnormalities (ARIA) or other magnetic resonance imaging (MRI) findings, or adverse immune 
reactions. Exploratory results of central nervous system (CNS) biomarker data, following 
continuous exposure over 18 months to CAD106-induced antibody titers, were largely 
consistent with the expected effects of an Aβ-immunotherapy.  
Further details on CAD106 are provided in the CAD106 Investigator’s Brochure (IB). 
CAD106 will be studied in Cohort I of the study API015A2201J, which will start when the first 
participant is randomized in the study.  
CNP520 
CNP520 is an orally active BACE-1 inhibitor with an approximately 3-fold selectivity for 
BACE-1 over BACE-2 and no relevant off-target binding or activity. 
In animals, CNP520 reduces Aβ concentrations in cerebrospinal fluid (CSF) and the brain by 
up to 90%, following single and chronic administration. CNP520 has been investigated in 
fertility and early embryonal development study in rats, safety pharmacology and repeat-dose 
toxicity studies of up to 26 weeks duration in rats and 39 weeks in dogs by oral gavage. The 
results of these studies have not raised major safety concerns for clinical use.  
CNP520 appeared generally safe and well-tolerated in four Phase I studies and one Phase IIa 
study with up to 3-month exposure duration conducted in healthy adults ≥60 years of age. 
Clinical data generated so far includes a total of 422 subjects who have been administered with 
CNP520 (n=335) or with matching placebo (n=87). Approximately two thirds (n=213) of the 
subjects were ≥60 years of age, thereby reflecting the age group of the proposed study 
population. A total of 100 subjects ≥60 years of age have received CNP520 for 3 months. 
Approximately 30% of participants were carriers of at least one APOEε4 allele.  
In healthy subjects ≥ 60 years of age, CNP520 reduced CSF Aβ concentrations in a dose-
dependent manner by up to approximately 80% at the maximum single dose tested (750 mg) 
and 95% after multiple dosing at the highest dose tested (300 mg q.d.). Aβ40 concentrations in 
CSF decreased by 91% compared to baseline after 3-month exposure at CNP520 85 mg q.d. 
CNP520 undergoes predominantly oxidative metabolism via CYP3A4/5. Following 3 months 
of multiple dose administration of up to 85 mg CNP520 once daily, the mean terminal 
elimination half-life was approximately 150 hours. CNP520 showed good brain penetration, 
indicated by cerebrospinal fluid (CSF) concentrations similar to the unbound plasma 
concentrations following both single and multiple dose administrations.  
Further details on CNP520 are provided in the CNP520 IB. 
In October 2018, results of completed clinical trials evaluating other BACE inhibitors were 
made public: 
• A Phase II study with elenbecestat showed a trend towards a positive effect on CDR-SB 
over placebo (p=0.55) in patients with MCI or mild to moderate AD (Lynch et al 2018). 

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• LY3202626 did not indicate a decline in cognitive performance over the duration of the 
trials (Lo et al, 2018).  
• Two other compounds (verubecestat and atabecestat) were found to be associated with a 
decline in performance on tests of memory and other aspects of thinking starting in the 
first three to six months of treatment, along with more neuropsychiatric symptoms. The 
declines in cognitive performance were reported as mild and generally not detected at the 
individual level. (Egan et al 2018; Romano et al 2018) 
Although CNP520 and the drugs being tested by other pharmaceutical companies all belong to 
the same class of drugs (BACE inhibitors), each drug has unique safety profile. Encouraging 
results obtained with a dose of LY3202626 that results in a 57% of CSF Aβ lowering indicates 
that benefit may still be expected at a medium level of BACE inhibition. (Lynch et al 2018).  It 
is unknown whether the negative effects observed are due to BACE inhibition per se or due to 
other properties of the drugs.  Thus it is unknown whether similar effects will be observed also 
for CNP520.  
1.2 
Purpose 
The purpose of this study is to determine the effects of each of the two therapies given separately, 
each targeting amyloid, on cognition, global clinical status, and underlying pathology in 
participants at risk for the onset of clinical symptoms of AD. Cognitively unimpaired 
individuals with APOE4 HM genotype and age 60 to 75 years, inclusive, are selected as they 
represent a population at particularly high risk of progression to MCI due to AD and/or 
dementia due to AD. 
2 
Study objectives 
2.1 
Primary objectives 
• To demonstrate the effects of CAD106 and CNP520 vs. respective placebo on Time-to-
event (TTE), with event defined as a diagnosis of MCI due to AD or dementia due to AD, 
whichever occurs first during the course of the study, 
• To demonstrate the effects of CAD106 and CNP520 vs. respective placebo on cognition 
as measured by the change from Baseline to Month 60 in the APCC test score. 
2.2 Secondary objectives 
Key secondary objective 
• To assess the effects of CAD106 and CNP520, vs. respective placebo on global clinical status 
as measured by the change from Baseline to Month 60 in Clinical Dementia Rating Scale 
Sum of Boxes (CDR-SOB) score.  

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3.1.1 
Pre-screening Epoch and Genetic Disclosure Follow-up 
Informed consent #1 includes consent to receive disclosure of APOE genotype, description of 
all Pre-screening activities leading to genetic disclosure, the basic trial design and risks of 
investigational drugs for potential study participation of HMs, as well as the Genetic Disclosure 
Follow-up assessment telephone calls for all participants who received disclosure of their 
genotype.  
The population participating in the Pre-screening Epoch and Genetic Disclosure Follow-up will 
consist of HMs and non-HMs in the age range of 60-75 years, inclusive, at the time of Screening 
(ICF#2). Age distribution will be controlled for HMs eligible to continue in Screening Epoch, 
with a maximum of about 20% of the participants are 60 - 64 years old, inclusive at Informed 
consent #2. Beyond this threshold, the population eligible will be limited to participants in the 
age range of 65-75 years. 
Potential study participants will be invited for Pre-screening through a variety of sources and 
methods.  Examples are presented in Appendix 2. Potential participants may be genotyped in 
an initial step with no commitment to be invited for the study. In such cases, the site will apply 
a ratio of HMs and non-HMs to avoid implicit disclosure by invitation.  
Upon signature of Informed consent #1 (Figure 3-2), participants will be screened using a 
limited set of eligibility criteria (see Section 4.1). The fulfillment of these criteria does not 
automatically signify eligibility to enter the Screening, Treatment and Follow-up Epochs. It is 
recommended that study personnel performing the Pre-screening assessments prior to genetic 
disclosure be blinded to the genotype of the participant, unless the participant joins with prior 
knowledge of her/his genotype. If this is not possible, site personnel must take additional 
precautions to avoid inadvertent disclosure of APOE4 genotype to the participant prior to the 
formal disclosure session with the genetic counselor.  
Following the completion of the Pre-screening assessments, a genetic counselor, or such 
equivalent according to local regulations (e.g. trained psychologist, study nurse or clinician), 
will speak with the study personnel who performed the Pre-screening assessments to share the 
assessment scores. For those referrals without prior genotype disclosure, the counselor will then 
assess the participant’s psychological readiness to receive her/his APOE genotype based on the 
participant’s Pre-screening assessment scores (including specific cut-offs described in Section 
4.1) and the counselor’s and investigator’s clinical judgment. It is recommended that the genetic 
counselor is blind to the participant’s APOE4 genotype prior to the counseling session (unless 
the genotype was already known to the participant), to ensure an unbiased counseling session. 
After psychological readiness is confirmed by the Investigator, the counselor will proceed with 
the genetic counseling session and confirm with the participant during the counseling session 
that she/he is ready and willing to receive his/her genotype. Once confirmed, the counseling 
session will continue with genetic disclosure using Standardized APOE Risk Information across 
all sites, which will have been reviewed by the ECs/IRBs.   

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If a participant fails eligibility, he/she will be considered as “prescreening failure” prior to 
genetic counseling/disclosure.  Genetic disclosure will the therefore not occur unless local 
regulations mandate the right to know genotyping results.   If the participant still requests to 
learn his/her genotype, communication of the result may be considered on a participant by 
participant basis if deemed appropriate by the Investigator, as long as psychological readiness 
has been verified.  Communication of the genotyping results in such cases will be organized by 
the Investigator in accordance with local regulations, including any follow-up requirements, 
outside of this clinical study.   
All participants who were informed of their genotype will be assessed, via telephone 
questionnaires, for the impact of genetic disclosure. For HMs, these assessments will occur 
approximately 2 to 7 days, 6 weeks, 6 and 12 months later (see Schedule of Assessments, Table 
6-1). For non-HMs, only the first (2 to 7 day) evaluation is required.  All participants who 
declined to receive information about their genotype or were deemed not ready psychologically 
to receive it, will be considered as Pre-Screen failures.  
At the 6-week genetic disclosure follow-up phone call, the site should follow up with any 
eligible HM that has not already signed ICF#2 to determine confirmation of the participant’s 
interest to continue to the next part of the study. The population eligible for the Treatment Epoch 
does not include participants who carry only one APOE4 allele (HTs); these participants may 
have the option to enroll in the Novartis Study CCNP520A2202J. If the participant consents to 
this sister study, personal data and other information from that other study may be transferred 
to the database of study CCNP520A2202J. 
An independent Disclosure Monitoring Advisory Group (DMAG) will monitor the genetic 
disclosure safety data. The DMAG is responsible for assisting the Data Monitoring Committee 
(DMC) in an advisory capacity. (Refer to Section 8.6)  

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Figure 3-2 
Pre-screening Epoch and Genetic Disclosure Follow-up flow chart 
 
*If a participant fails I/E, he/she will be registered as “prescreening failure” prior to genetic 
counseling/disclosure and therefore genetic disclosure will not occur.  If the participant still requests to 
learn his/her genotype, communication of the result may be considered on a participant by participant 
basis, as long as psychological readiness has been verified.  Communication of the genotyping results 
in such case will be organized by the investigator outside of this clinical study, unless local regulations 
mandate the right to know genotyping results.   
IC = Informed consent; HM = homozygote E4; non-HM = heterozygotes or non-carriers; I/E = Inclusion 
and Exclusion criteria 
3.1.2 
Screening Epoch and Treatment Epoch 
3.1.2.1 
Screening Epoch - for APOE4 homozygotes only 
The population participating in the Screening Epoch will consist of only APOE4 HMs. Age 
distribution will be controlled by ensuring that a maximum of about 20% of the participants 
randomized are <65 years, with the remaining 80% of the participants randomized in the 65 
years and older age bracket. Eligible HMs will be invited to sign the Informed consent #2 after 
the impact of the genetic disclosure is assessed, at least 2 to 7 days later. Additionally, the 
investigator/mental health care provider (as per local regulation), will apply clinical judgment 
and invite only those participants who continue to show psychological readiness for 
participating in the study. 

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Informed consent #2 will be signed at the start of the Screening Epoch and will describe the 
detailed assessments for the entire trial. The Screening Epoch assessments will be performed 
over a maximum of 12 weeks duration from the timing of ICF#2 signature (see Section 4.2 and 
Section 6.2). This 12-week time frame may be extended in case of logistical issues (e.g. some 
assessments may have been unexpectedly rescheduled) only if the certain conditions are met. 
Refer to Section 6.3.5. 
Participants who fail eligibility during the Screening process for a temporary condition (e.g. 
active infections, concomitant medications, etc.) should be screen failed, however will be 
allowed to be re-screened at a later stage, when all inclusion and exclusion criteria will have to 
be re-verified.  At the Baseline visit, eligible participants will be randomized to one of the four 
treatment arms across the two cohorts (see Section 5.3).  
3.1.2.2 
Treatment Epoch - for APOE4 homozygotes only 
The Treatment Epoch will consist of approximately 1340 participants to be randomized in 
approximately 145 centers worldwide across the two cohorts (target of N = 690 in Cohort I 
(recruitment halt after approximately 65 randomized, see Section 3.2) and N = 650 in Cohort II).  
Only participants who are confirmed to be HMs and satisfy all of the Screening and Treatment 
Epoch eligibility criteria will be randomized to the double-blind Treatment Epoch. Participants 
will be randomly allocated to either Cohort I or Cohort II in a 1:4 ratio to favor recruitment to 
Cohort II (see Section 3.2 and Section 5.3 for rationale) until Cohort II is fully recruited. Once 
approximately 65 participants are randomized in Cohort I, allocation will be shifted to Cohort 
II only until results of the futility analysis are obtained). Recruitment in Cohort I may resume 
based on the results of the CNS activity futility analysis. (See rationale below in Section 3.2, 
and details of the CNS activity futility analysis in Section 9.6).  
• If CAD106 meets the futility criteria no further participants will be randomized to Cohort 
I and the cohort will be closed. Previously treated participants in Cohort I will be 
discontinued from treatment and offered to be re-randomized in Cohort II (see Section 
5.5.9).   
If CAD106 does not meet the futility criteria and sufficient CNS activity is observed, 
randomization will re-commence until all planned participants to Cohort I are recruited (see 
Section 5.3).Within each cohort respectively, an unbalanced randomization (active: placebo) of 
5:3 ratio in Cohort I (430 CAD106: 260 placebo) and 3:2 ratio in Cohort II (390 CNP520: 260 
placebo) will be applied. Cohort I participants will receive intramuscular (i.m.) injections of 
CAD106 with Alum or placebo with Alum at the study site every 6 weeks for the first 3 
injections and then every three months (approximately 13 weeks).  
Cohort II participants will be dispensed medication supplies for 3-month treatment with 
CNP520 or matching placebo for oral intake. 

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From the Baseline visit on, participants will attend clinic visits every three months for 
dispensation of study medication and at 3 months and 6 months during the first year and then 
every six months to assess full safety and efficacy. In addition, Cohort I participants will also 
attend visits at Weeks 7, 9 and 15 specifically for antibody titer measurements. Following 
completion of the Treatment Epoch, participants will be asked to attend a Follow-up visit 3 
months later, i.e. 6 months after last injection in Cohort I or within 3 months of mTEC visit for 
Cohort II.  
Safety assessments, as detailed in Section 6.5, will include regular standard assessments (e.g. 
vital signs, electrocardiograms [ECGs], laboratory tests), as well as specific assessments related 
to potential CNS or other safety assessment requirements (e.g. skin assessment for CNP520), 
depending on the cohort. Brain MRI scans, for monitoring of cerebrovascular pathology and 
detection of ARIA, will be completed every 6 months during the first year, and on an annual 
basis subsequently in both cohorts. The scans will be read centrally at the Imaging Clinical 
Research Organization (CRO), with safety reports provided to the Investigators and Medical 
Monitor. Guidance to the Investigators in case of new findings is provided in Section 13.  
Efficacy assessments, as detailed in Section 6.4, will be conducted every six months until the 
end of the study. Although the study partner is expected to come to the site with the participant 
to all relevant visits, if that proves impossible, his/her input can be obtained by telephone 
interview. At each visit, the Investigator will assess the participant for the presence of MCI or 
dementia using pre-specified criteria described in Section 6.4.1. In the event of a positive 
finding, the Investigator will submit a narrative description for assessment by the Progression 
Adjudication Committee (PAC), which will review the data according to a predefined charter 
(see Section 8.5). 
An independent Data Monitoring Committee (DMC) will monitor the safety and efficacy data 
(see Section 8.4). Multiple interim analyses (IAs), supervised by the DMC (Section 3.5), are 
planned based on data collected for safety, immunogenicity for CAD106, CNS biomarkers and 
clinical endpoints, throughout the study. The main purpose of the planned IAs will be safety 
monitoring and futility, with the potential consequence of discontinuing the applicable cohort 
in scope for the IA. If, at the time of the primary endpoint IA, futility for the applicable 
investigational drug is not met, the sponsor will plan an open-label extension study with the 
respective treatment to be initiated after individual participants complete the double-blind phase 
of the study.  
See Table 6-2, Table 6-3 and Table 6-4 for Screening Epoch, Treatment Epoch and Follow-up 
Epoch assessments. 

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3.1.2.3 
Biomarkers 
All eligible participants will be required to complete MRI and brain amyloid assessment with 
an amyloid PET scan (alternatively, a lumbar puncture to measure Aβ in the CSF could be used 
if amyloid PET scan is not available) prior to randomization. MRI evaluations at 6 – 12 months 
intervals will then be conducted in all participants. The second amyloid PET scan at 24 months 
will be conducted in all participants who had a baseline amyloid PET scan and must use the 
same amyloid locally approved PET ligand that was used at baseline (see Section 6.6.3.1). 
Individual results of the PET scans and any fluid biomarker assessments will not be disclosed 
to the Investigators or participants prior to study completion.  
Participants will be encouraged to contribute to additional investigations of AD and relevant 
biomarkers, upon specific consent. These include optional consent to Tau PET scans (at the 
subset of sites with access to the tau tracer, where locally permitted, and the required imaging 
capability, at Screening, Month 24 and Month 60, an additional amyloid PET scan at 60 months, 
), and CSF and blood-based soluble biomarkers at 
Baseline, Month 24 and Month 60 as described in Table 6-2 and Table 6-3.  In locations where 
compliance with total radiation exposure limits could be of concern, voluntary Tau PET scans 
will be prioritized 
. 
The participant will not have access to his/her individual results (e.g. fluid biomarkers, 
 or imaging results) as knowledge of the results (specifically in relation to 
amyloid or glucose metabolism) could inadvertently unblind the participant or investigator. 
Results of these tests will not be available until study completion. Any clinically significant 
safety findings that require follow up will be communicated to the participant and results of 
subsequent clinical scans will be shared in real-time. 
All data, samples and images collected during the study, including the biomarker data, will be 
anonymized and stored in central repositories. After recruitment has been completed, baseline 
characteristics might be shared with the research community for publication purposes. After 
study completion, data, images and biological samples may be made available to the research 
community per local requirements and regulations.  
The data sharing will be overseen by an independent oversight committee that will assess the 
scientific validity of the research proposals. 
3.1.2.4 
Extended SAE collection for Cohort I participants 
After the end of study (Follow-up visit), Extended SAE collection will be implemented for 1 
year after the last study visit or for 1 year after the last injection in case of premature withdrawal 
(see Section 6.2 and 7.2.2). This safety monitoring will consist of SAE collection to be 
conducted for all participants who received at least one injection of study medication. This will 
encompass up to four quarterly telephone calls to the participant and/or study partner for a 
maximum of 12 months. SAEs occurring during this 1 year extended monitoring will only be 
captured in the Novartis safety database and not in the clinical database/ electronic case Report 
Forms (eCRFs). 

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3.2 
Rationale for study design 
The design of this study addresses the primary objective, which is to assess independently the 
effects of two amyloid-targeting therapies vs. placebo in participants at risk for the onset of 
clinical symptoms of AD over at least 60 months. 
Population 
The identification of individuals within the target age group of 60-75 years with APOE4 HM 
genotype is employed as a prognostic enrichment strategy for selecting individuals with a 
greater likelihood of having substantial worsening in cognition in a reasonable time frame (FDA, 
draft AD Guidance for Industry, 2013). For AD in general, and also with the HM genotype, risk 
of progression to MCI due to AD or dementia due to AD increases with age (Genin et al 2013, 
Qian et al 2017, Janssen et al. 2016, Bonham et al 2016). To ensure that a sufficient proportion 
of participants progress towards diagnosis of MCI or dementia due to AD during the trial, the 
study will randomize no more than approximately 20% of participants in the lower age group 
(<65 years). Due to the stratified randomization, the randomization ratios will be reflected 
within the two defined age groups of <65 years and 65 years and older. Details are provided in 
Section 5.3).  
Design Features 
This study will evaluate two active treatments, CAD106 and CNP520, in separate cohorts, each 
with a matching placebo arm. In order to enable a concurrent read-out of Cohort II and the 
parallel study with CNP520 (CCNP520A2202J – Generation Study 2), a 1:4 ratio for Cohort I 
versus Cohort II has been implemented.  
A halt in randomization to Cohort I is introduced when approximately 65 participants are 
randomized to mitigate the risk that a large number of participants are exposed to CAD106 prior 
to the futility analysis on CNS activity. Although the extent of reduction of amyloid PET and 
the associated clinical effect in AD prevention are not known yet, recent data with 
immunotherapies indicate that a robust effect on CNS activity should be sought to maximize 
chances that a clinical benefit might emerge following longer treatment (Sevigny et al, 2016). 
In a previous study in mild AD (refer to CAD106 IB), CAD106 (n=11) showed ~3% difference 
in amyloid PET after 18 months in serological responders (80% of subjects) to placebo+non-
responders (n=4). Higher effects might be observed in the Study API015A2201J due to the 
longer exposure to antibodies and lower amyloid load in the earlier stage of the disease. The 
available data provided at 24 months from 65 randomized participants will provide sufficient 
evidence to assess the futility criteria based on current knowledge. Resuming the allocation to 
Cohort I will be determined by results of the futility analysis on CNS activity, as reviewed by 
the DMC.  
To optimize acceptability of the study, a greater proportion of participants will be allocated to 
active treatment or drug over placebo within each cohort. 
• Cohort I (CAD106 or placebo) will use a 5:3 randomization ratio, which also accounts for 
the 10% of participants who may demonstrate an insufficient serological response, based 
on the individual CAD106-induced Aβ-specific IgG titer values in serum. The Serological 
response criteria (see Section 9.5.5 for definition) were developed in the course of the 

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previous Phase II studies. Changes both in CNS biomarkers and peripheral plasma Aβ 
were observed in Serological responders (SR). In this study, participants who do not 
develop Aβ-specific IgG titers fulfilling the SR criteria will not be discontinued from 
treatment. This is deemed ethically and scientifically justified since potential benefit to 
these participants cannot be ruled out completely as the relationship of biomarker changes 
to clinical outcomes is unknown. The continued treatment along with other participants 
will allow reliable conclusions to be drawn with respect to both potential benefit in Non-
responders (NR) and cut-off for SR. Furthermore, risks in NR who are receiving CAD106 
are not deemed higher than in those receiving Placebo.   
• Cohort II (CNP520 or placebo) will use a 3:2 randomization ratio. 
The approach of testing two active treatments in one study was chosen since the main study 
design features (population, efficacy outcomes, and study duration) may be applied for both 
CAD106 and CNP520. It is thought that the benefits of the operational efficiencies of a single 
study and the opportunity to pool placebo outweigh the drawbacks associated with the 
complexity of the study design (see Section 9.4). Furthermore, providing two active treatments 
in a single study would provide additional options for this population: if one cohort is terminated, 
the participants may be eligible to be reassigned to the other cohort (See Section 5.5.9).  
Dose regimen modification 
For Cohort II, the initial regimen is a once daily dose of 50 mg CNP520 or matching placebo 
throughout the full treatment epoch. If it is determined that the current doses do not provide a 
suitable benefit/risk profile, a single Lower Dose Regimen (LDR) will be implemented for the 
active treatment arm through a Dose Regimen Modification (DRM) process (see Section 5.1.2 
and Section 5.2). This process may be triggered based on DMC recommendation and/or other 
data from studies becoming available for CNP520 or other BACE inhibitors.  
In case of DRM, the LDR will consist of a single lower dose regimen selected - either a 50 mg 
once weekly dose or a 6 mg once daily dose. Both dose regimens are expected to have a similar 
safety profile. The selection of the dose regimen will be based on both the timing of the DRM 
decision, as this may restrict options based on availability of supplies, and any further 
information available at that time, including PK/PD modeling, external data, etc.   
In case of DRM, the objective of the study will be to compare effects of the overall long-term 
exposure to CNP520 through the whole study duration across the dose and regimen used versus 
placebo. 
The decision to introduce the option for DRM was not driven by data of the clinical trial, but 
on other sponsor’s BACE inhibitor results. In addition, the DRM will keep main design features 
unchanged including the statistical testing procedure. 
Primary Endpoints 
There are two primary endpoint variables: the Time-to-event (TTE), with event defined as 
diagnosis of MCI due to AD or dementia due to AD and the APCC test score. The success of 
the study for each investigational drug will be determined by a positive result in at least one 
endpoint.  

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The main primary endpoint is defined as time to diagnosis of MCI due to AD or dementia due 
to AD (whichever is diagnosed first). Postponing the diagnosis of MCI and/or dementia 
represents an important clinical outcome with high face validity. The diagnostic criteria 
proposed by the National Institute on Aging Alzheimer’s Association working group will be 
used (Albert et al 2011, McKhann et al 2011), alongside a centralized adjudication process 
(further details see Section 6.4.5).  
The alternative primary endpoint, APCC test score, will allow examination of drug effects using 
a continuous measure of cognition. The APCC test was developed based on data from multiple 
longitudinal observational cohorts in unimpaired individuals at baseline in the target age-range. 
This was empirically derived from a series of independent analyses in six cohort datasets. The 
APCC test score has the sensitivity to detect and track preclinical cognitive decline in 
individuals who subsequently progress to the clinical stages of LOAD. It provides a single 
measure of multiple cognitive domains (e.g. episodic memory, executive function, visuospatial 
function) capable of detecting and tracking cognitive decline in people at particularly high risk 
for developing symptoms due to AD. Although the APCC test is expected to have the greatest 
sensitivity to detect and track cognitive decline in preclinical AD (decline that is due to AD and 
not aging), it is acknowledged that the APCC test score’s sensitivity to treatment effects is still 
unproven. Additional APCC data is planned to be collected outside the API015 study, so that 
its relevance can be established in validating the natural history of the disease as well as its 
value to predict functional decline. 
Individual assessments selected for inclusion in the APCC test battery are described in Section 
6.4.2.  
Secondary Endpoints 
CDR-SOB (global measure widely used in clinical research in AD), RBANS total score (clinical 
tool used to assess the neuropsychological status), and ECog (measurement  of daily function 
and subjective/study partner memory concerns) will be included as secondary endpoints, in 
order to fully capture potential drug effects and to further contribute to the assessment of clinical 
relevance of the potential treatment effects (see further information in Section 6.4).  
The study will also investigate the effects of CAD106 and CNP520 on the underlying AD 
pathology (amyloid pathology and neurodegeneration) assessed by biomarker data.  
These AD biomarker data will be used to assess CNS activity (target engagement and 
downstream effects) for each investigational treatment in an unblinded futility analysis (see 
Section 3.5): 
• Cohort I: Amyloid PET, CSF Aβ together with markers of tau pathology and neuronal 
activation. 
• Cohort II: Brain atrophy (volumetric MRI), CSF Aβ, together with markers of tau 
pathology and neuronal activation. 
In addition, it is anticipated that changes in AD biomarkers over time, in combination with 
positive findings on a primary clinical outcome may provide information regarding the potential 
of either treatment to modify the course of the disease.  

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Furthermore, biomarker data would potentially allow assessment of the effects of CAD106 and 
CNP520, respectively, vs. placebo on preclinical staging progression using the research criteria 
for preclinical AD proposed by the Preclinical Working Group of the National Institute on 
Aging (NIA) and Alzheimer’s Association (AA) (Sperling et al 2011). The NIA-AA criteria for 
preclinical AD propose ordered stages for cognitively normal individuals with abnormal 
amyloid markers (stage 1), abnormal amyloid and neuronal injury markers (stage 2), and 
abnormal amyloid and neuronal injury markers and subtle cognitive changes (stage 3).  
Safety considerations 
In terms of safety, amyloid-based immunotherapies (particularly monoclonal antibodies such 
as bapineuzumab), have been associated with micro-hemorrhages in preclinical models and 
increases in Amyloid Related Imaging Abnormalities (ARIA) – both vasogenic edema (ARIA-
E) and micro-hemorrhages (ARIA-H) - in humans. These findings appear to occur at a higher 
incidence in participants carrying the APOE ε4 allele and occur most frequently in HMs. 
Additionally, in untreated participants, APOE ε4 has been linked to development of cerebral 
amyloid angiopathy (CAA), which is a risk factor for spontaneous ARIA-like phenomena 
(vasogenic edema) and micro-hemorrhages (Kinnecom et al 2007, Oh et al 2004, Poels et al 
2011, Vernooij et al 2008, Goos et al 2010). BACE inhibitors such as CNP520 might have 
potential to reduce vascular amyloid load and to therefore have beneficial effects on CAA. 
Appropriate monitoring with T2/fluid-attenuated inversion recovery (FLAIR) and T2* Gradient 
Echo (GRE) MRI sequences will be implemented to monitor these potential imaging events in 
both cohorts with actions to be followed by the investigators described in Section 13. The 
appropriateness of safety evaluations for each compound is described in Section 6.5.9. 
A 12-month Genetic Disclosure Follow-up period was established to assess psychological and 
behavioral impact of disclosure of APOE genotype (Green et al 2009). 
3.3 
Rationale for dose, regimen, route of administration and duration of 
treatment 
Based on the mechanism of action of the investigational drugs, no short-term benefit is expected, 
particularly in this preclinical stage. It is expected that if the investigational drugs delay the 
underlying pathological or pathophysiological disease processes, these changes will emerge 
only gradually over time. As discussed in the EMA Guideline on the Clinical Investigation of 
Medicines for the Treatment of Alzheimer’s Disease and other Dementias (January 2018) 
prevention trials require long treatment durations, typically of at least 5 years. In this study, 
participants will be treated for at least 60 months (5 years) up to a maximum of 96 months (8 
years), and no longer than the time until the target number of events for the TTE endpoint has 
been observed and confirmed in the respective cohort. This longer-than-usual treatment 
duration addresses the current understanding of intervention in the AD prevention setting and 
generates long term safety data for both compounds. 

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The minimum treatment duration of 60 months was chosen based on the likelihood of detecting 
(1) sufficient number of events and (2) sufficient cognitive decline as measured by APCC test 
score in the placebo arm to allow the detection of clinically meaningful treatment effects on the 
primary endpoints. Prolonging treatment beyond 60 months until a maximum of 96 months in 
initially recruited participants will allow for collection of sufficient number of events to test the 
primary study hypothesis, while also capping the participation in the study for all participants.  
Safety data collected during the study will be summarized in a blinded manner in the annual IB 
updates submitted to EC and Health Authorities to support continuation of treatment (e.g. IB 
updates will be classified as Substantial amendments for reporting purposes in the EU). 
Outcome and decisions from the DMC based on the interim analyses will also be described in 
the IB updates. Any corresponding changes to study design, including required safety 
monitoring, will be submitted for approval as a protocol amendment. 
The two investigational treatments will be administered using different routes of administration 
(intra-muscular (i.m.) vs. oral (p.o.) and frequency (quarterly vs. daily). Each cohort will be 
fully blinded by using a matching double-blind placebo. 
CAD106 
Cohort I will include a single dose regimen of CAD106 450 μg with Alum 450 μg administered 
quarterly i.m., with the second injection administered at week 7 (6 weeks after the first injection). 
Different doses and dosing regimens were evaluated in the Phase I (CCAD106A2101) and 
Phase II (CCAD106A2201, 2202, 2201E1, 2202E1 and 2203) studies conducted to date (for 
further information, refer to CAD106 IB).  
The objective of the previous CAD106 dose and regimen finding studies was to identify a 
suitable CAD106 + adjuvant combination to induce Aβ-IgG titers in the majority of the 
participants, with acceptable safety and tolerability profile. The combination of CAD106 450 
μg with Alum 450 μg administered quarterly i.m. was identified as the best regimen associated 
with strong and persistent Aβ-IgG response and suitable tolerability profile for long-term 
clinical studies of active immunization against Aβ (see Section 3.6). 
Previous studies were not powered to evaluate clinical efficacy, however biomarker evidence 
of CNS activity was observed as changes on amyloid load (i.e. correlation of plaque reduction 
with higher antibody titers) and neurodegeneration markers, (refer to Section 3.6 and IB). The 
relationship of biomarker changes to clinical outcomes is unknown, but current assumption is 
that the greater the Aβ reduction, the greater the clinical efficacy of CAD106.  
Since IgG generation and affinity maturation will require repeated injections, the onset of 
efficacy is expected to be 3-6 months later than with monoclonal antibodies. The effects of 
antibody response to CAD106 vs. placebo are measured by the change from Month 6 to 
Month 60 in the APCC test score and in CDR-SOB.  

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CNP520 
Cohort II will include a single oral dose regimen of CNP520 50 mg once daily or the selected 
LDR if activated. The 50 mg daily dose was initially chosen due to the expected positive 
risk/benefit in APOE4 HMs based on the current data at that time.  
The initial targeted dose of 50 mg once daily was selected based on the safety and tolerability 
as well as CSF Aβ lowering results obtained in the first-in-human study CNP520X2101 and the 
3-month dose-ranging safety and tolerability study CNP520X2102 in healthy adults > 60 years 
of age. In addition, the non-clinical toxicological findings and current understanding of the 
physiological role of BACE-1 were considered. Based on predictions from pharmacometric  
modelling utilizing Phase I clinical data, the proposed dose of 50 mg achieves approximately 
80% CSF Aβ lowering in 90% of the subjects. The corresponding median CSF Aβ lowering is 
86%.  
Genetic data suggest that a life-long 30% reduced Aβ generation is sufficient to significantly 
reduce the AD risk (Jonsson et al 2012). Since treatment with CNP520 will start late in life, and 
Aβ deposition may have already started, it was previously thought that greater inhibition will 
be required to demonstrate efficacy.  
The non-clinical safety profile of CNP520 was studied in rats and dogs and provides adequate 
support for the proposed doses and duration of dosing clinically. The safety margins compared 
to the NOAEL provide substantial coverage for the 50 mg dose. The predicted safety margins 
(AUC) between the animal NOAEL and the 50 mg dose are: 8-fold (male rats; maximum dose 
tested (200 mg/kg/day), ≥11-fold (female rats; focal skeletal muscle atrophy without functional 
effects at 200 mg/kg/day) to ≥15-fold (female and male dogs; CNS effects at > 30 mg/kg/day).  
Lower Dose Regimen (LDR) for Cohort II 
Since the start of this study, some of the other sponsors developing other BACE inhibitor 
compounds reported dose-dependent increases in neuropsychiatric events and early decline in 
cognitive performance with their compounds. These effects were seen with doses resulting in 
60-80% CSF Aβ lowering, however trend for beneficial effects was observed with elenbecestat 
targeting 57% CSF Aβ lowering (Lo et al 2018). 
Based on these results and since the median CSF Aβ lowering expected with the original dose 
(i.e. 86%,) is above 60%, the option for a lower dose regimen (LDR) targeting 50-60% median 
CSF Aβ lowering is pre-planned.  
The independent DMC monitors the safety of CNP520 assessing regularly the unblinded data 
from the ongoing CNP520 clinical studies. If the DMC recommends a lower dose based on 
CNP520 safety findings and/or in light of new data for CNP520 or other BACE inhibitors, the 
DRM may be activated.  
Based on human genetic and animal model studies (Jonsson et al 2012; Vassar et al 2014) along 
with the results on BACE inhibitors disclosed in October 2018 (AlzForum 2018), a 50% 
lowering of Aβ may be sufficient to prevent amyloid deposition and plaque formation, while 
maintaining a sufficient level of BACE function to avoid off-target effects that may be 
detrimental. In support of this, a lower level of BACE inhibition, with a dose of elenbecestat 
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3.5 
Purpose and timing of interim analyses/design adaptations 
Three types of interim analyses (IA) are pre-planned (see Section 9.6): (1) regular safety 
reviews by the DMC, together with immunogenicity assessments of CAD106; (2) biomarkers 
of CNS activity when a pre-defined number of participants reach 24 months; and (3) review of 
primary endpoints. An additional post-treatment IA was conducted by an independent team to 
assess the need for continued of the follow-up of participants after treatment termination.  
The main purpose of the planned IAs will be safety monitoring and assessment of futility or 
overwhelming efficacy, with the potential consequence of discontinuing the respective futile 
active treatment arm and corresponding placebo. Safety reviews will be semi-annual, with an 
increased frequency as needed, to appropriately evaluate the safety/tolerability profile of the 50 
mg CNP520 daily dose and the decision to maintain or activate the DRM. 
The primary endpoint IA is planned to be conducted in each cohort as early as possible when a 
sufficient number of events is observed to assess futility. 
3.6 
Risks and benefits  
Given the safety profile of CAD106 and CNP520 shown to date, and the positive data on 
amyloid pathway biomarkers, an investigation of their potential in slowing/postponing 
cognitive decline in pre dementia stages of AD disease offers potentially important benefits.  
The overall risk to participants in this study is expected to be low due to extensive precautions 
and safety monitoring planned to ensure the safest possible testing of CAD106 and CNP520.  
Overall, based on available non-clinical and clinical safety data, potential risks are considered 
manageable by applying appropriate safety monitoring as well as eligibility and discontinuation 
criteria. 
In addition, all available unblinded safety data will be regularly review by an independent DMC. 
Genetic Disclosure 
Use of standardized genetic counseling protocols for the disclosure of APOE genotype has been 
found to be safe and well-tolerated (Green et al 2009, Green et al 2014). Data from the Risk 
Evaluation and Education for Alzheimer’s Disease (REVEAL) program support the 
psychological safety of disclosing APOE genotype using standardized genetic counseling 
talking points.  
Although the disclosure of APOE genotype results to REVEAL participants did not result in 
significant short-term untoward psychological effects, individuals with high levels of emotional 
distress before undergoing genetic testing were more likely to have emotional difficulties after 
disclosure (Green et al 2009, Green et al 2014).  
Therefore, this current study has specific criteria to exclude participants whose scores on pre-
screening assessments indicate lack of psychological readiness to receive APOE genotype 
results. All HM participants who receive disclosure of their APOE genotype in this study will 
be followed for 12 months (consistent with the REVEAL program) to monitor the longer-term 
untoward psychological effects.  Additionally, genetic counseling with standardized talking 
points is required with the actual disclosure in the study.   

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CAD106 
CAD106 has been administered to 206 patients with predominantly mild dementia due to AD 
in four double-blind, placebo-controlled studies or their extensions. Data collected so far in mild 
AD patients is considered to be relevant to the preclinical APOE4 HM population that will be 
recruited in this study since the populations are expected to be comparable in terms of age 
ranges, concomitant conditions, amyloid positivity and genetic risk factors. 
In the completed studies, patients were, on average, followed for 16 months. Following 
completion of these studies, the study site staff contacted patients every three months during 
the 2 years after their last study visit for occurrence of serious adverse events (SAEs), which 
were to be reported independently of a relationship to investigational drug. The median number 
of injections of CAD106 was six per patient, resulting in a total of > 1200 injections. Across all 
studies, CAD106 showed an acceptable safety and tolerability profile to support long-term 
dosing. Local pain (75.8%), redness (61.4%), and swelling (56.2%) were the most frequently 
reported local reactions, while fatigue (56.2%) and myalgia (51%) were the most frequently 
reported systemic reactions with CAD106. These reactions were generally mild or moderate 
and lasted for less than 7 days. Addition of the adjuvant Alum to CAD106 450μg improved 
tolerability compared to CAD106 450μg without adjuvant, in particular in respect to systemic 
reactions including fever.  
There are minimal safety concerns for the use of Alum as adjuvant with CAD106 or with 
placebo. Aluminum-containing adjuvants have been used for more than 70 years in billions of 
doses of vaccines, and have an excellent safety record (Butler et al 1969, Edelman 1980, 
Jefferson et al 2004). Alum doses used for this study are half of the levels used in infants in first 
year of life (approximately 2 mg Alum/year in the API015 study).   
CAD106 was not associated with meningoencephalitis, adverse immune reactions, or deaths. 
Based on the currently available data, the risk for ARIA for CAD106 is considered to be low 
compared with other immunotherapies.  
CAD106 has not been associated with significant risk of ARIA in animals or humans. In AD 
patients, out of whom the great majority had amyloid pathology, only asymptomatic ARIA 
findings were observed.  
A total of ten cases of asymptomatic ARIA were reported across 186 patients from the phase II 
studies. A total of 9 cases of ARIA-H were observed, of which eight patients (8/160, 5.0%) 
were on CAD106, while one patient (1/26, 3.8%) received placebo prior to the MRI scan with 
the finding. Among patients on CAD106, incidence of asymptomatic ARIA-H appears not to 
be APOE4 gene-dose dependent (APOE4 homozygotes 1/24, 4%; APOE4 heterozygotes 5/67, 
8%; non-carriers 1/38, 2%; missing genotype 1/24, 4%).There was only a single case of 
asymptomatic ARIA-E in patient receiving CAD106 (1/160, 0.6%). 
Explorations of biomarker data, obtained from continuous exposure over 18 months to 
CAD106- induced antibody titers, were largely consistent with the expected effects of an 
Aβ-immunotherapy. Serum Aβ IgG titer AUC correlated with longitudinal decreases in brain 
amyloid load over a 78 week period, as measured by florbetapir PET. 

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Participants and investigators are required to be alert to signs and symptoms related to CNS 
disorders. Clinical study protocol incorporates multiple precautions to ensure the safest possible 
testing of CAD106. Particular attention is paid to diagnosing clinically manifest 
meningoencephalitis and other severe autoimmune reactions, but also to monitoring of any not 
clinically apparent findings that might raise safety concerns.  
Additional details are summarized in the CAD106 IB. 
CNP520 
The safety and tolerability of CNP520 has been assessed in 422 subjects across four Phase I 
studies and one Phase IIa study with three-month exposure duration. A total of 335 subjects 
were exposed to CNP520 and 87 to placebo. The studies included mainly healthy volunteers, 
from which a majority were ≥ 60 years of age. The single maximum tolerated oral dose of 750 
mg identified in healthy adults appeared to be safe and well tolerated in healthy subjects ≥ 60 
years of age. Multiple oral doses up to 300 mg q.d. (maximum dose tested) over 2 weeks and 
up to 85 mg q.d. (maximum dose tested) over 3 months appeared to be safe and well tolerated. 
Across completed studies, the adverse event (AE) incidence was similar for CNP520 versus 
placebo both in adults and subjects ≥60 years. Most AEs were mild, not suspected to be study-
drug related and resolved. No dose-dependent AEs were identified.  
In Study CCNP520X2102, with the longest exposure duration so far (i.e. 3-month exposure in 
subjects ≥60 years of age), there was no indication for an imbalance in AE incidence between 
CNP520 and placebo in any of the SOCs except for skin and subcutaneous tissue disorders that 
occurred at a higher incidence on CNP520 than on placebo (18.0% vs. 4.2%) with no indication 
of dose dependence. Each of these events was mild and transient except for a single subject 
with generalized pruritus of moderate severity leading to discontinuation on CNP520 85 mg. 
There were no clinically relevant alterations of laboratory, vital signs, ophthalmological 
assessments (visual acuity/field) or ECG data or any indication for systematic changes over 
time or as a function of dose. 
There was also no indication for impaired neurological function during the study and after 
follow-up, based on routine neurological examination and monthly cognitive testing with the 
Cogstate computerized battery. However, one subject on 85 mg discontinued the study due to 
an AE of amnesia.  Narratives for the AEs leading to discontinuation are provided in the IB. 
Data from monthly dermatological assessments performed by a dermatologist did not raise any 
safety concern. In particular, there was no indication for hypopigmentation over time.  
A pooled concentration-effect analysis of Holter- and 12-lead-ECG QT data from the first-in-
human study (CCNP520X2101), the 3-month safety and tolerability study (CCNP520X2102) 
and the Japanese ethnic sensitivity study (CCNP520X1101) was performed. Results did not 
indicate any relevant QT prolongation by CNP520 (Refer to IB). 
Based on currently available clinical safety data, there are no identified risks for CNP520. 
Potential or theoretical compound and class risks are based on non-clinical toxicology findings, 
safety observations in the current clinical program and non-clinical or safety findings reported 
in publications with reference to other BACE-1 inhibitor programs.  

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Good Laboratory Practice (GLP) embryo-fetal development studies for CNP520 have been 
completed and CNP520 has  demonstrated neither genotoxicity nor teratogenicity; therefore, 
use of a condom is no longer required during intercourse for male participants who have female 
partners of child-bearing age. 
Based on Drug-Drug-Interaction (DDI) study results it is expected that concomitant 
administration of strong CYP3A4 inhibitors or strong CYP3A4 inducers will affect CNP520 
exposure. Restrictions or prohibited concomitant medications are described in Section 5.5.8. 
Biomarker results in human studies suggest that CNP520 may itself be a weak inducer of 
CYP3A4. Based on in vitro and in vivo (4β-hydroxycholesterol levels in Healthy Volunteers) 
data, exposure to concomitant medications that are CYP3A4 substrates may be reduced when 
treatment with CNP520 is initiated. However, importantly, the effect of potential auto-induction 
on systemic exposure of CNP520 is not considered to be clinically relevant since there was no 
decrease in exposure to CNP520 over 3-month treatment. 
No efficacy data have been generated to date. However, pharmacodynamic data has been 
obtained. In healthy subjects ≥60 years of age, CNP520 reduced CSF Aβ concentrations in a 
dose-dependent manner by up to approximately 80% at the maximum single dose tested (750 
mg) and 95% after multiple dosing at the highest dose tested (300 mg q.d.). Aβ40 concentrations 
in CSF decreased by 91 % compared to baseline after 3-month exposure at CNP520 85 mg q.d. 
Similar changes in Aβ40 concentrations in CSF after CNP520 administration were obtained for 
carriers of the APOEε4 allele vs. non-carriers. Additional details are summarized in the 
CNP520 IB. 
Given the safety profile of CNP520 shown to date and the positive data on amyloid pathway 
biomarkers, an investigation of its potential in slowing/postponing progression to cognitive 
symptoms in pre-clinical AD stages of the disease offers potentially important benefits. 
Two compounds from other companies with the same main mechanism of action as CNP520, 
i.e. BACE inhibition, were associated with an increase in neuropsychiatric symptoms, along 
with a decline in performance on tests of memory and other aspects of thinking starting in the 
first three to six months of their respective studies (Egan, et al 2018, Romano, et al 2018). The 
doses utilized lowered CSF Aβ by 60%-80%.  One other BACE inhibitors did not report these 
effects in small studies with doses targeting 60% and 90% Aβ lowering and one compound 
showed trend towards efficacy in a Phase II study using a dose achieving a 57% CSF Aβ 
lowering (Lo et al 2018; Lynch et al 2018). These four compounds and CNP520 have different 
physicochemical properties (e.g. BACE1/2 selectivity) and were studied in different 
populations or disease stages. (AlzForum 2018). 
At this point in time, these effects have not been observed with CNP520. Prior studies with 
CNP520 in healthy elderly volunteers with a 3-month duration did not show any negative 
impact on memory or thinking tests.  

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The Generation studies (current study and CCNP520A2202J study) focus exclusively on 
APOE4 carriers (exclusively homozygotes in this study) who may benefit more from CNP520 
based on their higher risk for progression to symptomatic stages of AD. Presence of the APOE4 
allele has been linked to increased amyloid-β secretion and to an earlier onset of amyloid 
deposition (Huang et al 2017). Treatment with a BACE inhibitor may therefore be more 
effective in APOE4 carriers, compared to non-carriers, in whom amyloid load may be increased 
by other mechanisms, such as reduced clearance (Mawuenyega, et al 2010). 
The hypothesis that BACE inhibition could slow or delay AD progression in preclinical stage 
may hold true through the early stages of the pathophysiological changes, even if a symptomatic 
decline in cognition is seen upon treatment initiation. Both effects may co-exist based on the 
potential disease modifying mode of action (preventing amyloid production) along with 
potential CNS side-effects (symptoms of neurological or psychiatric disorders). The clinical 
relevance of the decline in cognitive performance in other BACE inhibitor studies is not fully 
understood, but appears to be distinct from a worsening of AD progression. For this assessment, 
follow-up data in addition to the details of the trials with the other BACE inhibitors along with 
their respective biomarkers of neurodegeneration will need to be assessed as results become 
available. 
The overall risk to participants in this study is expected to be low and acceptable due to the 
strong scientific rationale for the approach, the lack of alternatives to delay the onset of 
symptoms of Alzheimer’s disease in a population at high risk, and the precautions and safety 
monitoring planned during treatment with CNP520. Based on available non clinical and clinical 
safety data, potential risks are considered manageable by applying appropriate safety 
monitoring as well as eligibility and discontinuation criteria. Nonetheless, there may be yet 
unidentified risks to CNP520 and these could potentially be serious. 
In addition, all available unblinded safety data will be reviewed regularly by an independent 
DMC. The addition of cognitive and neuropsychiatric assessments at Month 3 will allow early 
detection of a decline in cognition and/or occurrence of psychiatric symptoms, if any, as seen 
for some but not all other BACE inhibitors. The DMC will review all data relevant for such 
evaluation at an increased frequency.  Should the DMC conclude that the current dose does not 
provide a favorable benefit/risk profile, they will recommend to lower the dose which is one of 
the criterion for activation of the DRM.  The recommendation from each DMC meetings are 
shared with Health Authorities and any recommendation impacting the study design as a 
consequence from a safety signal will be shared with all parties without delay. 
In case of DRM activation, and to protect participants from further exposure to the original 
higher doses, the LDR will be implemented according to the process described in the DRM 
Notification document. For sites or countries where the protocol v05 has not yet been approved 
by regulators at the time of DRM, the switch to the LDR may be managed through the Urgent 
Safety Measure process. 

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4 
Population 
4.1 
Pre-screening Epoch and Genetic Disclosure Follow-up 
Prior to the Genetic Disclosure visit, participants must meet the Pre-screening eligibility criteria. 
Medical history, including concomitant medications, will be assessed during an interview with 
the participant. The same criteria will then be reviewed against the participant’s medical records 
by the Investigator during Screening.  
4.1.1 
Inclusion criteria  
1a. Written informed consent (Informed consent #1) obtained before any assessment is 
performed, including consent to receive disclosure of their APOE genotype  
2a. Male or female, age 60 to 75 years inclusive, at the time of signing Informed consent 
#1 (same age restriction also applied at Informed consent #2). 
• Once the cap of approximately 20% of total participants in the age group 60-64 
years at time of signature of ICF#2 is met, a restriction to this age group will 
apply.  
• Note: the same age limitations of 60-75 years, inclusive is also applied at the time 
of signing Informed consent #2 
3a. Females must be considered post-menopausal and not of child bearing potential. 
Confirmation will be obtained for those who continue on to the Screening Epoch (see 
Section 4.2). 
4a. Mini-Mental State Examination (MMSE) total score ≥ 24 (can be based on 
documented result obtained within the previous 3 months). 
5a. Psychological readiness to receive APOE genotype information based on pre-
disclosure rating scales, specifically: 
a. Geriatric Depression Scale (GDS) total score ≤ 6.  
If the score is between 7 and 10 (inclusive), the participant can only be 
included based on investigator’s  judgment, with special attention given to the 
questions: 
i. Item 3: “Do you feel your life is empty?” 
ii. Item 6: “Are you afraid that something bad is going to happen to you?” 
iii. Item 12: “Do you feel pretty worthless the way you are now?” 
iv. Item 14: “Do you feel your situation is hopeless?” 
b. Six Item Subset Inventory of the STAI-AD total score ≤17. 
If the score is 18 or19, the participant can only be included based on the 
investigator’s judgment.  
6a. Participant is fluent in, and able to read, the language in which study assessments are 
administered (e.g. completion of at least 6 years of regular schooling or sustained 
employment). 
7a. Participant’s willingness to have a study partner for the Screening and Treatment epoch 
(see Screening and Treatment Epoch Inclusion criteria #6 below). 

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4.1.2 
Exclusion criteria  
1a. Any disability that may prevent the participant from completing all study requirements 
(e.g., blindness or deafness that is not appropriate for age, severe language difficulty, etc.).  
2a. Current medical or neurological condition that might impact cognition or performance on 
cognitive assessments e.g., MCI, dementia, Huntington’s disease, Parkinson’s disease, 
Lyme disease, syphilis, schizophrenia, bipolar disorder, active major depression, attention-
deficit / hyperactivity disorder (ADD / ADHD),  multiple sclerosis (MS), amyotrophic 
lateral sclerosis (ALS), active seizure disorder, alcohol/drug abuse or dependence 
currently, or dependence within the last two years,  history of traumatic brain injury with 
loss of consciousness and ongoing residual transient or permanent neurological 
signs/symptoms including cognitive deficits, and/or associated with skull fracture.   
Note: the available Investigator Guide provides guidance on the interpretation of 
laboratory tests for Lyme disease. 
3a. Advanced, severe progressive or unstable disease that may interfere with the safety, 
tolerability and study assessments, or put the participant at special risk, e.g. active 
hepatitis or HIV infection (based on a positive lab result for HBV/HCV and/or HIV, to be 
performed during screening if not available from the last 12 months), severe renal 
impairment, severe hepatic impairment, uncontrolled or significant cardiac disease 
including recent (within six months) myocardial infarction, congestive heart failure (New 
York Heart Association [NYHA] functional class III-IV), unstable angina, or long QT 
syndrome.  
Note: the available Investigator Guide provides guidance on the interpretation of 
laboratory tests for HBV and HCV. 
4a. History of malignancy of any organ system, treated or untreated, within the past 
60 months, regardless of whether there is evidence of local recurrence or metastases. 
However, localized nonmalignant tumors not requiring systemic chemo- or radio-therapy, 
localized basal or squamous cell carcinoma of the skin, in-situ cervical cancer, localized 
vulvar carcinoma and localized prostate carcinoma with no progression over the past two 
years are permitted. 
5a. History of hypersensitivity to any of the investigational drugs or their excipients/adjuvant, 
or to drugs of similar chemical classes. 
6a. Indication for or current treatment with ChEIs and/or another prescription AD treatment 
(e.g. memantine). 
7a. Contraindication or intolerance to MRI or PET investigations (with fluorinated 
radioligands). 
4.2 
Screening, Treatment and Follow-up Epochs 
4.2.1 
Inclusion criteria  
Participants eligible for inclusion must fulfill all of the following criteria prior to randomization: 
1b. Written informed consent (Informed consent #2) for participation to the Screening, 
Treatment  and Follow-up Epochs  (Participant must still be between 60-75 years, 
inclusive, at the time of signing Informed consent #2; after reaching the maximum of 20% 
in the younger age group of 60-64 years, only those 65-75 years will be eligible) 

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2b. Continue to meet all eligibility criteria from Pre-screening Epoch and Genetic Disclosure 
Follow-up, as confirmed by the review of the medical records by the Investigator, 
including continued psychological readiness for participating in the study as determined 
by clinical judgment. 
3b. Homozygous APOE4 genotype. 
4b. Cognitively unimpaired as defined by: 
At screening visit, score of 85 or greater on the RBANS delayed memory index score 
AND global CDR score of 0 with two exceptions: 
a. If the RBANS delayed memory index score is between 70 and 84 (inclusive) 
AND the global CDR score = 0, the participant may be allowed to continue 
ONLY  if investigator judges that cognition is unimpaired following review of 
the MCI/dementia criteria. 
b. If the global CDR score = 0.5 AND the RBANS delayed memory index score is 
85 or greater, the participant may be allowed to continue ONLY if investigator 
judges that cognition is unimpaired following review of the MCI/dementia 
criteria. 
5b. Females must be considered post-menopausal and not of child bearing potential, i.e. they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile (e.g. age appropriate, history of vasomotor symptoms), or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal 
ligation at least six weeks before the Amyloid PET.  
6b. Study partner, who spends sufficient time with the participant, and agrees to participate in 
the study must have an adequate functioning (e.g., intellectual, visual, and auditory) and 
be fluent in, and able to read, the language in which study assessments are administered. 
(see definition in Appendix 4) 
Additionally the study partner must be capable of and willing to: 
• Accompany the participant to all required twice yearly visits  
• Meet the definition of a “study partner” as described in Appendix 4.  
4.2.2 
Exclusion criteria 
Participants fulfilling any of the following criteria prior to randomization will be excluded.  
Participants, who fulfill one or more exclusion criteria due to a temporary condition, or to the 
use of treatment requiring a specific time window prior to randomization, can be re-screened at 
a later stage. 
1b. Brain MRI results from the central reading showing findings unrelated to AD that, in the 
opinion of the Investigator, might be a leading cause of future cognitive decline, might 
pose a risk to the participant, or might confound MRI assessment for safety monitoring 
(e.g. extensive white matter lesions (score of 3 on the Wahlund’s scale in 2 or more 
bilateral brain regions), recent stroke, recent cerebrovascular disease evidenced by more 
than one lacunar infarct ≤ 20 mm or any single infarct > 20 mm, evidence of cerebral 
contusion, encephalomalacia, aneurysms, vascular malformation, subdural hematoma or 
space-occupying lesions).  

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For Cohort I (CAD 106) only, in addition to the above, evidence of ARIA-H as 
demonstrated by: 
• More than four cerebral microhemorrhages (defined as having a diameter ≤ 10 mm on 
T2* sequence) regardless of their anatomical location 
• Single area of superficial siderosis of the CNS or evidence of a prior cerebral 
macrohemorrhage (> 10 mm diameter) 
2b. Score “yes” on item four or item five of the Suicidal Ideation Section of the eC-SSRS if 
this ideation occurred in the past six months, or “yes” on any item of the Suicidal 
Behavior Section, except for the “Non-Suicidal Self-Injurious Behavior” (item is included 
in the Suicidal Behavior Section) if this behavior occurred in the past two years prior to 
screening (refer to Section 7.6 for management). 
3b. A positive drug screen at Screening, if, in the Investigator’s opinion, this is due to drug 
abuse or dependence. Participants with a positive drug screen not believed to be related to 
drug abuse or dependence (e.g. presence of prescription drugs in urine without evidence of 
prescription drug abuse), can be re-screened once. 
4b. Significantly abnormal laboratory results at Screening as described in the Appendix 13.4 
OR meeting the exclusionary alert values as specified in the Laboratory Manual, 
considered as clinically significant in the opinion of the Investigator. If an abnormal 
finding is the result of a temporary condition, the laboratory test can be repeated once.  
5b. Clinically significant “active” infection which has not resolved within two weeks prior to 
initial dosing. In that particular case, delayed randomization may be considered.  
6b. Current significant ECG findings as reported by central reader that are assessed as 
clinically significant by the investigator (e.g. sustained ventricular tachycardia, significant 
second or third degree atrioventricular block without a pacemaker, long QT syndrome or 
clinically meaningful prolonged QT interval). QTc interval > 500 ms is exclusionary. 
7b. Use of other investigational drugs prior to screening until: 
• Blood concentration has returned to Baseline (or below Serological responder 
threshold) for biologics, e.g. antibodies induced by active immunotherapy; or 
• Within 30 days or five half-lives, whichever is the longest for monoclonal antibodies 
or small molecules e.g. BACE-1 inhibitors. 
8b. Treatment 
a. in the four weeks prior to randomization with any drug or treatment known for their 
potential to cause major organ system toxicity, i.e. drugs that may require periodic 
safety monitoring of a specific organ or body fluid (examples include, but are not 
limited to, clozapine, cancer medical treatments like tamoxifen, systemic 
immunosuppressive drugs like methotrexate and interferon or other 
immunosuppressive biological medicines for rheumatic diseases or multiple sclerosis. 
b. in the four weeks prior to randomization and/or current treatment with any CNS 
active drug(s), with exceptions described in Table 5-3. 
c. For Cohort I (CAD106) only, treatment with warfarin or other coumarin derivatives, 
or with a combination of acetylsalicylic acid and an anti-platelet agent (e.g. 
clopidogrel) within seven days (five half-lives) prior to randomization, or current 
indication for chronic treatment with a direct oral anti-coagulant.  

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d. For Cohort II (CNP520) only: Current chronic treatment (> 3 months) with (see Table 
5-2, expanded list is available in the Investigator Guide): 
• strong CYP3A4 inducers or strong CYP3A4 inhibitors;  
• or drugs with a narrow therapeutic index known to be primarily metabolized by 
CYP2C or CYP3A isoenzymes, and sensitive Pgp substrates   
9b. Violations of concomitant medication restrictions as described in Table 5-3.  
10b. 
Donation or loss of 400 mL or more of blood within 8 weeks prior to screening blood 
sampling and/or Lumbar Puncture if applicable. 
11b. 
Previous or planned Nuclear Medicine Radiology exposure that will exceed the 
dosimetry acceptable exposure in the country, when adding the scheduled study PET scans 
or allergy to low doses of fluorinated radioligands.  
12b. 
For Cohort II (CNP520) only: Participants with clinically relevant depigmenting or 
hypopigmenting conditions (e.g. albinism, vitiligo) or active / history of chronic urticaria 
in the past year. 
13b. 
For Cohort I (CAD106) only: Participants with previous organ transplantation or stem 
cell transplantation. 
Exclusion criteria for participation in the Lumbar Puncture  
14b. 
Contraindication to lumbar puncture, e.g. low platelet count, abnormal prothrombin 
time international normalized ratio (PT-INR), history of lumbar-spinal surgery (with the 
exception of microdiscectomy or laminectomy over one level), signs or symptoms of 
intracranial pressure, spinal deformities or other spinal conditions that in the judgment of 
the Investigator would preclude a lumbar puncture. 
No additional exclusions may be applied by the Investigator in order to ensure that the study 
population will be representative of all eligible participants. 
5 
Treatment 
5.1 
Investigational treatment 
5.1.1 
Cohort I  
CAD106: 
• CAD106 will be available as a white lyophilizate powder for reconstitution. Each vial of 
CAD106 individual vials contain the equivalent of 0.5 mg of CAD106, extractable after 
reconstitution.  
• Alum as adjuvant will be provided as a separate medication pack. 
Prior to administration, CAD106 lyophilizate will be reconstituted with sterile water for 
injection and mixed with the provided vial of Alum. 
Placebo: 
• Placebo will consist of a lactose powder with same appearance as CAD106 lyophilizate. 

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• Alum as adjuvant will be provided as a separate medication pack. 
After reconstitution with the same volume of sterile water for injection, the placebo vial will 
present with the same appearance and viscosity as the reconstituted CAD106 solution.  
Prior to administration, the reconstituted placebo will be mixed with the provided vial of Alum.  
CAD106 with Alum and placebo with Alum are to be prepared by a Pharmacist or appropriate 
delegate, as described in the Medication Manual.  
Sterile water for injection for placebo and CAD106 reconstitution will be purchased locally. 
All study treatments, including placebo, must be stored according to the storage conditions 
specified on the medication labels and in accordance with regulations governing investigational 
medicinal products and local regulations. Detailed instructions will be provided in the 
Medication Manual. 
5.1.2 
Cohort II 
CNP520 
CNP520 50 mg for oral administration once daily will be provided as capsules in separate 
bottles supplied for at least 3 months of treatment. An overage is included to account for the 
permitted treatment windows.   
In case of DRM, new study medication and/or alternative investigational drug packaging will 
be made available. The sites, EC/IRBs and HAs will be notified of the DRM activation and the 
selected LDR as described in the DRM Notification Document. Instructions for sites to notify 
the ongoing participants and the new dispensing instructions, timelines and process to 
implement will be described in the DRM Notification Document. 
• An interim dispensing to once weekly regimen for all treatment arms using the currently 
dispensed medication packs may be implemented until updated LDR medication packs are 
available at sites. 
Matching placebo will be provided as capsules in separate bottles supplied for at least 3 months 
of treatment. An overage is included to account for the permitted treatment windows. 
All study treatments, including placebo, must be stored according to the storage conditions 
specified on the medication labels (below 25°C) and in accordance with regulations governing 
investigational medicinal products and local regulations.  
5.1.3 
Additional study (procedural) treatment 
Other study treatments include:   
• an amyloid PET tracer (e.g. 18F-florbetapir, 18F-Flutemetamol, or 18F-Florbetaben 
according to local regulation (e.g. in Germany, only the commercially available amyloid 
tracer florbetaben) will be used and  
• a tau PET tracer (18F-flortaupicir (AV-1451), MK-6240 or PI-2620), voluntary for a subset 
of site that have access to the tau tracer, imaging capabilities and where locally permitted 
(i.e. not in Germany; applicable for USA and Canada with flortaucipir only)  

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• 
 
Further information can be found in the respective Investigator Brochure for the selected 
tracer(s) in the country or Summary of Product Characteristics (drug labelling information if 
approved in the country), will be provided to the sites and submitted to Institutional Review 
Boards (IRBs)/ Ethics Committees (ECs) and Health Authorities (HAs), as appropriate. 
5.2 
Treatment arms 
The study consists of two cohorts with a total of four treatment arms. 
Participants will be assigned to one of the following four treatment arms in a ratio of 5:3 in 
Cohort I and 3:2 in Cohort II.  
The IRT (Interactive Response Technology) system will take into account the cohort-specific 
exclusion criteria. The IRT will assign participants across cohorts in parallel, applying the 
appropriate ratio, and will also account for any applicable cohort specific exclusion criteria and 
concurrent completion of cohort allocation (including pause in allocation to Cohort I (see 
Section 3.2)). Participants eligible to both cohorts will not be offered the opportunity to choose 
one of the two cohorts.  
Cohort I (CAD106 and placebo): 
Arm #1: CAD106 450 µg + Alum 450 µg given i.m.  
Arm #2: Placebo to CAD106 + Alum 450 µg given i.m.  
Participants will be given i.m. injections at Weeks 1, 7, 13 and quarterly i.m. injections 
(approximately every 13 weeks) thereafter, until the last injection 3 month prior to completion 
of  the Treatment Epoch, e.g. for the last participant the last injection will be administered at 
Month 57.  
Cohort II (CNP520 and placebo)  
Arm #3: CNP520 50 mg capsule for once daily oral (p.o.) administration; or CNP520 LDR if 
DRM is activated 
Arm #4:  Placebo to CNP520 50 mg capsule for once daily oral (p.o.) 
administration; or placebo to CNP520 LDR if DRM is activated. If DRM is 
activated: 
All participants already assigned to Arm #3 will be transitioned from CNP520 50 mg daily to 
the selected LDR (either 50 mg capsule for once weekly oral (p.o.) administration or 6 mg 
capsule for once daily oral (p.o.) administration). 
All participants already assigned to Arm #4 will be transitioned to matching Placebo for LDR. 

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5.3 
Treatment assignment, randomization 
At Visit 301, all eligible participants will be randomized via Interactive Response Technology 
(IRT) to one of the available treatment arms. The Investigator or his/her delegate will contact 
the IRT after confirming that the participant satisfies all the inclusion/exclusion criteria. The 
IRT will assign a randomization number to the participant, which will be used to link the 
participant to a treatment arm and will specify a unique medication number(s) for the package 
of investigational drug to be administered (Cohort I) or dispensed (Cohort II) to the participant. 
The randomization number will not be communicated to the caller. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and Investigator staff. A 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of participant numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. The corresponding separate medication list will be produced by, or under the 
responsibility of Novartis Drug Supply Management, using a validated system that automates 
the random assignment of randomization numbers to investigational drug packs containing each 
of the investigational drugs.  
The randomization scheme for participants will be reviewed and approved by a member of the 
Novartis Randomization Office. 
In total, in Cohort I, about 690 eligible participants will be randomized via IRT to one of the 
two treatment arms. This will be implemented via central randomization to achieve a ratio of 
5:3, CAD106 vs. placebo.  A total of approximately 650 participants will be randomly assigned 
centrally into Cohort II with a ratio of 3:2 CNP520 vs. placebo.  
Participants who are eligible for both investigational drugs will be randomly assigned to one of 
the two cohorts in a 1:4 ratio favoring recruitment to Cohort II; this randomization ratio will be 
active until approximately 65 participants have been randomized in Cohort I. At that time, 
allocation will shift to Cohort II only (thus changing the allocation ratio between cohorts from 
a 1:4 ratio to a 0:5 ratio until approximately 650 participants in total are randomized in Cohort 
II). Upon positive results from the CNS activity IA on Cohort I, allocation into Cohort I may 
resume until the remaining participants required for Cohort I (approximately 690 in total) are 
randomized.  Randomization ratio would recommence at 1:4 ratio.  However, at the time of 
futility analysis, it is anticipated that recruitment to Cohort II would be complete; if this is the 
case, then allocation would be then be solely into Cohort I. Upon assignment to a cohort, the 
participant will be randomized to one of the two treatment arms (active or placebo) in that 
cohort. New participants who are eligible for only one of the two cohorts will be randomly 
assigned via IRT to one of the two treatment arms in the corresponding cohort. Randomization 
across the cohorts will be implemented via central adapted randomization such that the cohort 
specific randomization ratio will be achieved.  
Randomization will be stratified by age group (60 to <65 and ≥65) and region (North 
America/other, Europe). Region is known to be a surrogate of many measured and unmeasured 
factors and is chosen as stratification factor for randomization to optimize balance of potential 
prognostic factors. Rationale for stratifying by age group is provided in Section 3.2.  

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Note: The stratification by age is using age at randomization, not age at screening. Participants 
who were 75 years old at screening and reached age 76 at randomization due to the long 
screening time are still eligible and will be randomized into age stratum ≥65. 
5.4 
Treatment blinding 
Participants, site personnel, and data analysts will remain blind to the identity of the treatment 
within each cohort from the time of randomization until database lock using the following 
methods:  
Randomization data are kept strictly confidential until the time of database lock and will not be 
accessible by anyone else involved in the study with the following exceptions: 
• Authorized independent bioanalysts, programmers, statisticians, and data managers in 
charge of the antibody titers for CAD106 
, not otherwise 
involved in the daily study management activities. 
• DMC members and unblinded statisticians and programmers in charge of the interim 
DMC outputs and Interim analyses (including statisticians from external vendors involved 
in data analyses). 
• Key sponsor personnel reviewing group-level outputs from post-treatment data pooled 
across the two Generation studies at post-treatment IA. This additional analysis (see 
Section 3.5) was conducted by the same independent statistical team  
Further details for each of the personnel involved in data collection or reporting are presented 
in Table 5-1.  
Table 5-1 
Blinding status up to database lock 
Groups involved in the Study 
Access to Randomization list  
Participants, study partner, site personnel  
No (blinded) 
Sponsor and CROs involved in the study conduct 
No (blinded) 
Progression Adjudication Committee (as per charter) 
No (blinded) 
*Participant eDiary vendor, Analysts at T-cell activation assay 
laboratory, AD biomarker analysts, PET analyst at the Imaging CRO, 
pharmacist 
No (potential to unblind unless futility at 
any IA) 
Analysts in charge of antibody titer (Cohort I) 
 
 (Cohort II) 
Yes (unblinded) 
Drug Supply Management (including IRT provider) 
Yes (unblinded) 
DMC (as per charter) and independent statistical team 
Yes (unblinded) 
Key sponsor personnel 
Partially (only group-level and pooled 
across the 2 studies for CNP520 only) 
*The data with a potential to unblind recipients (typically markers of the treatment effect) will 
be stored in a restricted area of the database until database lock. Although the randomization 
list will NOT be communicated to them, the following personnel will be considered as 
unblinded due to the results post-baseline: 
• Participant diary vendor (tolerability data in Cohort I) 
• Analysts at T-cell activation assay laboratory (Cohort I) 

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• AD biomarker analysts (Aβ, Total-tau and Phospho-tau in CSF and Aβ in plasma, NFL in 
blood and CSF) 
• PET and MRI analyst at the Imaging CRO (Amyloid, Tau, 
 volMRI scans) 
Within each cohort, treatment packaging, labeling, schedule of administration, appearance, taste, 
and odor will not differentiate active study medication from placebo. 
• The identity of the CAD106 treatment is protected by providing a matching placebo 
powder of same appearance requiring the same reconstitution and mixing procedure. After 
reconstitution, the CAD106+Alum solution will have a same appearance (color and 
viscosity) as the matching Placebo+Alum. However, during the process of reconstitution, 
full blinding may not be possible for the pharmacist (or appropriate delegate); therefore 
the pharmacist should remain independent from other study activity to maintain the 
blinding for the study. 
• The identity of CNP520 will be concealed by the use of an identical matching placebo 
capsule and similar packaging.  
Unblinding will only occur in case of participant emergencies (see Section 5.5.11), and at the 
conclusion of the study. 
All other data with potential for unblinding (as for instance tolerability data) will be treated 
similarly as randomization data with regards to blinding: the data will be loaded into a restricted 
area. Access will only be granted to members of the authorized independent unblinded team. 
In the case that CAD106 meets the futility analyses criteria, data for Cohort I participants will 
no longer be treated as restricted, to allow for monitoring of the antibody titer levels needed to 
assess timing of  re-randomization (Refer to Section 5.5.9) 
5.5 
Treating the participants 
5.5.1 
Participant numbering 
Each participant is uniquely identified in the study by a combination of his/her center number 
and participant number.  With the addition of the preliminary genotyping step (ICF#1A), the 
participant ID assigned at this step may be kept throughout the study or may be changed at 
ICF#1B for the remainder of the study.  
Upon signing the Informed consent #1B for the Pre-screening Epoch and Genetic Disclosure 
Follow-up, the participant ID must be used as described below: the center number is assigned 
by the sponsor to the investigative site, and the participant is assigned a participant number by 
the Investigator.  
The Investigator or his/her staff will contact the IRT and provide the requested identifying 
information for the participants to register them into the IRT before randomization (i.e. at Visit 
201 (Screening Visit). The site should select the Case Report Form (CRF) book with a matching 
Participant Number from the Electronic Data Capture (EDC) system to enter data. 

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Once assigned to a participant, any participant number will not be reused, regardless if used 
under preliminary genotyping or pre-screening. If the participant fails to be randomized in the 
Treatment Epoch for any reason, IRT must be notified that the participant was not randomized. 
The reason for not being randomized will be entered on the Screening Epoch Study Disposition 
CRF, and the Demography eCRF should also be completed. 
5.5.2 
Dispensing the investigational treatment 
Each study site will be supplied with the investigational treatment in packaging of identical 
appearance by cohort. 
A unique medication number is printed on each part of this label which corresponds to one of 
the four treatment arms. The study site personnel will identify the study drug package(s) to 
dispense to the participant by contacting the IRT at Baseline (randomization). 
Further calls to IRT are required for re-supply at each of the 3-month visits to obtain the 
medication number(s) and identify the pack(s) to be dispensed. If participant has suspended 
study treatment, the call to IRT is still required to indicate the visit occurred but no drug was 
dispensed. 
Upon DRM, a new set of supplies may be provided for replacement. 
5.5.3 
Handling of investigational treatment, exposure and compliance 
Investigational treatment must be received by a designated person at the study site, handled and 
stored safely in a temperature controlled environment, according to label requirements, and kept 
in a secured location, to which only the Investigator and designees have access. Upon receipt, 
all investigational treatment should be stored according to the instructions specified on the 
labels.  
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the appropriate Sponsor Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the investigational treatment but no 
information about the participants, except for the medication number. 
The Investigator or designee must maintain an accurate record of the shipment and dispensing 
of investigational treatment in a drug accountability log. Monitoring of drug accountability will 
be performed by monitors during site visits, and at the completion of the trial. Participants 
allocated to Cohort II (CNP 520 or matching placebo) will be asked to return all unused 
investigational treatment and packaging at each study visit and at the end of the study, or at the 
time of discontinuation of investigational treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all unused investigational treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the site monitor or to the address provided in the 
Investigator file at each site. 
Compliance will be assessed for study participants in Cohort II by the Investigator and/or study 
personnel at each visit as described above. 

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5.5.4 
Instructions for prescribing and taking investigational treatment 
Cohort I (CAD106 or placebo) 
A Pharmacist, or qualified person for handling medication as per local law, will perform the 
reconstitution of the CAD106 lyophilizate or matching placebo powder with water for injection, 
and mixing of the reconstituted solution with Alum according to the treatment arm assigned by 
central randomization, and managed via IRT.  
Detailed guidance for reconstituting the CAD106 lyophilizate, mixing with adjuvant, preparing 
and injecting the investigational drug will be provided in the Medication Manual. 
The Pharmacist will provide the reconstituted syringe with the assigned study medication to the 
Study Nurse for i.m. injection to the participant. The total volume injected for the 450 µg dose 
of CAD106 or placebo with Alum 450 µg will be of 0.90 mL per injection. 
Each participant is scheduled to receive at most 33 i.m. injections of CAD106 or placebo with 
Alum, at Baseline, weeks 7, 13, 26, and quarterly thereafter until the last injection 3 months 
prior to completion of Treatment Epoch.  
Study medication administration will take place under ambulatory conditions at the study center. 
The study drug must be administered where emergency resuscitative equipment and personnel 
trained in the management of anaphylaxis are immediately available to treat any systemic 
reactions under the direct supervision of a physician. The injection will be performed 
intramuscularly on the upper arm or gluteus. The location of each injection should alternate 
from the previous injection. Details of the injection (date, time, and location) will be entered on 
the Drug Administration Record pages of the eCRF. 
Prior to the first injection at Baseline, all inclusion/exclusion criteria will be checked by the 
Investigator. Prior to each of the following injections, the pre-dose assessment results 
(physical/neurological assessments, vital signs, laboratory test, and last MRI results) will be 
reviewed. In case of fever or abnormal findings, the injection should be postponed as specified 
in Section 5.5.5. In case of SAEs (see Section 13), the Investigator will conduct additional 
appropriate investigations (including lumbar puncture and/or MRI, as appropriate) prior to 
proceeding with the next injection. 
The first record into the participant eDiary will be completed at the site, before the participant 
leaves the study center (see Section 6.5.7), to ensure understanding and access to the eDiary. 
After each injection, vital signs will be measured at 30 (±5) and 60 (±10) minutes post-dose. 
Thereafter, the participant will be allowed to leave the site once the Investigator or a designee 
with adequate clinical experience (e.g. co-Investigator, nurse), has checked the participants 
condition and confirmed there are no clinical findings precluding their discharge. 

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In case of vaccination (e.g. flu, herpes zoster) within two weeks of the next scheduled injection 
in Cohort I, the injection of CAD106 or placebo should be held until two weeks after the 
vaccination but no later than four weeks after scheduled injection date, in accordance with the 
defined allowable visit windows. Similarly, in case of fever, signs of inflammation on 
laboratory tests, abnormal physical/neurological examinations (including signs or symptoms of 
infections such as colds, urinary tract infections, cough, etc.), the injection should be postponed 
until recovery and no later than four weeks after scheduled injection date. 
In case an injection is postponed for reasons described above, or is missed for any reason for 
more than four weeks after the scheduled injection date, it should be skipped and treatment 
should resume at the next regularly scheduled injection.  
Dose adjustment of CAD106 or Alum is not permitted. 
Cohort II (CNP520 or placebo) 
Dose adjustments of CNP520 are not permitted by the site or participant.  
In case a daily dose was omitted, it can still be taken until approximately 6 hours after the usual 
daily intake time, otherwise it should be skipped and treatment resumed next day at regular time.  
In the case that the timing of the site visit deviates from the regular time that the participant 
takes the study medication, the study medication can still be administered at the site visit if it is 
within ±6 hours of the usual time, i.e. the dose can be given 18 to 30 hours after the previous 
dose.   
If the DRM is activated for a weekly administration and a weekly dose is missed, it can still be 
taken within 3 days (72 hours) of the missed regular weekly dosing day. Otherwise, the dose 
should be skipped and treatment resumed at the regular day of the next week. At scheduled 
visits every 3-months, the weekly dose should be withheld until the site visit occurs.  In case 
that one or more dose(s) is missed, study drug treatment should resume as soon as possible. 
Any missed doses must be recorded in the Dosage Administration eCRF page. Refer to Section 
5.5.9 for reasons to discontinue or suspend study treatment. 
Study treatment can be suspended temporarily for the following reasons: 
• participant no longer has a study partner for a period of > 3 months; when the replacement 
study partner is identified, study treatment can be resumed for the participant 
• during the time the participant is taking medications listed in Table 5-2 leading to 
temporary suspension of investigational treatment (e.g. for an acute condition) 
• condition/decision leading to suspension of study treatment at any time for any reason 
• participant’s request to suspend study treatment temporarily 
Study treatment can be resumed at any point later in the study after the condition above has 
resolved, and participant attended the scheduled visits / assessments per protocol during the 
duration of the suspension. 
5.5.6 
Rescue medication 
No medication is currently available for treating preclinical AD. Following randomization, the 
investigator should avoid initiating a symptomatic treatment (such as ChEIs or memantine) until 

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Cohort 
Medication 
Action to be taken during 
treatment phase 
 
Strong CYP3A inhibitor (e.g. clarithromycin, 
grapefruit juice,  itraconazole)   
Drugs with a narrow therapeutic index (TI) 
known to be primarily metabolized by CYP2C 
(e.g. warfarin) or CYP3A (e.g. cyclosporine, 
ergotamine, fentanyl) isoenzymes, and sensitive 
Pgp substrates (e.g. digoxin, talinolol). 
Acute use: Suspend 
investigational treatment; continue 
monitoring the participant at 
scheduled study visits, resume 
investigational treatment upon 
discontinuation of the drug.    
Chronic use (>3 months): 
Discontinue investigational 
treatment; continue monitoring 
participant at scheduled study 
visits until PPW or EoS. 
Both Cohort I and 
Cohort II 
Any drug or treatment known for its potential to 
cause major organ system toxicity, i.e. drugs 
that require monitoring of a specific organ or 
body fluid. Examples include but are not limited 
to clozapine, cancer medical treatment like 
tamoxifen, systemic immunosuppressive drugs 
like methotrexate or interferon, or other 
immunossuppressive biological medicines for 
rheumatic diseases or multiple screlosis  
Discontinue investigational 
treatment, continue monitoring 
participant at scheduled study 
visits until PPW or EoS 
 
CNS active drugs including drugs associated 
with abuse, e.g. methylphenidate, 
amphetamine, atomoxetine or modafinil, unless 
otherwise specified in Table 5-3 
Acute use: Suspend 
investigational treatment; continue 
monitoring the participant at 
scheduled study visits, resume 
investigational treatment upon 
discontinuation of the drug.  
Chronic use: Discontinue 
investigational treatment; continue 
monitoring participant at scheduled 
study visits until PPW or EoS. 
   EoS = End of Study; PPW = Premature participant withdrawal 
Parenteral immunoglobulin preparations, blood products, plasma derivatives, and certain CNS-
active agents are restricted as described in (Table 5-3). 
No medication is currently available for treating worsening of symptoms in preclinical AD. 
Following randomization, the Investigator should avoid initiating symptomatic treatments (such 
as ChEIs or memantine) until worsening has been confirmed as meeting criteria for dementia 
due to AD (McKhann 2011). Symptomatic treatments for AD (such as ChEIs or memantine) 
can be prescribed as per standard of care, in addition to the investigational treatment. Once these 
medications are introduced, their dosage should not be adjusted in the 6 weeks preceding a 
clinical evaluation. 
Table 5-3 
Restricted treatments 
Cohort 
Medication 
Restrictions / action to be taken during treatment 
phase 
Cohort 1 only 
 
 
Vaccination (e.g. flu shot) 
Postpone injection to allow 2 weeks lag from the 
vaccination no later than 4 weeks after scheduled 
injection date, in accordance with the defined visit 
windows 
Antibiotics or antiviral 
Postpone injection according to Section 5.5.5 

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Acute use of immunosuppressive 
therapies such as systemic 
corticosteroids 
In case of treatment within two weeks of the next 
scheduled injection, the injection of CAD106 or placebo 
should be delayed until appropriate medication 
washout, but no later than four weeks after scheduled 
injection date, in accordance with the defined allowable 
visit windows. 
Parenteral immunoglobulin 
preparation, blood products, 
and/or plasma derivatives 
Postpone injection according to Section 5.5.5 
Direct Oral Anticoagulants 
(DOAs) 
Allowed if DOA dosage is adequate to control their 
coagulation (including appropriate prothrombin  
laboratory test and/or clinical judgment, as required) 
Both Cohort 1 
and Cohort 2 
Cholinesterase inhibitors or 
memantine (permitted only after 
diagnosis of dementia due to AD 
and not during the preclinical or 
MCI stage) 
If initiated during the study, maintain a stable dose in 
the 6 weeks prior to clinical evaluations  
Other anti-coagulants (non-
coumarin related) 
Other anti-coagulant treatments are allowed.  However, 
when appropriate, review the International normalized 
ratio (INR) level and adjust dosage according to the 
prescribing information.  
Sedative hypnotics  
Will be allowed if, in the opinion of the Investigator, use 
does not constitute abuse, does not affect cognition 
AND participants are currently treated with a stable 
regimen (defined as no change to the participant’s 
medication intake pattern rather than adherence to the 
prescribed regimen) for at least 12 weeks prior to 
randomization. 
If initiated during study, maintain a stable regimen 
(including in the 6 weeks prior to clinical evaluation).  
Resting state fMRI need not be performed during MRI 
examinations if taken chronically. 
If taken as-needed, these must be withheld for 72 hours 
prior to cognitive assessments, FDG PET scan or/and 
fMRI (as applicable). 
Opioid-containing pain 
treatments (e.g., codeine, 
morphine, hydromorphone, 
oxycodone, propoxyphene and 
its variations, and combination 
products that contain a narcotic) 
Chronic use (>3 months) is exclusionary.   
Acute use for temporary conditions is allowed if, in the 
opinion of the investigator, use does not constitute 
abuse and does not affect cognitive testing. 
Resting state fMRI need not be performed during MRI 
examinations unless taken as-needed. 
If taken as-needed, these must be withheld for 72 hours 
prior to cognitive assessments and/or fMRI (as 
applicable). 

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Pregabalin, and gabapentin 
(when used for neuropathic pain 
and/or postherpetic neuralgia 
and/or fibromyalgia and/or 
restless leg syndrome) and 
pramipexole, ropinirole and 
rotigotine  (when used for 
restless leg syndrome) 
Will be allowed if, in the opinion of the investigator, use 
does not affect cognition (for example, because of 
excessive somnolence and/or dizziness) AND 
participants are currently treated with a stable regimen 
(defined as no change to the participant’s medication 
intake pattern) for at least 12 weeks prior to 
randomization. 
If initiated during study, maintain a stable regimen 
(including in the six weeks prior to clinical evaluation). 
Selective serotonin re-uptake 
inhibitors (SSRIs, e.g. 
paroxetine, sertraline, citalopram, 
escitalopram), serotonin 
norepinephrine re-uptake 
inhibitors (SNRIs, e.g. 
venlafaxine, duloxetine), atypical 
antidepressants such as 
vortioxetine, antipsychotics, and 
low dose tricyclic 
antidepressants. 
Will be allowed if, in the opinion of the Investigator, use 
does not represent an exclusionary condition (for 
example, active major depression) AND provided 
participants are currently treated with a stable regimen 
for at least 12 weeks prior to randomization. 
If initiated during study, e.g. for mood stabilization, 
maintain a stable regimen in the 6 weeks prior to 
clinical evaluation. 
 
Use of Tetra-Hydro-Cannabinoid 
(THC) / cannabinoid containing 
substances is allowed if their use 
does not constitute abuse per 
local regulations and/or local 
medical practice. 
Will be allowed if, in the opinion of the investigator, use 
does not represent an exclusionary condition,  does not 
constitute abuse, does not affect cognition AND 
provided participants are currently treated with a stable 
regimen for at least 12 weeks prior to randomization. 
If initiated during study, e.g. for mood stabilization or 
pain, maintain a stable regimen in the six weeks prior to 
clinical evaluation.  Resting state fMRI need not be 
performed during MRI examinations unless taken as-
needed. 
If taken as-needed, these must be withheld for 72 hours 
prior to cognitive assessments and/or fMRI (as 
applicable). 
5.5.9 
Discontinuation of investigational treatment 
Participants may voluntarily discontinue the investigational treatment for any reason at any time. 
In case of permanent study treatment discontinuation, participants are encouraged to continue 
attending study visits and remain in the study. IRT should be notified of permanent treatment 
discontinuation so that no more drug resupplies are planned for this participant. 
Participants who progress to MCI/dementia due to AD should continue on their assigned 
investigational treatment. The Investigator should discontinue the investigational treatment for 
a given participant if, overall, he/she believes that continuation would be detrimental to the 
participant’s well-being.  
Investigational treatment may also be discontinued at the individual or study level, following 
regular safety evaluations or futility analysis review by the DMC.  
The following circumstances will require stopping further investigational drug administration, 
in the respective participant, as assessed by the Investigator: 
• In the case of progression to late-moderate or severe dementia or loss of capacity to 
consent, the participant should be discontinued from the study 

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• Withdrawal of study consent (participant wish) (Section 5.5.10) 
• In the unlikely event of pregnancy  
• Use of prohibited treatment leading to discontinuation as per Table 5-2 or meeting criteria 
for treatment discontinuation with restricted medications listed in Table 5-3, in the 
corresponding cohort 
• Any other protocol deviation that results in a significant risk to the participant’s safety 
• Meeting the criteria for discontinuing the investigational treatment due to: 
• Clinically notable SAEs that require discontinuation of treatment (Section 13.1) 
• Other clinically notable findings including symptomatic ARIA-E or ARIA-H for 
Cohort I (Section 13.2) 
• Diagnosis of dementia not due to AD after confirmation of diagnosis by the 
Progression Adjudication Committee (PAC)  
• Clinically significant results of safety assessments deemed to be related to 
investigational drug that might put the participant at risk, including, but not limited to: 
MRI, clinical chemistry, hematology, vital signs, ECG (Section 13.3, Section 13.4).  
In addition, investigational treatment should be suspended for participants when: 
• Study partner is not available for a period of more than 3 months. When available again or 
a replacement study partner is identified, study treatment can be resumed 
• They are taking medications listed in Table 5-2 for an acute condition 
The appropriate personnel from the site and the Sponsor will assess whether 
study/investigational treatment should be discontinued for any participant whose treatment code 
has been broken inadvertently for any reason. 
Participants who discontinue the investigational treatment should NOT automatically be 
considered withdrawn from the study unless there is explicit withdrawal of study consent from 
the study. They can continue attending study visits according to protocol assessments as 
planned in Table 6-2 to 6-4. If they fail to return for these assessments for unknown reasons, 
every effort (e.g. telephone, e-mail, and letters) should be made to contact them as specified in 
Section 5.5.11.  
For participants who discontinue study injections in Cohort I for any reason, Extended SAE 
collection for safety monitoring is required to continue per protocol until a minimum of one 
year has elapsed since the last injection. If the participant does not attend the scheduled visits, 
quarterly telephone calls to detect SAEs will be placed to monitor safety until 12 months after 
the last injection has elapsed (see Section 6.2). 
This strategy will allow monitoring safety in the participants in the initial phase of induction of 
the immune response in the first year of treatment, as well as over the 12 months after their last 
injection where antibody titers are expected to decline towards Lower limit of quantification in 
a large proportion of participants. 
Participants enrolled in Cohort II (CNP520 or placebo) should be followed for 3 months 
(approximately 12 weeks) after their last intake of investigational treatment (once it is 
determined as a permanent study drug discontinuation) or PPW visit performed at which time 
they will perform the Follow-up visit assessment (EoS).  

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The Investigator must also contact the IRT to register the participant’s discontinuation from 
investigational treatment, and also register the visits with no treatment dispensed until 
PPW/Treatment Epoch Completion (TEC) and EoS.  
Re-randomization due to early termination of either cohort 
Participants who discontinued the investigational treatment will not be eligible for renewed 
access to investigational treatment, unless the cohort they were originally randomized to is 
terminated early, in which case they may be eligible to be randomly reassigned and treated in 
the other cohort. This may apply specifically in case CAD106 meets the futility criteria after 
the CNS activity futility analysis. However, consideration for lowering the CNP520 dose will 
be given before terminating Cohort II; this decision will be made with all available data for 
CNP520 and in agreement with the DMC. 
Re-randomization may also occur after the recruitment in a given cohort is complete, following 
an appropriate washout period: 
• Cohort I: for CAD106, Aβ-specific antibody titers should be below serological responder 
threshold (Aβ-specific IgG titers ≥26.8 units)  
• Titers should be drawn every 3 months (i.e. at the study visits as the participants are 
encouraged to continue with the assessment schedule) for those participants that 
desire to be considered for re-randomization to Cohort II.   
• Participants who choose not to be considered for re-randomization, will have end of 
treatment date confirmed when titers are below threshold, unless they prematurely 
discontinue. 
or  
• Cohort II: for CNP520, last dose should have been administered at least 30 days or 5 half-
lives ago, whichever is longest.  
If there are specific safety eligibility criteria for the ongoing cohort, participants will need to be 
rescreened and meet the criteria to be eligible for the ongoing cohort (beside age>75 will be 
waived). Following random reassignment, in the case that recruitment for the cohort has already 
been met, participants will receive study drug for the remaining duration that the treatment 
epoch is ongoing, (i.e. treatment duration may be less than 5 years for some re-randomized 
participants). Data handling from these participants will be described in detail in a protocol 
amendment that would be required in this situation (see details in Section 5.5.14).  
5.5.10 
Withdrawal of study consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent from the study is defined as when a participant: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 

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and 
• Does not allow analysis of already obtained biologic material  
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.  
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
5.5.11 
Loss to follow-up 
For participants with unclear status because they fail to appear for study visits without stating 
an intention to withdraw, the Investigator should show “due diligence” by contacting the 
participant, study partner, family, or family physician, as agreed in the informed consent, and 
by documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be formally considered lost to 
follow-up until the time for his/her scheduled EoS visit has elapsed. 
5.5.12 
Emergency breaking of assigned treatment code 
Emergency treatment code breaks should only be undertaken when it is essential to ensure 
participant safety. Most often, investigational treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study participant who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the Investigator contacts the system to break a treatment code for a participant, he/she must 
provide the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The Investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the site monitor for the site and the Global 
Trial Lead that the code has been broken. 
It is the Investigator’s responsibility to ensure that there is a procedure in place to allow access 
to the IRT in case of emergency. The Investigator will inform the participants how to contact 
his/her backup in cases of emergency when he/she is unavailable. The Investigator will provide 
the protocol number, investigational treatment name if available, participant’s number, and 
instructions for contacting the Sponsor (or any entity to which it has delegated responsibility 
for emergency code breaks) to the participants in case an emergency treatment code break is 
required at a time when the Investigator and backup are unavailable. 
5.5.13 
Study completion and post-study treatment 
A participant will be considered a completer when he/she has completed all visits up to the 
Month 60 scheduled visit, either on/off treatment, including follow-up visits where required. 
The study will be considered completed when both the following conditions are met: 
1. All individual participants have completed their month 60 scheduled visit 
2. Target number of events has been reached in both cohorts 

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Upon study completion (assuming futility for one or both investigational drugs was not met), 
participants may have the opportunity to enter an extension under a separate study, if eligible. 
All SAEs, deemed suspected to study medication or not, which are reported during the Extended 
SAE collection for Cohort I will be collected in the Novartis safety database but will not be 
recorded in the clinical study data after the database lock (see reporting process in Section 7.2.2). 
Assuming the target number of events was reached, the Treatment Epoch will complete at TEC 
visit within 3 months of when the last participant randomized and still receiving study treatment 
reaches month 60. This timing will be closely monitored and all sites will be notified in the 
preceding 6 months to schedule the TEC visit. All assessments described in the TEC column 
will be completed unless they were performed in the timeframe specified in footnotes 18 and 
22 in Table 6-4.  
5.5.14 
Early study termination 
Novartis may terminate the trial or Cohort for reasons related to the benefit risk assessment of 
treatment for participants in the study, or for regulatory or medical reasons (including slow 
enrolment) in consultation with the DMC. In the event that the study or either Cohort is 
terminated early, an amendment will be submitted for approval to Health Authorities and the 
IRBs/ECs. The amendment will include information on reasons for the early termination and 
the process to prematurely withdraw the participants (or, in the case of a terminated Cohort, a 
detailed benefit-risk assessment of the administration of CAD106 in patients previously treated 
with CNP520 and vice-versa and the process to re-randomize to the other Cohort). In general, 
the participant should be seen as soon as possible and assessed as a prematurely withdrawn 
participant from the study. The withdrawal process may include additional procedures to be 
followed, in order to ensure that adequate consideration is given to the protection of the 
participant’s interests.  
6 
Visit schedule and assessments 
6.1 
Pre-screening Epoch and Genetic Disclosure Follow-up 
assessments 
Individuals who present to the study site (with or without prior genetic information) will sign 
Informed consent #1B before Pre-screening assessments are performed. For those without 
knowledge of APOE genotype, all pre-disclosure clinical scales will be collected by study 
personnel, who are blinded to the participant’s APOE genotype until disclosure. The study 
personnel will communicate results of the Pre-screening assessments to the counselor prior to 
disclosure. Only the genetic counselor, (or such equivalent according to local regulations (e.g. 
trained psychologist, study nurse or clinician) will have access to the individual genotype after 
the genetic counseling was conducted in order to proceed with disclosure of the participant’s 
APOE genotype. The counselor will use the provided APOE risk information and talking points 
standardized across all sites. It is the responsibility of the investigator to confirm that the 

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Cohort II (CNP520 or placebo) 
Follow up 
Visit Name 
mEOS15 
Visit Numbers 
401 
MCI/dementia diagnostic verification 
 
Physical / Skin/ Neurological exam12 
 
ECG26 
 
Safety laboratory tests 
 
RBANS (APCC), Raven’s (APCC), MMSE7 
 
CDR, ECog, 
7, 8 
 
Body Weight  
X (only if on-site visit) 
 23 
 
Adverse events / Concomitant medications 
X  
eC-SSRS 
X (only if on-site visit) 
TEC =Treatment Epoch completion; PPW= Premature Participant Withdrawal; APCC = API Preclinical composite cognitive; CDR = Clinical dementia rating; C-SSRS = 
Columbia Suicide Severity Rating Scale; ECog = Everyday Cognition scale; PRO = Patient reported outcome; 
; MCI = Mild cognitive 
impairment; MedDRA = Medical Dictionary for Regulatory Activities; MFAS= Modified full analysis set; MMRM = Mixed model repeated measure; MMSE = Mini‑Mental 
State Examination; MRI = Magnetic resonance imaging; 
; PET = Positron emission tomography; RBAN =Repeatable 
Battery for the Assessment of Neuropsychological Status. 
1. 
Note: On treatment days, all assessments should be performed prior to dosing unless otherwise noted. Participants should be seen for all visits on the designated week 
or within a window of ±1 week for visits up to week 26 and ±4 weeks for visits beyond week 26. Obtain informed consent prior to conducting any assessments. Informed 
Consent Forms must be signed by the participant and study partner.  
2. 
Ensure participant has signed the required informed consent for voluntary participation for the PET scans (Year 2 and Year 5 Amyloid PET, tau PET (at subset of sites) 
 
, collection of CSF (exception: mandatory at screening if amyloid PET is not feasible) and blood for biomarkers and blood for DNA before performing these assessments. 
Although part of the screening period, eligibility is not dependent upon PET (amyloid, tau 
) results.  In locations where compliance with total radiation exposure limits could 
be of concern, voluntary tau PET scans are to be prioritized over voluntary FDG PET scans. 
3. 
All PET scans, as well as biomarker collection (CSF and blood) should be performed after the participant is deemed eligible on the basis of all other screening assessments, including 
the MRI. Site should allow sufficient time to receive MRI safety interpretation prior to performing any PET scan or lumbar puncture.  
4. 
Review study criteria to ensure that the participant still qualifies to participate in the study.  
5. 
All baseline assessments must be completed before first administration dispensing of investigational treatment (Day 1). 
6. 
Sample should be taken on the same day consent was obtained to ensure adequate time for testing and reporting of results. Safety laboratory tests at screening include urine drug 
test for eligibility and serology for HIV and Hepatitis B and C (verified as described in Section 6.5.4) and urine sample for analysis of creatinine, albumin and total protein and their 
respective and ratios. PT/INR also required for participants that consent to Lumbar Puncture.  

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7. 
Cognitive assessments should not be administered to the participant immediately after any potentially stressful procedures (e.g. blood draws, LP, imaging). Also, participants should 
not perform these assessments while fasting. For each participant, best efforts should be exerted to perform subsequent assessments at the same time of day as the baseline 
/screening assessments. MMSE at V201 may be skipped if the V101 MMSE was administered by a certified rater and in the previous 3 months  (refer to Section 3.1.2.1) 
8. 
Scale requires presence from the study partner: ECog is self-reported by the Informant, and CDR needs to be on-site for audiorecording required for central review. However, 
 
 only can be collected over the phone. 
9. 
, tau PET and amyloid-PET should be performed according to instructions from the Imaging Manual. For each participant, the same PET tracer should be used at all 
amyloid PET scans, and best efforts should be exerted to perform subsequent PET scans at the same time of day as screening scan (note that results of the tau PET is not required 
for eligibility. In exceptional cases related to documented scheduling issues, tau PET scan can be performed within a maximum 4 weeks after the randomization date.). In case 
sedation is required for Amyloid PET scans, allow for 72 hours before cognitive assessments. No sedative are allowed in the 72 hours prior to 
.  If amyloid 
PET is not feasible, then CSF amyloid assessment is mandatory at Screening (Refer also to Footnote #2.) 
.   
11. LP should be performed preferably in the morning and at the same time of the day before dosing. A light breakfast is allowed and should be taken 2 hours prior to LP, however, 
fasting is not prohibited. Participants will be required to stay in the clinic for approximately 2-hour after the LP for safety follow-up. For each participant, best efforts should be exerted 
to perform subsequent LP’s at the same time of day as the baseline LP  
12. Assessment to be recorded on source documentation only and will not be entered into the eCRF.  In the case of findings): record corresponding adverse event. In case of 
dermatological findings during skin examination for Cohort II: take a picture for central dermatological reading; if participant is at home, arrange for site visit and perform unscheduled 
skin examination.  
13. Cohort I: During visits where investigational treatment is administered on site, vital signs should be taken prior to dosing, and then 30 minutes post-dose (±5 minutes) and one hour 
post-dose (±10 minutes). 
14. Follow-up MRI to be scheduled 2 weeks before each respective visit, to ensure that safety assessments from the central reader are available before the scheduled drug 
administration. In case sedation is required allow for 72 hours before cognitive assessments. 
15. End of Study Follow-up visits are to be scheduled 26 weeks after last injection of CAD106 for Cohort I and for Cohort II : within 12 weeks after mTEC visit. Can be converted to phone 
call in case of logistical constraints. 
16. The Screening Epoch assessments will be performed over a maximum of 12 weeks  
17. Visit is only applicable to Cohort I (CAD 106 or matching placebo).  These visits should always be as close as possible from 2 weeks (14 days) from the actual day of last injection. Do 
not calculate back in reference to baseline. 
18. Participants who withdraw prematurely during the course of the trial will be asked to come to the site for a PPW visit. The same procedures are expected at PPW as for the Treatment 
Epoch Completion visit (TEC). For Cohort I only: Conditional assessments to be repeated upon PPW/TEC: MRI and blood AD biomarkers if last one were more than 6 months ago, 
tau PET, amyloid PET scans and Lumbar Puncture if last one was more than 18 months ago with in addition, PET scans, CSF and blood for biomarkers to be performed on 
participants who consented at screening if PPW occurs before year 5 and at least 18 months after previous biomarker assessments (e.g. 18 months after baseline or year 2). For 
Cohort I, this visit should always be scheduled at least 3 months after last injection of study medication. 
  
  
21. For Cohort I: Extended SAE collection for 1 year after the last study visit. Safety telephone call to be placed by the site to the participant, his caregiver and/or his general practitioner 
at 3, 6, 9 and 12 months after the last study visit (EoS or PPW). Any SAE (whether suspected to be related to study medication, or not) will be recorded (see Section 7.2.2).  
22. Treatment Epoch Completion (TEC) after early study termination, all ongoing participants will come to their next scheduled visit to perform the TEC visit. In Cohort II, the tau PET and 
Amyloid PET scans are cancelled at the mTEC. 
23. In Cohort II, Aβ1-40 in plasma will be assessed at every 
 time-point.   
24. In Cohort II, at Visit 226 (Week 416): last dose administered; no study medication will be dispensed.  

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25. ECG at Visit 303 (week 13) is only applicable to Cohort II. 
26. All ECGs to be taken in triplicate ECGs. During the treatment period, ECGs to be taken approximately 2.5 hours after treatment administration at the site (see Section 6.5.5) 
27. Last drug administration (Cohort I) or dispensing (Cohort II) will be at the visit which is 3 months prior to the planned Treatment Epoch Completion visit. 
28. Screening genotyping can be waived if the participant was genotyped under ICF#1 Part1A and using a generation program Covance buccal swab kit.  
29. Tau PET not performed in Germany 
30. Interim check in at Week 7 to assess compliance, 

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6.3 
Screen failures, demographics/other Baseline characteristics  
6.3.1 
Information to be collected on screening failures 
All participants who have signed Informed Consent #2 at entry in the Screening Epoch but 
screen failed and are not randomized, will have the study completion page for the previous 
Epoch, demographics, screening inclusion and exclusion criteria, and SAE data collected. AEs 
related to the genetic disclosure will be captured in the eCRF. AEs that are not SAEs and not 
related to the genetic disclosure will be followed by the Investigator and collected only in the 
source data. 
In addition, results from safety MRI, volumetric MRI, and Amyloid PET standardized uptake 
ratio (SUVR) obtained during the Screening period will be collected also for participants who 
screen fail when available. 
6.3.2 
Demographics/other Baseline characteristics 
Participant demographic and Baseline characteristic data to be collected on all participants 
include: date of birth (year only, where applicable), sex, race, ethnicity, referral source, family 
history of AD, and years of education. 
Relevant medical history/current medical conditions present before signing the Informed 
consent #2 will be recorded, preferably as diagnoses instead of symptoms, when possible. Refer 
also to Table 7-1.  If the condition was identified/diagnosed during Screening (after ICF#2), 
this should be recorded as an AE (i.e. does not have to be related to Genetic Disclosure).   
In addition, all scheduled assessments during the Pre-screening and the Screening on-site visits 
will be collected and used as Baseline reference vs. post-randomization measures. In case an 
assessment is repeated, the latest one will be used as the Baseline. 
Investigators will have the discretion to record abnormal examination findings on the medical 
history eCRF that, according to their judgment, the examination abnormality occurred prior to 
the Informed consent #2 signature. 
The study partner characteristics will be collected on the Virgil® tablet. It will capture the study 
partner’s relationship with the participant and frequency of contact with the participant. 
Temporary unavailability of or changes in study partner will also be recorded on the eCRF. 
6.3.3 
Assessment of unimpaired cognition at Screening: Diagnostic 
Verification Form 
Criteria for diagnosis at screening will be assessed by the investigator as described in Section 
6.4.1 and will complete the diagnostic verification form (DVF) on the Virgil® tablet. The DVF 
must be completed as specified in Table 6-2. It is recommended to complete the DVF one week 
after CDR and RBANS have been completed to ensure centralized review by the cognitive 
vendor has occurred, when applicable. The feedback from centralized review must be addressed 
and scores adjusted accordingly by the respective raters and before the PI or his/her delegate 
completes the DVF (note DVF should not be completed by the CDR rater). 

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Diagnostic has to be verified as unimpaired cognition before invasive procedures such as MRI 
or later amyloid assessments such as PET/LP.  
6.3.4 
Other screening considerations  
Scheduling of the screening activities should be closely monitored when approaching the 
completion of recruitment, to ensure the participant can still be randomized before enrollment 
is completed. 
A missing or rescheduled assessment or combination of screening steps may be permitted if not 
impacting the 12-week timeline for assessment of eligibility criteria.  
Participants who fail eligibility during the screening process for a temporary condition (e.g. 
physical, concomitant medications, etc.) will be allowed to be re-screened at a later stage. When 
all inclusion and exclusion criteria will have to be re-verified a new participant number will be 
assigned. A participant initially excluded for a condition no longer exclusionary upon a protocol 
amendment can also be re-screened.   
6.3.5 
Screening extension beyond 12 weeks 
The total duration of 12 weeks for screening assessments may be extended only if the following 
conditions are met: 
• The participant has not failed any eligibility criteria (if so, see below for potential re-
screening in case of temporary conditions). 
• Any screening (including Baseline) assessment supporting eligibility criteria must be 
collected within 12 weeks before the date of randomization. Assessments that are 
collected again during screening/baseline per Table 6-2, can be used to verify eligibility in 
the 12-week timeframe, with an exception for MRI that can support eligibility if collected 
within 16 weeks before randomization. Screening results from amyloid PET scan/lumbar 
puncture (performed under this study) to verify brain amyloid levels are valid without any 
time limitation (i.e. 12 week period) and do not need to be repeated before randomization. 
This is relevant in the event of logistical issues related to scheduling of imaging (MRI, 
PET scans) or lumbar puncture. 
• For cognitive scales, CDR and RBANS are required for eligibility. While RBANS is 
repeated at both screening and baseline, CDR is only collected once at screening and must 
be collected within the 12 weeks prior to randomization.  
• In such case, the corresponding repeat CDR will be collected in Virgil ideally 5 days 
before Randomization to allow for centralized review (if applicable). On the same day, the 
cognitive scales scheduled for Baseline should be administered (including RBANS Form 
A to verify the DMI score for inclusion). This approach leads to a split of assessments 
from Baseline on 2 different calendar days. Before randomization, the Diagnostic 
Verification Form (DVF) must be updated with the corresponding CDR and RBANS 
Delayed Memory Index (DMI) scores to verify eligibility. 
Also see Section 6.4.2 for APCC requirements during Screening. 

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6.4 
Efficacy 
All scales listed and described in this section are administered directly on Virgil tablet used as 
electronic Source Document. Various clinical and participant/informant reported scales will 
assess changes in cognition, functional status, and neuropsychiatric symptoms: RBANS, 
Raven’s Progressive Matrices, MMSE, CDR, ECog, 
, 
 
. They will be performed prior to randomization, with the last assessment being used 
as the baseline reference score. 
Cognitive testing must be administered by a clinician/rater certified by the Rater Training 
Program of the dedicated Cognition vendor. The selected raters will complete a pre-
qualification survey. Criteria for granting “pre-qualification” status is based on a rater’s 
education, experience with the population and their prior experience with each scale. A rater’s 
final qualification will require training on the Virgil® system, and specific training for the 
selected scale.  
When possible, the same evaluator should administer a given test across all visits for a given 
participant. The initials of the evaluator will be collected for all primary efficacy scales on the 
Virgil® tablet. The CDR rater should be different from the evaluator administering the other 
clinical scales listed above. The CDR rater for a given participant will have no access to either 
the cognitive or other test results (i.e. using a separate user ID on the Virgil® tablet).  The 
physician completing the diagnostic evaluation form should not have rated the CDR at that visit. 
If not available from previous 3 months documentation, the initial MMSE at the first Pre-
Screening visit may be administered by a non-certified rater using a paper version of the MMSE 
(not transcribed to Virgil in such case). 
Instructions as to how to perform these assessments and their optimal sequence will be provided 
in the rating scales administration information from the Cognition vendor. The scales used for 
the primary and key secondary endpoints (i.e., MMSE, RBANS, CDR) will undergo a central 
review based on an algorithm implemented by the Cognition vendor. The central review is 
intended to ensure enrollment of participants who fit protocol parameters, to maintain high level 
of accuracy and reliability of endpoints by review of divergent scoring across sites or between 
raters. All data from the clinical scales will be recorded on the Virgil® tablet, collected in the 
database from the Cognition vendor and transferred to Novartis, except for the audio recording 
that will not be transferred to Novartis.  
Completed questionnaires will be reviewed and examined by the investigator for responses that 
may indicate potential adverse events (AEs) or serious adverse events (SAEs). The investigator 
should review not only the responses to the questions in the questionnaires but also any 
unsolicited comments from the participant. If AEs or SAEs are confirmed, then the physician 
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6.4.1 
MCI due to AD or dementia due to AD (MCI/dementia) criteria 
assessment 
The core clinical diagnostic criteria proposed by the National Institute on Aging - Alzheimer’s 
Association Working Group will be used for diagnosis of MCI (Albert et al 2011) or dementia 
(McKhann et al 2011). Application of these criteria requires the judgment of an experienced 
clinician, taking into account clinical, cognitive, and functional criteria that define these 
syndromes. 
Criteria for MCI due to AD will be defined by the following: 
1. Clinical and cognitive criteria  
a. Concern regarding a change in cognition  
b. Impairment in one or more cognitive domains 
c. Preservation of independence in functional abilities 
d. Not demented 
2. Examine etiology of MCI consistent with AD pathophysiological process: 
a. Rule out vascular, traumatic, medical causes of cognitive decline, where possible  
b. Provide evidence of longitudinal decline in cognition, when feasible 
The MCI diagnosis is expected to be the first diagnosis for the majority of the participants. With 
the six month visit intervals for cognitive assessments and potentially rapid progression in 
APOE4 HMs, it is possible that some participants may be diagnosed directly with dementia. 
The differentiation of dementia from MCI will rest on the determination of whether or not there 
is significant interference in the ability to function at work or perform usual daily activities; 
based on clinical judgment of the individual circumstances of the participant, the review of 
relevant scales using both participant and informant component scores, and the description of 
daily activities of the participant obtained from the participant and from the study partner. 
Criteria for diagnosis will be assessed by the Investigator based on his or her overall clinical 
judgment and supported by review of measures of cognitive function (RBANS, MMSE), global 
measure of function/cognition (CDR-SOB), measures of daily function and measure of 
Subjective/observer memory concerns (ECog – both informant [study partner] and participant 
versions), Baseline data and other assessments (e.g. 
, MRI or other safety tests as 
needed).  
In addition to the diagnosis made by the Investigator, an independent Progression Adjudication 
Committee (PAC) will review all MCI/dementia diagnoses. The PAC will be managed by the 
Cognition vendor. A description of the adjudication process, role and function of the PAC 
members are briefly presented in Section 8.5 and will be described in details in a specific 
charter.   
The adjudication process will be triggered by: 
• A change in diagnostic status as captured on the Diagnostic Classification Form on the 
Virgil® tablet; or 
• Any increase from baseline on the global CDR score until the diagnosis of dementia has 
been established. 

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The final diagnosis will require confirmation at the next protocol-specified cognitive 
assessment visit. Any participant identified as having progressed from normal to MCI due to 
AD or dementia due to AD or any increase on the global CDR score, will have data from both 
the current visit and the next protocol-specified visit sent for PAC review/adjudication.  
If there is a complaint of unexpected cognitive or functional deterioration reported by the 
participant or study partner between 6-monthly cognitive assessment visits, an unscheduled 
visit will be performed. The Investigator will evaluate non-AD related potential causes of 
cognitive decline as appropriate (e.g. Physical/Neurological evaluation, labs, ECG, MRI, 
including unscheduled assessments if needed). Full cognitive assessments and initiation of the 
adjudication process will be conducted at the next scheduled visit. A minimum window of 4 
months from the previous cognitive assessment visit would be required to still fit in the allowed 
+/- 4 weeks window between 2 visits. 
If there is any reason to suspect a non-AD etiology for the participant’s change in diagnostic 
classification, an unscheduled visit may be performed for evaluation of possible non-AD related 
causes of cognitive decline as appropriate. 
A diagnosis of MCI due to AD or Dementia due to AD made at any time other than a 6-monthly 
cognitive assessment visit will not trigger the adjudication process. The process will be 
triggered at the next cognitive assessment visit with the investigator updates the diagnostic 
verification form or the results of cognitive assessments support the diagnosis as described 
above. 
Once the adjudication process is triggered, the change in diagnostic classification must be 
confirmed at the next 6-monthly cognitive assessment visit. Once confirmed, the date of the 
initial adjudicated diagnosis (not the clinical diagnosis in the event it is made between cognitive 
assessment visits) will be used to establish the date for the time to event analysis. 
If the PAC and the Investigator do not agree on diagnosis, the PAC diagnosis will be used for 
analysis purposes. 
The PAC diagnoses will be communicated to the sites.  The date and final diagnosis after the 
adjudication process is completed will be captured in the database and used for analysis. 
No submitted cases will be re-adjudicated unless additional information provided by the trial 
site has a potential impact on the adjudication of the case. 
6.4.2 
API Preclinical Composite Cognitive (APCC) battery 
The APCC score will be derived from the 7 following tests performed as part of the cognitive 
scales administered during the study (see Table 6-2, Table 6-3 and Table 6-4, if applicable) 
• MMSE: 
Orientation to Time 
Orientation to Place 
• RBANS: 
• List Recall 
• Story Recall 
• Coding 

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• Line Orientation 
• Raven’s Progressive Matrices – subset  
All scales used to derive the APCC test score (RBANS, MMSE and Raven’s) will be 
administered twice during the Screening Epoch: first to assess inclusion (Screening) and a 
second time prior to randomization (Baseline pre-dose).  A minimum interval of 4 weeks should 
be respected between two administrations of the APCC scales or CDR. 
Of note: In case a repeat assessment of to confirm unimpaired cognition (Refer to Section 6.1).  
Of note: In case a repeat assessment of CDR and RBANS is required during screening to 
confirm unimpaired cognition (see Section 3.1.2.1), CDR and RBANS can be repeated 5 days  
before the scheduled Randomization (using the Baseline scales that include RBANS Form A, 
and the other APCC scales).  
Refer to Appendix 4 for details on assessment from study partner and conditions of 
administration/presence at visits. 
6.4.3 
Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS) 
The RBANS (Randolph 1998) is a clinical tool that was specifically designed for both 
diagnostic purposes and for tracking change in neurocognitive status over time. One of the key 
design goals of the battery is to detect and characterize the earliest neurocognitive changes 
associated with the earliest stages of dementia. The RBANS has no floor or ceiling effects in 
either cognitive normal older adults or in patients with amnestic MCI, despite the fact that these 
two groups have mean scores on the RBANS nearly two standard deviations apart (Karantzoulis 
et al 2013).  RBANS scores have been reported to be correlated with cerebral amyloid in both 
cognitive normal individuals (Duff et al 2013) and in patients with MCI due to AD (Mukai et 
al 2015).   
The RBANS is relatively brief (< 25 minutes) to administer, has four equivalent alternate forms, 
and 25 linguistically- and culturally-validated translations. The RBANS generates age-adjusted 
index scores for five neurocognitive domains which are used to calculate a Total Scale Index 
score.  
The RBANS is comprised of the following domains, with associated subtests used for Index 
scores: 
• Immediate Memory – List Learning and Story Memory (IMI) 
• Visuospatial/Constructional – Figure Copy and Line Orientation 
• Language – Picture Naming and Semantic Fluency 
• Attention – Digit Span and Coding 
• Delayed Memory – List Recognition and Sum of (List Recall, , Story Recall, and Figure 
Recall; DMI) 

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The test consists of five Sections (orientation, registration, attention, recall, and language) with 
a total score ranging from 0 to 30. A higher score indicates better cognitive function. The 5 sub 
scores as well as the total score will be recorded. 
Although all components of the MMSE will be assessed, for calculation of the APCC test score, 
only the Orientation to Time and Orientation to Place scores from the MMSE (each of which 
ranges from 0 to 5) will be used. 
The initial MMSE at first screening visit may be skipped if documentation of a MMSE 
performed in previous 3 months exists. When administered in the first screening visit, it can be 
done on paper and not uploaded in Virgil if rated by a non-certified rater. 
All other screening, baseline and post-baseline tests will be administered and collected using 
the Virgil® tablet, except for the MMSE drawing and sentence pages that will be paper based. 
Pictures of the drawing and sentence will be taken and uploaded electronically to the tablet.  
6.4.7 
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB)  
The CDR is a global measure that evaluates cognition and functional performance and is widely 
used in clinical research in AD (Morris 1993). The scale assesses six domains: Memory, 
Orientation, Judgment & Problem Solving, Community Affairs, Home & Hobbies, and Personal 
Care. Each domain is assigned a score, which are summed to obtain the sum of boxes (SOB) 
score. 
The necessary information for assessment is obtained through a semi-structured interview of 
the participant and a reliable informant or collateral source (i.e. study partner). Descriptive 
anchors are provided for each score that guide the clinician in making appropriate ratings based 
on interview data and clinical judgment, in order to evaluate the staging severity of the dementia.  
The global CDR scores and CDR-SOB scores will be collected. Global scores range from 0 to 
3, with greater scores indicating greater disease severity. CDR-SOB scores range from 0 to 18 
with greater scores indicating greater disease severity. 
Clinician judgment of MCI or dementia (see Section 6.4.1) and/or a change in the global CDR 
score will trigger the adjudication process. 
6.4.8 
Everyday Cognition Scale (ECog) 
The ECog measures cognitively-relevant everyday abilities comprised of 39 items covering 6 
cognitively-relevant domains: Everyday Memory, Everyday Language, Everyday Visuospatial 
Abilities, Everyday Planning, Everyday Organization, and Everyday Divided Attention (Farias 
et al 2008).  
The questionnaire is a self-reported measure completed by both participant and study partner 
(informant). 
Within each domain, ability to perform a specific task is rated on a six-point scale ranging from: 
1) no difficulty, 2) mild difficulty, 3) moderate difficulty, 4) severe difficulty, or 5) unable to 
do.  

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Preclinical cognitive decline due to AD is expected to be detectable with the proposed APCC 
test score. Decline on the APCC test score will provide a continuous measure of cognitive 
decline associated with progression to the clinical stages of MCI and/or dementia due to AD.  
The APCC battery includes well-established, validated cognitive assessments that are expected 
to begin to decline prior to the onset of MCI or dementia due to AD and continue to decline 
during the clinical course of the disease. The composite is constructed from validated cognitive 
assessments across multiple cognitive domains (e.g., episodic memory, executive function, 
visual-spatial function) that reflect the spectrum of cognitive deficits of AD. Decline in these 
cognitive domains is associated with and predictive of functional decline in AD (Farias et al 
2003). In addition, many of the cognitive domains included in the composite measure have been 
shown to correspond directly to participant and caregiver concerns in early disease (v et al 2014). 
The derivation of the proposed APCC battery and its resulting test score is described Section 
9.4. 
Secondary endpoints are chosen to evaluate the effects of the two selected investigational drugs 
on other clinical aspects of the disease and underlying AD pathology through appropriate 
soluble and imaging biomarkers. 
The ECog combines subjective report of both cognitive and instrumental difficulties of daily 
living obtained from participants, as well as from a study partner who knows the participant 
well, which makes it especially appealing for assessing individuals with preclinical AD and 
those who expected to progress to MCI.  
The long term impact of genetic disclosure is captured using various scales described in Section 
6.1 aimed at assessing psychological impact. 
6.5 
Safety and tolerability 
The current protocol describes general safety and tolerability assessments for both study 
investigational drugs (Cohort I: CAD106 and Cohort II: CNP520).   
Clinically notable test findings are defined in Appendix 1. Only clinically significant 
abnormalities should be reported on the eCRF AE page for any of the assessments listed below. 
6.5.1 
Physical (including skin) and neurological examination  
Physical examinations will be performed by a qualified clinician. They will include an 
examination of general appearance, skin (and skin reactions), neck (including thyroid), eyes, 
ears, nose, throat, lungs, heart, abdomen, back, lymph nodes and extremities and vascular. 
Neurological examinations (in particular, potential signs of adverse immune reaction for 
CAD106/Cohort I (Refer to Section 5.5.6)) will be performed by a qualified clinician. It will 
include mental status, cranial nerve function, function, motor function (tone, strength and 
reflexes), sensory function (small fiber, large fiber and cortical), coordination (cerebellar 
function) and balance/gait.   
Information about both, the physical (including skin) and the neurological examinations, must 
be present in the source documentation at the study site. All significant findings which meet the 
definition of an AE must be recorded on the Adverse Event eCRF page  

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Investigator Guide for interpretation), syphilis and HIV should be performed if not 
available from the past 12 months as is required to confirm eligibility criteria. 
• In addition for participants consenting to the lumbar puncture procedure, prothrombin time 
international normalized ratio (PT/INR) will be measured for assessment of coagulation at 
screening and results required prior to the procedure. 
Hematology 
A standard hematology panel with differential counts will be performed. Hemoglobin (Hb), 
hematocrit, red blood cell count, platelet count, and white blood cell count with differential 
count as well as prothrombin time international normalized ratio (PT/INR) will be measured. 
In case treatment with a DOA is initiated during the study in a participant of Cohort I, additional 
laboratory testing to assess coagulation may be performed as required by the investigator. 
Clinical chemistry 
A standard blood chemistry panel will be performed: Albumin, total protein, alkaline 
phosphatase, total bilirubin, calcium, chloride, sodium, potassium, magnesium, inorganic 
phosphorus, bicarbonate, cholesterol (total / LDL / HDL), triglycerides, creatinine, creatine 
phosphokinase (CPK), gamma-glutamyl transferase (γ-GT), lactate dehydrogenase (LDH), 
lipase, α-amylase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), glycated 
hemoglobin (HbA1c), blood urea nitrogen (BUN), uric acid C-reactive protein (CRP), thyroid 
stimulating hormone (TSH), Vitamin B12 and folate will be measured.  
The creatinine clearance will be estimated from serum creatinine concentrations using the 
Cockroft-Gault formula.  
The results should be available and reviewed before the MRI scans if gadolinium injection is 
required due to findings on the previous MRI scans.  
Urinalysis 
Dipstick measurements for specific gravity, protein, glucose, and blood will be performed at 
the site. In case of clinically significant abnormality, a urine sample will be sent to the central 
lab for analysis of the same parameters and in addition, creatinine, total albumin, 
albumin/creatinine ratio, white blood cells (WBC) and red blood cells (RBC) sediments. 
6.5.4.1 
CSF cell count 
For participants in whom a CNS-related safety concern arises, an aliquot of CSF will be used 
for local measurement of CSF cell counts. Cell counts will include erythrocytes (as an indicator 
of blood contamination) and total white blood cells. The location of the facility where the 
lumbar puncture procedure is done must take into account that samples can only be analyzed if 
processed within two hours at the local laboratory facility. The data will be entered on the 
corresponding eCRF pages. 

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Based on an event rate of 6% for meningoencephalitis as seen with AN-1792, (Orgogozo et al 
2003), the probability of observing at least one case of Aβ-specific T-cell activation in 31 
patients on active treatment, is 85.3%. 
To evaluate T-cell response to the Aβ1-42 peptide, the Aβ1-6 peptide and the Qβ protein 
(positive control), specific Enzyme-Linked ImmunoSpot (ELISPOT) assays will be performed 
on PBMC samples at a central analytical laboratory specialized in such assays. 
Peripheral blood sampling and PBMC isolation 
Whole blood will be sampled at Baseline and Week 9 (two weeks after the 2nd injection) for 
peripheral blood mononuclear cell (PBMC) isolation. The samples will be kept at room 
temperature, protected from the light until shipment at ambient temperature using the specific 
shipment box and transporter on the day of collection. Each clinical center personnel will 
receive specific training on procedures for sampling and shipment of whole blood samples for 
PBMC isolation. 
PBMC isolation will be performed at the selected laboratory according to specific instructions 
on blood sampling for PBMC isolation until shipment to the T-cell assay specialized laboratory.  
In addition, in case of signs and symptoms of CNS inflammation or symptomatic ARIA-E, an 
unscheduled PBMC collection will be performed to test for T-cell activation in the identified 
participant as close to the event as possible and no later than 4 weeks after. This event-triggered 
additional sample for an individual participant who is experiencing the signs or symptom 
applies to any participant, i.e. will not be limited to the 50 participants included in the scheduled 
T-cell activation test. 

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PET scans 
Amyloid and tau deposition and cerebral metabolism will be assessed using a PET/CT scanner 
meeting requirements specified in the PET Imaging manual. Amyloid, PET and tau PET 
scanning procedural details will be provided to the participating PET imaging facilities in a 
separate document. The same scanner should be used for each participant for all PET 
evaluations throughout the study. Images will be analyzed centrally per the data analysis plan 
and archived. If PET images are acquired during screening, and there is a risk that the image to 
be acquired at year 2 may not allow for longitudinal analysis (e.g. change on scanner), the year 
2 scan should be skipped to protect participant from unnecessary radiation exposure. 
All tracers used for the PET scans are radiolabeled with 18F, and will be delivered to the 
participant as an intravenous bolus injection at the PET site. The site will communicate the 
height and weight of the participant. The approximate target activity is specified below for each 
type of scan. 
The approximate scanning time, during which the participant will be lying on his or her back, 
will be 10 to 30 minutes depending on the PET tracer. Participants will be supervised during 
each PET-scan. CT scans may be used to correct the PET images for radiation attenuation and 
scatter. After the PET-scan has been completed, participants will be allowed to leave the PET 
center if there are no prohibitive findings or events, as assessed by a physician. 
Since PET scan data have the potential to un-blind individual participants, the results will be 
imported into a restricted database with controlled access and managed as described in Section 
5.4. The PET scan images, including the baseline scan, are also not intended to be shown to 
participants while the study is ongoing. 
Amyloid PET 
Amyloid PET will be performed in all participants at Screening and Month 24 (unless site 
cannot access an amyloid PET tracer). Another assessment at Month 60 will only be performed 
in participants who consent to the additional biomarker assessment.  
Locally permitted PET tracer utilized (e.g. 18F-florbetapir, 18F-flutemetamol or 18F-florbetaben), 
date, time, batch, volume, and radiation dose of the injection for each scan (according to the 
Imaging manual) and any AEs occurring at the PET center will be recorded on the eCRF.  
Cerebral-to-reference region standard uptake value ratios (SUVRs) will be calculated using pre-
defined and automatically generated cerebral and reference regions-of-interest.  
If amyloid PET tracer is not available locally, refer to Section 6.6.3.2. 
Tau PET 
Tau PET, where available, is voluntary and requires a specific consent. Tau PET will be 
performed to detect the effect of experimental treatment on neurofibrillary tangle burden. The 
same locally permitted radiotracer (18F-flortaupicir (AV-1451), MK-6240 or PI-2620) will be 
used for all scans of a given participant. Corresponding documentation will be submitted, if 
required (i.e. not in Germany).  

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The occurrence of AEs should be sought by non-directive questioning of the participants at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
participants during or between visits or through physical examination, laboratory test, or other 
assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least 1 of the 
following criteria: 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require medical intervention  
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
Baseline or the previous visit, or values which are considered to be non-typical in participants 
with underlying disease. Investigators have the responsibility for managing the safety of 
individual participants and identifying AEs. Alert ranges for labs and other test abnormalities 
are included in Section 13.2. 
Refer to Section 7.7 for additional guidance on adverse events that may be related to genetic 
disclosure and Section 6.5.8.2 for additional guidance on pruritus. 
Adverse events should be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information.  
The following severity grades will be used: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
All AEs should be treated appropriately. Treatment may include one or more of the following:  
• no action taken (i.e. further observation only)  
• study investigational treatment permanently discontinued due to this AE  
• concomitant medication given  
• non-drug therapy given  
• participant is hospitalized/participant’s hospitalization is prolonged 
The AE outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown) should be recorded. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the investigational drug, the interventions 
required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure or will be communicated between IB updates in the form of 
Investigator Notifications. This information will be included in the participant’s informed 
consent and should be discussed with the participants during the study as needed. 

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The Investigator should also instruct each participant to report any new AE (beyond the protocol 
observation period) that the participants, or the participant’s personal physician, believe might 
reasonably be related to the investigational treatment. This information should be recorded in 
the Investigator’s source documents; however, if the AE meets the criteria of an SAE, it must 
be reported to the local Novartis safety desk. 
7.2 
Serious adverse events 
7.2.1 
Definition of SAE 
An SAE is defined as any AE (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• is fatal or life-threatening  
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (specify what this includes) 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission  
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• is medically significant, i.e. defined as an event that jeopardizes the participant or 
may require medical or surgical intervention, including Appendix 1.3: Clinically 
notable SAEs that require discontinuation of treatment . 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or, development of dependency 
or abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
SAE. 

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7.2.2 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality to study drug treatment or 
genetic disclosure, occurring after the participant has provided informed consent (Refer to Table 
7-1) and for 30 days after the last study visit (EoS or PPW) must be reported to Novartis safety 
within 24 hours of learning its occurrence Detailed instructions regarding the submission 
process and requirements are to be found in the investigator folder provided to each site. Any 
SAEs experienced after the 30 day period after the last study visit (EoS or PPW) for Cohort II 
or last telephone call from the one year Extended safety monitoring for Cohort I should also be 
reported to Novartis if the investigator suspects a causal relationship to study treatment. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the Investigator receiving the follow-up information. An SAE that is 
considered completely unrelated to a previously reported SAE should be reported separately as 
a new event. 
Cohort I (CAD106) only: 
Extended safety monitoring for 1 year is required for Cohort I due the potential persistence of 
antibody titers. Any SAEs occurring during the 1 year extended monitoring (and after 30 day 
window after the last study visit), the SAE will only be captured in the safety database and not 
in the clinical database/eCRFs. 
At the study completion or upon early termination, all Cohort I participants will be followed for 
an extended safety monitoring over 1 year. The extended SAE collection after study completion 
/ premature patient withdrawal will be handled by the investigator through telephone calls to 
the participant, study partner and/or general practitioner, every 3 months. These telephone calls 
and the participant current condition and recent history since last telephone call will be 
documented in the participant’s charts. The correspondence between the investigator and the 
medical team involved in assessing the participant’s safety (e.g. radiologist, GP) will be 
archived as source documents. Visits to the site may be organized by the investigator as required 
to monitor the participant’s safety according to his/her usual clinical practice.  
During the extended SAE collection, the participant is no longer bound to the criteria defined 
in this clinical study protocol. In particular, no limitations in concomitant medications or other 
therapies will be required any longer.  
At the end of the extended SAE collection period (see Section 3.1.2.4), the investigator will be 
contacted by Novartis to confirm the outcome of any unresolved SAEs and the latest available 
participant health status. The SAEs reported during the 1-year extended safety monitoring will 
only be collected in the Novartis safety database. The information of SAEs reported in this 
period will be summarized in an addendum to the Clinical Study Report and reported to all 
Health Authorities where required. 
In case participants from Cohort I get re-randomized to Cohort II (see section 5.5.9) the safety 
monitoring will be captured within the study visits and do not require separate phone calls. 
Any SAEs experienced after this one year period should only be reported to Novartis if the 
investigator suspects a causal relationship to the investigational treatment drug.  

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SAE collection 
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English on the electronic Serious Adverse Event Report (eSAE) Form within the Oracle 
Clinical/Remote Data Capture (OC/RDC) system (wherever available and/or feasible) or on the 
paper SAE Report Form that should be used as back-up, especially in case where there is no 
feasibility of the use of eSAE Form.The Investigator must assess the relationship of each SAE 
to  study treatment (CAD106 or CNP520).  
SAEs (initial and follow-up) that are recorded electronically in the OC/RDC system should be 
entered, saved and e-signed within 24 hours of awareness of the SAE or changes to an existing 
SAE. These data will automatically be submitted to Novartis Chief Medical Office and Patient 
Safety (CMO&PS) immediately after investigator signature or 24 hours after entry, whichever 
occurs first.  
Follow- up information is submitted as instructed in the investigator file. Each re-occurrence, 
complication, or progression of the original event should be reported as a follow-up to that event 
regardless of when it occurs. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, whether the blind was broken or not, and 
whether the participant continued or withdrew from study participation. 
If the SAE is not previously documented in the IB and is thought to be related to the 
investigational treatment a Pharmacovigilance Department associate may urgently require 
further information from the Investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN) to inform all Investigators involved in any study with the 
same investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries. 
7.3 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events will be followed.  
The following two categories of abnormalities will be considered AEs during the course of the 
study and reported as such: 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter(s) 
• Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver eCRF pages 
Please refer to Table 13-7 for complete definitions of liver laboratory triggers and liver events.  
Every liver laboratory trigger or liver event as defined in Table 13-7 of Appendix 1.5 will be 
followed up by the in Investigator or designated personnel at the trial site as summarized below. 
Detailed information is outlined in Table 13-8 

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For the liver laboratory triggers, liver function tests (LFTs) will be repeated within the next 
week to confirm elevation. 
These repeat LFTs will be performed using the central laboratory, if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
participant. Repeat laboratory tests will then be performed at central laboratory as soon as 
possible. If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver eCRF pages. 
If the elevation is confirmed, close observation of the participants will be initiated, including 
consideration of treatment interruption if deemed appropriate. 
For the liver events: 
• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the participants if appropriate 
• A causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications) 
• An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology assessments, and 
hepatologist consultation, based on Investigator’s discretion. All follow-up information, and the 
procedures performed should be recorded on appropriate eCRF pages, including the liver event 
overview eCRF pages. 
7.4 
Renal safety monitoring 
To ensure participant safety and enhance reliability in determining the nephrotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
renal events will be followed.  
The following two categories of renal abnormalities will be considered and reported as AEs 
during the course of the study: 
1. Serum event: 
• Confirmed (after ≥ 24 h) increase in serum creatinine of ≥ 25% compared to Baseline 
during normal hydration status 
2. Urine event   
• New onset (≥ 1+) proteinuria, hematuria or glycosuria; or 
• Doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine 
ratio (PCR) (if applicable). 
Please refer to Table 13-9 for complete definitions of renal laboratory triggers and renal events. 
Every renal laboratory trigger or renal event should be followed up by the Investigator or 
designated personnel at the trial site as summarized in Table 13-9 . 

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7.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE, and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE. 
Table 7-2 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not associated 
with a SAE 
7.6 
Pregnancy reporting 
Participants eligible for this study will be 60 to 75 years of age, and women of childbearing 
potential are excluded from the study. Fertility in this age range is therefore not within the scope 
of this study. 
7.7 
Prospective suicidality assessment 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a questionnaire that prospectively 
assesses suicidal ideation and suicidal behavior. The scale must be administered on site, at each 
visit, including unscheduled visits. 
A validated shorter electronic version called eC-SSRS will be used to capture self-reported C-
SSRS data by the participant via a web-based system. The eC-SSRS is a participant self-
reported outcome assessment (PRO) that uses a detailed branched logic algorithm evaluating 
each participant’s suicidality ideation and behavior in a consistent manner. At the conclusion 
of each assessment, the Investigator will receive a detailed eC-SSRS Findings Report via e-mail 
or fax. The investigator will review the report before the participant is discharged and leaves 
the site. If the system assesses the participant as having positive suicidal signs, the Investigator 
will be immediately notified by either fax, email and/or via telephone. 

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7.10 
Meningoencephalitis monitoring 
To ensure participant safety and enhance reliability in determining the meningoencephalitis 
potential of an investigational drug, a process for identification, monitoring and evaluation of 
meningoencephalitis, or other severe immune reaction events will be followed. 
Cases of meningoencephalitis will be considered and reported as clinically notable SAEs during 
the course of the study 
Please refer to Section 13.1 for recommended test for suspected cases of meningoencephalitis 
and reporting procedures. 
8 
Data review and database management 
8.1 
Site monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor 
representative will review the protocol and eCRFs with the Investigators and their staff. During 
the study, Novartis employs several methods of ensuring protocol and Good Clinical Practice 
(GCP) compliance and the quality/integrity of the sites’ data. The field monitor will visit the 
site to check the completeness of participant’s records, review I/E criteria, the ICFs signature 
and date, the accuracy of entries on the eCRFs, the adherence to the protocol and to GCP, the 
progress of enrollment, and to ensure that investigational treatment is being stored, dispensed, 
and accounted for according to specifications. Key study personnel must be available to assist 
the field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized CRO. Additionally, a central analytics organization may analyze 
data, identify risks and trends for site operational parameters, and provide reports to Novartis 
and the selected CRO to assist with trial monitoring. 
The Investigator must maintain source documents for each participants in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on the eCRFs must be traceable to these source documents in the participant’s file. 
The Investigator must also keep the original informed consent form signed by the participant (a 
signed copy is given to the participant). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. The Sponsor monitoring standards require full verification 
for the presence of informed consent, adherence to the inclusion and exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 
8.2 
Data collection 
Designated investigator staff will enter the data required by the protocol into the EDC system. 
Designated investigator site staff will not be given access to the system until they have been 
trained.  

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Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. The Investigator must certify that 
the data entered into the electronic Case Report Forms are complete and accurate. After 
database lock, the investigator will receive copies of the participant data for archiving at the 
investigational site.  
8.3 
Database management and quality control 
Novartis staff will review the data entered into the eCRFs by investigational staff for 
completeness and accuracy and instruct the site personnel to make any required corrections or 
additions. Queries are sent to the investigational site using an electronic data query. Designated 
investigational site staff is required to respond to the query and confirm or correct the data.  
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomic Therapeutic Chemical (ATC) classification 
system. Concomitant procedures, non-drug therapies and AEs will be coded using the MedDRA 
terminology. 
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis. ECG readings will be processed centrally and the results will be sent electronically to 
Novartis. 
MRI images will be read centrally for safety evaluation and volumetric measures of brain 
regions. The results will be sent electronically to Novartis. The PET imaging data from amyloid 
 will be analyzed centrally. The results will be sent electronically to Novartis.  
All clinical scales administered by the clinician or self-reported by the participant or the 
informant will be collected on an eSource (Virgil® tablet) provided by the Cognition vendor 
who will also manage the database. The database will be sent electronically to Novartis with 
the exception of the audio recordings. 
Diary data will be entered by the participant into an electronic diary hosted on a web platform 
or via an IRT system. The system will be supplied by a vendor, who will also manage the 
database. The database will be sent electronically to Novartis. 
Photographs will be sent by the site to the central dermatology imaging vendor if there are 
treatment emergent skin AEs.  Only reports (not photographs) from the central dermatologic 
imaging vendor will be sent electronically to Novartis.  
Randomization codes and data about all investigational drug(s) administered or dispensed to 
the participants and all dosage changes will be tracked using an IRT. The system will be 
supplied by a vendor, who will also manage the database. The database will be sent 
electronically to Novartis. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor.  The 
code break functionality will remain available until study shut down or upon request of Novartis.  

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The DMC will be provided with individual participant’s data (unblinded), as well as summaries 
and graphs as appropriate. The tables, listings and graphs will be prepared by independent 
statisticians and statistical programmers who are not otherwise involved in the planning and 
conduct of the trial. Content and format of the tables, listings, and graphs will be agreed with 
the DMC. 
The DMC will be composed of recognized academic experts and will be assisted by an 
independent statistician and programmer.  
8.5 
Progression Adjudication Committee 
A process for the adjudication of MCI/dementia diagnoses will be implemented with an external 
Progression Adjudication Committee (PAC) managed by the Cognition vendor. Details of the 
diagnostic criteria are described in Section 6.4.1 and a description of the PAC members, role, 
and function will be described in a specific charter applicable until treatment termination.  
The communication steps between the site and the PAC as well as key coordinating roles from 
the Sponsor and the Cognition vendor will also be detailed. 
The PAC will be provided with the available participant data to assess for possible progression 
and potential confounding factors.  
Adjudication data will be collected and maintained by the Cognition vendor, and transferred 
to Novartis at pre-defined frequency. 
8.6 
Disclosure Monitoring Advisory Group (DMAG) 
The DMAG is responsible for assisting the DMC in an advisory capacity, monitoring the safety 
of the participants in relation to the genetic disclosure. The responsibilities of the DMAG, as 
also outlined in the DMAG Guidelines, are: 
• Reviewing the outputs (e.g. table/figure/listing of the data from the relevant scales, 
adverse events (AE) and serious adverse events (SAE) reports (those deemed related to 
genetic disclosure)) and making recommendations regarding changes or adjustments 
(including limiting the disclosure follow-up to 2-7 days in non-HMs) 
• Providing summary reports to the DMC prior to each data review meeting summarizing 
any findings related to the safety monitoring of genetic disclosure.  
The DMAG will be composed of recognized academic experts, as described in the DMAG 
Guidelines. 

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9 
Data analysis  
The final analysis for each respective cohort will occur once the targeted number of events for 
the cohort has been reached and all participants have completed their month 60 assessment. The 
final analysis of the cohort which completes earlier will be performed first and independently 
from the final analysis of the other cohort. Specific analyses which involve data from both 
cohorts together will be performed when both cohorts are completed. The details of the final 
statistical analyses are described in the Statistical Analysis Plan (SAP).In general, data will be 
reported by treatment arm. Summaries including only baseline data, may also present a total 
group (all participants). In case of DRM in Cohort II, summaries may also include the sub-
group of participants randomized to the active treatment arm after the DRM, i.e. those who 
started on the LDR. Descriptive statistics (mean, median, standard deviation, minimum, and 
maximum) will be presented for continuous variables for each cohort. The number and 
percentage of participants in each category will be presented for categorical variables for each 
cohort. 
In Cohort II, the primary treatment arms for efficacy analysis will include the following 
participants based upon whether or not the DRM has been implemented.  
• In the case that the DRM does not occur, the 2 treatment arms would remain the same as 
planned originally. The primary treatment arms are CNP520 50 mg once daily or 
matching placebo in a respective ratio of 3:2. The primary treatment arms include 
participants who received either CNP520 50 mg once daily or matching placebo. In this 
case, the primary active arm is Arm #3, i.e. the CNP 50 mg once daily active arm.  
• In case the DRM is implemented, the same randomization ratio is maintained, 3:2 active 
versus placebo. The primary active arm (Arm #3) consists of the following participants: 
• Those who received CNP520 50 mg once daily dose followed by CNP520 LDR 
(those who were originally randomized to 50 mg once daily, and subsequently switch 
to the lower dose regimen),  
• Those who received CNP520 LDR dose only (those who were randomized to active 
treatment arm after the DRM).  
• The primary placebo arm (Arm #4) consists of all the participants who have been 
randomized to Arm #4 and received placebo regardless of DRM. 
9.1 
Analysis sets 
The Randomized analysis set (RAS) will consist of all participants who received a 
randomization number, regardless of receiving study medication. 
The Safety analysis set (SAF) will consist of all participants who have started study medication 
and have had at least one safety assessment after first dose administration.  
The Full analysis set (FAS) will consist of all randomized participants who started study 
medication.   
In general and if not otherwise specified, efficacy analyses will be conducted on data from 
participants in the FAS, safety analyses will be conducted on data from participants in the SAF. 

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Cohort I Only 
The modified FAS (MFAS) will be defined as the subset of the FAS which excludes the 
serological non-responders (NR) to CAD106. 
The classification of participants into Serological Responders (SR) and serological NR to 
CAD106 will be based on the individual CAD106-induced Aβ-specific IgG titer values in serum. 
The classification rules have been developed on available data from previous Phase II studies.  
Participants of the CAD106 cohort will be classified in the following categories: Placebo, NR, 
SR. SR will be defined in the following way based on titer assessments up to and including 
Week 26 of the Treatment Epoch:  
Participants whose Aβ-specific IgG titer in serum is both greater than 16 units after 2nd and 
before 3rd injection and greater than 3 times the LLOQ (LLOQ=8.93 units as determined in the 
phase II program, 3*LLOQ=26.8 units) after the 3rd injection.  
NR will be participants that do not meet the SR definition. 
9.2 
Participant demographics and other baseline characteristics 
Demographic variables and other Baseline characteristics will be summarized for each 
treatment arm and all participants (total).  
In addition, all relevant medical history will be summarized following the same strategy. 
9.3 
Treatments 
For Cohort I (CAD106 or placebo), a data listing and a summary of the administered 
investigational drug injections will be provided. In addition, serological responder rates and 
summary parameters for serum Aβ-specific IgG titers will be tabulated.  
For Cohort II, data for investigational drug administration will be summarized and listed. In 
case of DRM, summaries will also include the sub-group of participants randomized to the 
active treatment arm after the DRM, i.e. those who started on the LDR. 
The number and percentage of participants receiving concomitant medications and significant 
non-drug therapy will be summarized by preferred term (coded by WHO Anatomic Therapeutic 
Chemical classification [ATC]) and by treatment arm, and be listed. 
9.4 
Analysis of the primary variable(s) 
For each investigational drug, the primary analysis will contrast each primary active treatment 
arm vs. matching Placebo based on the FAS.  
There are two primary endpoint variables: TTE, with event defined as diagnosis of MCI or 
dementia due to AD, and the APCC test score. Both endpoints are considered to be clinically 
relevant. Success of the trial will be determined independently for each investigational drug by 
a positive result in at least one primary endpoint. In addition, each cohort will undergo an 
Interim Analysis based on data from the two primary endpoints. To control the overall family-
wise type I error rate within cohorts for testing two endpoints at two points in time, an 
appropriate multiplicity adjustment will be applied to the analyses of the primary efficacy 

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variables. The strategy to adjust the overall family-wise type 1 error (α = 5%) is described in 
Section 9.7.  
9.4.1 
Variable(s) 
Two primary variables will be used: 
• TTE, defined as the time from randomization to the first event that is the first confirmed 
diagnosis of MCI or dementia due to AD. The criteria for diagnosis and confirmation are 
specified in Section 6.4.1. The date of the initial investigator diagnosis will be used to 
establish the date of the event (not the date of the confirmation). In case no confirmed 
event has been observed for an individual, the observation will be censored, and the 
censoring date will be defined as the last date when the diagnostic classification has been 
assessed. Time to censoring date will also be calculated from the date of randomization. 
• APCC test score change from baseline to Month 60.  
The APCC test score is defined as a weighted sum of the following test items:  
• Raven’s Progressive Matrices – subset  
• MMSE: 
• Orientation to Time 
• Orientation to Place 
• RBANS: 
• List Recall 
• Story Recall 
• Coding 
• Line Orientation 
The range of the APCC test score is from 0 to 100 where higher scores correspond to better 
cognitive performance. The APCC will be derived based on the test items using the formula: 
APCC test score = 1.360*RBANS List Recall + 1.100* RBANS Story Recall +1.390* Raven’s 
Progressive Matrices (subset) + 0.321*RBANS Coding + 0.510*RBANS Line Orientation + 
2.140*MMSE Orientation to Place + 2.240*MMSE Orientation to Time. 
9.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analyses will consist of testing hypotheses related to the 2 active investigational 
drugs. The primary analyses will compare primary active vs. matching placebo in both cohorts 
separately, i.e. the primary analysis will consist of testing hypotheses related to the 2 
investigational drugs. As the design includes separate placebo arms in each of the 2 cohorts, 
these are considered as independent comparisons similar to the testing in 2 independent trials. 
As a consequence, an adjustment of the type one error rate to account for the multiple testing 
in the two cohorts is not needed. For Cohort II, the same primary objective and hypotheses will 
be applied to the primary active arms. 
For each of the two investigational drugs, the following two null hypotheses will be tested 
corresponding to the two primary endpoints: 

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• H01: The primary active treatment arm does not differ from matching placebo with 
regard to the distribution of time to first diagnosis of MCI or dementia due to AD; 
• H02: The primary active treatment arm does not differ from matching placebo in the 
mean change from Baseline to Month 60 in the APCC test score; 
The corresponding alternative hypotheses are: 
• H11: The primary active treatment arm differs from matching placebo with regard to 
the distribution of time to first diagnosis of MCI or dementia due to AD. 
• H12: The primary active treatment arm differs from matching placebo in the mean 
change from Baseline to Month 60 in the APCC test score. 
The type one error rate is α = 5%, an appropriate multiplicity adjustment will be applied to the 
analyses of the primary efficacy variables within cohorts (Section 9.7). 
The final primary analysis of the TTE endpoint will be performed only once the target number 
of events has been reached in the respective cohort and after all participants in the cohort have 
reached 60 months of follow-up (whichever occurs later) unless they discontinued prematurely. 
Any data collected after the cut-off date will not be used for the primary analysis of TTE. That 
means specifically that only confirmed events collected up to the data cut-off date will be 
counted. Confirmation information collected after the cut-off date confirming an earlier 
(meaning before the cut-off date) diagnosis of MCI or dementia due to AD will not be taken 
into consideration. As a consequence, the observation will be censored, and the non-confirmed 
diagnosis will not be counted as an event.  
The time required to observe the target number of events is estimated to be close to the 60-
month duration required for the APCC test score primary outcome. In case the target number 
of events needed for the final TTE analysis has not been reached when the last participant 
completes the 60 months follow-up, a decision will be made whether the follow-up time will 
be prolonged or whether the final analysis will be carried out earlier. The final primary analysis 
of the APCC score will be performed after all participants reached 60 months of follow-up, but 
all available data will be included in the final analysis.  
The primary analysis of the TTE endpoint will be based on a Cox proportional hazards (PH) 
model including treatment group (primary active treatment arm or matching placebo) as a factor 
and adjusted for important baseline covariates.  
Terms will be included for the following effects:  
• treatment group 
• baseline value of the APCC test score 
• age group at baseline 
• region 
• baseline amyloid load.  
The primary analysis of the APCC score will be performed using a longitudinal model for the 
change from baseline: the mixed repeated measure model (MMRM). 
An unstructured covariance matrix will be assumed, and the model will include the following 
fixed effects:  

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• treatment group 
• time as the discrete variable scheduled (mapped) visit 
• baseline value of the APCC test score 
• age group at baseline 
• region 
• baseline amyloid load,  
and the following interaction terms: 
• treatment group × visit  
• baseline APCC test score × visit 
• baseline amyloid load × visit. 
The adjusted least square means (LSM)s of change scores for each treatment group, the 
difference between the LSMs (active vs. placebo), the 95% confidence intervals and the 
unadjusted 2-sided p-values, comparing the active and placebo LSMs,  will be calculated from 
the MMRM analysis and presented for each visit. 
9.4.3 
Handling of missing values/censoring/discontinuations 
Primary endpoint time-to-diagnosis of MCI or dementia due to AD 
In general, an observation will be censored if no event has been observed at the TTE analysis 
cut-off date. The censoring date will be defined as the last date where the TTE endpoint has 
been assessed. 
The censoring date for each participant that did not have an event (i.e., a confirmed diagnosis) 
is defined as follows: 
1. For participants ongoing in the study without a confirmed diagnosis at the time of the cut-
off: the last day of a diagnosis assessment (the previous visit where a diagnosis assessment 
occurred prior to the cut-off date). 
2. For participants who permanently discontinued from the study prior to the cut-off: The last 
day of a diagnosis assessment prior to study discontinuation. 
The primary analysis method (Cox proportional hazards model) for the TTE endpoint is valid 
and consistent under a censored at random assumption, i.e. the probability of censoring is 
independent from the event (MCI or dementia due to AD).  
Sensitivity Analyses 
The robustness of the primary analysis results for the TTE endpoint will be further explored 
through sensitivity analyses using tipping point and controlled imputation approaches and under 
a plausible censoring not at random (CNAR) process. Scenarios for which these analyses will 
be conducted include: 
1. Data collected off-drug, i.e. beyond 12 weeks after permanent discontinuation of study 
drug; 
2. Missing data from participants who prematurely discontinued the treatment epoch due to 
an AE, death, or unsatisfactory therapeutic effect (UTE). 

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Explicit details will be further described in the SAP. 
The Cox PH model will be repeated including the time × treatment interaction which serves 
also to investigate the assumption of proportional hazards. These explorations will be 
complemented by graphical methods based on Kaplan-Meier plots and plots of the log-log 
survivor functions. 
In conjunction with the primary analysis Cox PH addition, a stratified log-rank test stratified 
for a selection of most critical baseline covariates may be performed in case there are no empty 
or sparse cells. Stratification factors are selected from the following list:  
• baseline value of the APCC test score (dichotomized) 
• age group at baseline 
• region  
• baseline amyloid load (dichotomized) 
An analysis corresponding to the primary analysis method will be conducted, but using the 
Investigator’s diagnosis to identify events based on two consecutive diagnoses by the 
investigator.  
Primary endpoint APCC 
This section includes discussion on the methodology for handling composite APCC scores that 
are either incalculable due to inadequate availability of the underlying components, or are 
completely missing for a participant at a particular visit. 
The methodology for handling missing individual item components that contribute to the 
composite APCC score for a participant at each visit will be described in full detail in the SAP. 
The primary analysis method (MMRM) for APCC test score is valid and consistent under a 
MAR assumption, i.e. given the observed data (responses and covariates) the probability of 
drop-out does not depend on the unobserved responses. 
For the following scenarios it is plausible not to regard the corresponding missing data as MAR: 
• Missing data after conversion to MCI or dementia due to AD, 
• Data collected off-drug, i.e., beyond 12 weeks after permanent discontinuation of study 
drug, 
• Missing data due to an AE, death, or UTE.  
To address missing data which may be not MAR, the following sensitivity analyses will be 
applied:  
• Tipping point analysis where a penalty to imputed MAR scores will be applied from the 
point onwards when the missing data fit any of the above mentioned reasons.; 
• Controlled imputation approach: within each treatment arm, the imputation model is built 
based on data from participants in the same arm who also had a similar disease 
progression but who remained in the study (‘retrieved data’). Such an analysis would only 
be possible if sufficient retrieved data are available to build an imputation model. 
The robustness of the primary analysis results for the APCC endpoint will be further explored 
through a sensitivity analysis under a plausible missing not at random (MNAR) process. 

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For this sensitivity analysis, missing values in the active arm will be imputed using a so-called 
‘copy reference’ imputation approach assuming that participants discontinuing due to AE, 
death (D), or unsatisfactory therapeutic effect (UTE) behave like participants from the placebo 
arm after study discontinuation. 
Missing data for other reasons and for all placebo arm participants will be imputed under a 
MAR assumption, that is missing data are imputed based on the treatment-specific information 
for the repeated measurements and covariates.   
For each imputed and thus completed data set, the primary analysis model is then fitted as 
specified in Section 9.4.2. The resulting sets of parameter estimates and associated covariance 
matrices are then combined to derive overall estimates, confidence intervals that adequately 
reflect missing data uncertainty, as well as associated p-values using Rubin’s rules (Little and 
Rubin 2002).  
9.4.4 
Supportive analyses 
Analyses on the MFAS for Cohort I (CAD106)  
For Cohort I (CAD106 or placebo), the primary analysis will be repeated based on the MFAS, 
i.e. the FAS excluding serological non-responders as primary supportive analyses to strengthen 
the interpretation of the primary analysis.  
This is based on the assumption that the response to treatment will be driven by the serological 
response to CAD106. Hence, the primary supportive between-group comparisons of the 
primary endpoint will be performed between SRs and placebo for benefit assessment. Although 
there is no rationale that potential serological non-responders may have a different natural 
course regards the primary endpoints as compared to potential SRs, these analyses will also 
take into account that participants in the control group would potentially have not shown 
serological response if they had been on active treatment. This approach will follow the method 
presented by Koepsell et al (2007) and is based on the assumption that the treatment effect is 
estimated most appropriately by comparing the participants who did respond to active 
immunization with the participants in the placebo arm who would have responded to active 
immunization. Although, these participants cannot be determined, based on some assumptions, 
the mean effect of the potential SRs in the placebo arm can be estimated from the available data. 
Comparison versus pooled placebo 
Comparisons of the active investigational drugs versus the pooled placebo group, i.e. pooling 
the placebo arms from both cohorts, will be performed as an additional primary supportive 
analysis for both investigational drugs once both cohorts are completed (i.e., study has 
completed). For both investigational drugs, the primary analysis will be repeated, but using the 
pooled placebo arm as control group instead of matching placebo. 

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The difference in mode of administration, quarterly injections vs. one daily oral capsule, is not 
expected to have an impact on the primary endpoint and is thus not assessed as a major issue 
for the primary analysis based on pooled placebo. Nevertheless, possible cohort effects will be 
investigated, specifically due to the time lag for start and finish of the two cohorts or due to the 
pause in Cohort I allocation for the CNS activity futility IA. The two placebo groups will be 
evaluated to determine whether there is a significant imbalance with regards to any relevant 
characteristic. 
Censoring data after discontinuation of study drug 
Comparisons of the active investigational drugs versus the matching placebo group will be 
performed for both investigational drugs on the FAS, taking into account whether a participant 
had continued, interrupted or permanently discontinued study-drug during the study. The same 
statistical methods as for the primary analysis will be implemented, i.e. with regard to the 
analysis model and the MAR assumption for missing data. For the Cohort I (CAD106), data 
collected later than 6 months after discontinuation from study drug will not be included in the 
supportive analysis.  For Cohort II (CNP520), data collected later than 3 months after 
discontinuation of study drug will not be included.  
Similar analyses will also be specified for insufficient exposure (i.e. for participants who did 
not take treatment for cumulative missed doses of more than 26 weeks (Cohort II) or >2 
injections (Cohort I) during the course of the study. 
Other analyses of the time-to-event endpoint 
A non-stratified log-rank test will be conducted to compare estimates of the hazard functions of 
the treatment groups at each observed event time.  
A model including the additional treatment group × baseline amyloid load interaction will also 
be implemented as an important primary supportive analysis. 
Other analyses of the endpoint APCC 
The primary analysis of the APCC test score will be supported by the following important 
primary supportive analysis: An MMRM is based on the same assumptions as the primary 
analysis model and including the same factors, but also the additional interaction terms 
treatment group × baseline amyloid load 
treatment group × baseline amyloid load × visit. 
An MMRM adjusted for a broader range of possible confounding factors such as site, gender, 
years of education, and hippocampal volume will also be implemented. Another MMRM based 
approach will investigate the average contrast over years 5 to 8. 
In addition, the primary analysis will be supported by an MMRM similar to the primary model, 
but introducing time as a continuous factor. The interpretation of results from the primary 
analysis will also be supported by the investigation of change in treatment effects over distinct 
time periods. 

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Potential drug-drug-interaction (DDI) 
Potential PD-mediated DDIs with frequent concomitant medications may include the use of 
cholinesterase inhibitors and/or another prescription AD treatment (e.g. memantine) in terms of 
transient interaction with cognitive readouts.  
Treatment interaction with CAD106 and CNP520 will be assessed as follows: 
• The primary efficacy analysis will be based on an intention-to-treat principle and will 
neither exclude participants who started ChEIs and/or another prescription AD treatment 
(e.g. memantine) during the study, nor exclude time points from the analysis after start of 
ChEIs and/or another prescription AD treatment (e.g. memantine). 
• Sensitivity analysis will be carried out to investigate the role of concomitant 
cholinesterase therapy and/or another prescription AD treatment (e.g. memantine) on the 
efficacy of CAD106 and CNP520, such as exclusion of time points from the analysis after 
initiation of ChEI therapy and/or another prescription AD treatment (e.g. memantine), or 
using this information as a stratification factor or as a time-varying covariate in statistical 
models. 
Sub-group analysis 
In case of DRM, analyses similar to the primary analyses will be performed on the subset of the 
FAS defined as participants who have been randomized after the DRM, i.e. who have been 
exposed to the LDR throughout the whole treatment epoch. 
In addition, analyses similar to the primary analyses will be performed on the subset of the FAS 
including only participants fulfilling criteria for classification for Stage 1 as defined in the draft 
FDA Guidance for Industry: Early Alzheimer’s disease: Developing Drugs for Treatment, 
February 2018. 
9.5 
Analysis of secondary variables 
CDR-SOB is the key secondary outcome variable. Additional secondary variables are ECog, 
the individual tests included in the APCC battery and RBANS, and the following AD related 
biomarkers: PET, Volumetric MRI, total tau and phosphorylated tau in CSF. All of the 
secondary endpoints will be analyzed using longitudinal models such as MMRM for the CDR-
SOB similar to the approach for the primary endpoint APCC with treatment as factor and 
adjusting for important covariates. Hypotheses on CDR-SOB will be tested and are included in 
the multiple testing strategy described in Section 9.7. For CAD106, change from Month 6 to 
Month 60 in the APCC test score and in CDR-SOB are additional secondary outcomes and will 
be analyzed using the same analysis strategy as for change from baseline to Month 60. 
In addition to the above listed efficacy and biomarker outcomes, the following safety and 
tolerability variables are secondary outcome parameters: safety MRI, AEs, laboratory tests, 
vital signs, and injection-related reactions for CAD106. 
For CAD106, the Aβ-specific IgG response over 60 months is an additional secondary 
outcome. 

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For CNP520, the same definition of treatment arms for primary analysis will also be applied to 
the analysis of secondary variables. 
9.5.1 
Efficacy variables 
Clinical Dementia Rating Scale (CDR) sum of boxes (SOB) 
To control the overall type I error rate, a multiplicity adjustment will be applied to the primary 
and the key secondary variables, which is specified in Section 9.7. 
For each of the two active investigational treatments, CAD106 and CNP520, respectively, the 
following null hypothesis will be tested in the framework of the multiple testing strategy:  
• H03: The primary active treatment arm does not differ from matching placebo in the 
mean change from Baseline to Month 60 in the CDR-SOB score; 
The corresponding alternative hypothesis is: 
• H13: The primary active treatment arm differs from matching placebo in the mean 
change from Baseline to Month 60 in the CDR-SOB score. 
The final secondary analysis of the CDR-SOB score will be performed after all participants 
reached 60 months of follow-up and will be performed using a longitudinal model for the 
change from Baseline to Month 60. A MMRM adjusted for important factors corresponding to 
the approach for the primary analysis model as specified for the APCC will be applied. Further 
specifications will be given in the statistical analysis plan (SAP). 
The adjusted least square means (LSMs) for each treatment group, the difference between the 
LSMs (active vs placebo), the 95% confidence intervals (CIs) and the unadjusted 2-sided 
p-values will be calculated from the MMRM analysis and presented for each visit. 
Descriptive statistics of the change from Baseline in CDR-SOB score will be presented over 
time by treatment group.  
Sensitivity analysis of the key secondary endpoint will mirror that of the APCC primary efficacy 
endpoint and described more explicitly in the SAP. 
Everyday Cognition scale (ECog) total score 
Descriptive statistics of the change from Baseline (taken at Visit 201-Screening) in ECog total 
score will be presented over time by treatment group. An analysis of change from Baseline will 
be also performed using longitudinal MMRM model as described in Section 9.4.2. 
Tests included in APCC and RBANS 
Descriptive statistics of the change from Baseline in the individual test scores included in the 
APCC battery and RBANS, as well as the RBANS Total Scale index score, will be presented 
over time by treatment group. An analysis of change from Baseline will be also performed using 
a longitudinal MMRM model as described in Section 9.4.2. 

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CAD106 
For Cohort I only, the change from Month 6 (when CAD106 immune response  is expected to 
be optimal) to Month 60 in the APCC test score will be analyzed following the same strategy 
as for the primary analysis for the change from Baseline to Month 60.  
9.5.2 
Safety variables 
In general, safety analyses will be carried out using the SAF. Descriptive summary tables will 
be provided by treatment for AEs, safety MRI and other safety parameters. 
For Cohort I (CAD106 or placebo), safety parameters will also be summarized by serological 
responders and serological non-responders for the active CAD106 treatment arm following the 
concept of the MFAS. This safety analysis is meant to complement the supportive analysis of 
primary efficacy variables based on the MFAS and to support the interpretation of the safety 
analysis by comparing the safety profile between serological responders and non-responders. 
AEs, SAEs and Deaths 
The number (and proportion) of participants with treatment-emergent AEs (events that started 
after the first dose of study medication or events present prior to the start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, primary system organ class, and preferred term  
• by treatment, primary system organ class, preferred term, and maximum severity 
• by treatment, Standardized MedDRA Query (SMQ), and preferred term 
Separate summaries will be provided for SAEs, death, study medication related AEs, AEs 
leading to discontinuation and AEs leading to dose adjustment.  
Laboratory data 
Summary statistics of change from Baseline laboratory results will be provided over time by 
treatment group. These descriptive summaries will be presented by laboratory test category, 
visit, and treatment group. 
Shift tables based on the normal laboratory ranges will be also provided. For the shift tables, 
the normal laboratory ranges will be used to evaluate whether a particular laboratory test value 
is normal, low, or high for each visit relative to whether or not the Baseline value is normal, 
low, or high. The shift from Baseline to the most extreme post-Baseline value will also be 
summarized. These summaries will be presented by laboratory test category, treatment and time 
(if applicable). 
The number and percentage of participants with clinically notable laboratory results after 
Baseline will be presented. The most extreme post-dose value is considered. Only participants 
with laboratory results at Baseline and post-Baseline from the central laboratory are included 
in the tabulations. 
The number and percentage of participants with predefined liver enzyme abnormalities 
occurring during the study will be summarized by treatment group. 

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9.5.3 
AD-related biomarkers 
The following AD related biomarkers are secondary variables: amyloid and tau PET (where 
tracers and assessments are locally permitted i.e. not in Germany), MRI, NFL in blood/CSF, 
total tau and phosphorylated tau in CSF. All analyses to support secondary biomarker objectives 
will be performed based on the FAS. 
In addition, biomarker analyses will be performed on the subset of FAS including only 
participants fulfilling criteria for classification for Stage 1 as defined in the draft FDA Guidance 
for Industry, Early Alzheimer’s disease, Developing Drugs for Treatment, February 2018.    
PET amyloid and tau imaging  
Imaging data from amyloid and tau PET scans will be analyzed using methods previously 
published in the literature. The SUVR of cortical areas to the selected reference region will be 
used as the outcome measure.  
The final secondary analysis of percent change from Baseline to Months 24 and 60 in the global 
cortical SUVR will be performed after all participants reached 60 months of follow-up and will 
be performed using a longitudinal model for percent change from Baseline: the mixed repeated 
measure model (MMRM). 
Terms will be included for the following effects:  
• treatment group 
• time as the discrete variable scheduled (mapped) visit 
• Baseline SUVR 
• age group at baseline 
and the following interaction terms  
• treatment group × visit 
• Baseline SUVR × visit. 
The LSMs for each treatment group, the difference between the LSMs (active vs. placebo), the 
95% confidence intervals, and the unadjusted 2-sided p-values will be calculated from the 
MMRM analysis and presented for each visit. 
Summary statistics will be presented for SUVR for the global cortical amyloid load. In addition 
to raw values, change, and % change from Baseline will be tabulated. 
Volumetric MRI 
Descriptive statistics of change and relative (%) change from Baseline in volume of specific 
brain regions of interest (ROIs) will be presented over time by treatment group. Main ROIs 
include hippocampus and whole brain. 
For CNP520, the following null hypotheses will be tested for specific ROIs:  
• The primary active treatment arm does not differ from placebo in the mean relative 
change from Baseline to Month 60 in volume of the ROI as measured by volumetric 
MRI; 

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The corresponding alternative hypothesis is: 
• The primary active treatment arm differs from placebo in the mean relative change 
from Baseline to Month 60 in volume of the ROI as measured by volumetric MRI. 
The final secondary analysis of changes in volume of ROI as measured by volumetric MRI will 
be performed after all participants reached 60 months of follow-up and will be performed using 
MMRM, a longitudinal model for the change from Baseline. 
Terms will be included for the following effects:  
• treatment group, 
• time as the discrete variable scheduled (mapped) visit, 
• normalized Baseline whole brain volume, 
• age group at baseline, 
and the following interaction terms:  
• treatment group × visit,  
• normalized Baseline whole brain volume × visit. 
The LSMs for each treatment group, the difference between the LSMs (active vs. placebo), the 
95% confidence intervals and the unadjusted 2-sided p-values will be calculated from the 
MMRM analysis and presented for each visit. 
Total tau and phosphorylated tau in CSF 
For each of the 2 active treatments, CAD106 and CNP520, respectively, the following null 
hypotheses will be tested:  
• The primary active treatment arm does not differ from placebo in the mean change from 
Baseline to Month 60 in phosphorylated tau in CSF; 
• The primary active treatment arm does not differ from placebo in the mean change from 
Baseline to Month 60 in total tau in CSF; 
The corresponding alternative hypotheses are: 
• The primary active treatment arm differs from placebo in the mean change from Baseline 
to Month 60 in phosphorylated tau in CSF. 
• The primary active treatment arm differs from placebo in the mean change from Baseline 
to Month 60 in total tau in CSF. 
The final secondary analysis of tau in CSF score will be performed after all participants reached 
60 months of follow-up and will be performed using MMRM, a longitudinal model for the 
change from Baseline. Terms will be included for effects of treatment group, corresponding 
Baseline value, scheduled (mapped) visit, and interaction terms treatment group × visit and 
Baseline value × visit. 
The LSMs for each treatment group, the difference between the LSMs (active vs. placebo), the 
95% confidence intervals and the unadjusted 2-sided p-values will be calculated from the 
MMRM analysis and presented for each visit. 

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Expected timing 
Main parameters under 
evaluation 
CNS activity futility analysis for 
CNP520  
At the latest when 24 month post-
baseline CSF data are available for 
270 participants across both studies 
API015A2201J (Cohort II) and 
CNP520A2202J 
Volumetric MRI, CSF and blood 
parameters 
Primary efficacy futility analysis 
Once approximately 75% of the 
targeted number of events have 
occurred, but not later than 2 years 
prior to planned final analysis. 
Primary endpoints (TTE and APCC 
test score) 
As outlined in Table 9-1 , the Interim analyses and data review by the DMC are pre-planned for 
1. Unblinded safety review by DMC:  
• Regular semi-annual and ad hoc more frequently as needed, evaluation of safety 
parameters, worsening in cognition as a safety measure together with data allowing 
risk/benefit assessment to be defined with the DMC and potential trigger for DRM in 
Cohort II 
• Evaluation of T-cell activation data (50 participants from Cohort I) 
2. Unblinded futility Interim Analysis of immunogenicity of CAD106 
3. Review of CNS activity for futility based on the following biomarkers (Refer to Section 
3.1 and 3.2  for allocation pause for Cohort I):  
• CSF: Aβ (only for Cohort II (CNP520)), tau pathology (tau and p-tau)  
• Blood/CSF NFLs 
• PET imaging data: amyloid, tau, 
  
• Volumetric MRI (only for Cohort II (CNP520))  
4. Primary endpoint: Un-blinded analysis of primary efficacy parameters (TTE and APCC 
test score) to assess futility or early stopping due to overwhelming efficacy. 
Interim analyses for safety  
Important safety information like AEs, safety MRI data, vital signs will be regularly reported 
and reviewed by the DMC. The review also includes the monitoring of potential worsening in 
cognition based on the RBANS test score and CDR-SOB.  
Interim analyses for immunogenicity of CAD106 
Immunogenicity will be reviewed by the DMC following pre-specified rules:  The first DMC 
review for the immunogenicity assessment will be scheduled at the latest after 40 participants 
from Cohort I (CAD106 or placebo) have received three injections and antibody titer data up to 
week 26 (time of 4th injection) are available. 

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Interim Analysis for Biomarkers of CNS activity 
Cohort I 
CNS activity of CAD106 will be assessed by means of a single unblinded interim analysis for 
participants that have had their Month 24 visit assessments. Data considered at this analysis will 
include %-change from Baseline in SUVR of amyloid PET at 24 months as well as all available 
CSF (Aβ, tau, p-tau) and volumetric MRI data (hippocampal and potentially ventricular or 
whole brain volume). Additional AD-related biomarkers obtained including tau PET 
, may also be used to further support decision making. The unblinded IA will be performed 
once all planned biomarker assessments have been collected for the participants randomized 
until the pause in Cohort I allocation.  
The unblinded IA will include available 24 months data from the CAD106 treatment arm as 
well as both Placebo treatment arms, pooled from both cohorts.   
Cohort II 
CNS activity of CNP520 will be assessed by means of a single unblinded interim analysis on 
treatment difference from Baseline for participants that have had their month 24 visit 
assessments. Data considered at this analysis will include volumetric MRI data (hippocampal 
and potentially ventricular or whole brain volume) at 24 months as well as all available CSF 
data (Aβ, tau, p-tau). Additional AD related biomarkers obtained including Amyloid, Tau and 
-PET, may also be used to further support decision making.  
The unblinded IA will consist of a pooled analysis across studies: Cohort II of CAPI015A2201J 
and CCNP520A2202J, and also separated by genotype i.e., HM and non-HM.  The unblinded 
IA will be performed at the latest when a total of approximately 270 participants across both 
studies in any of the CNP520 dose arms or corresponding placebo have provided CSF data at 2 
years post baseline. This preliminary sample size is based on exploration of the change over 2 
years from the longitudinal data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) 
cohort data.  
The exact futility decision rules for either cohort will be based on further investigation of 
internal and external data. Specific decision criteria and the exact timing of the analysis are 
under investigation and will be outlined in the DMC charter and specified in the DMC MAP.  
The main purpose of these IAs is futility. No alpha spending strategy will be employed. 
Primary endpoint Interim analysis 
The interim analysis based on the primary endpoints (see Section 3.5) will include the testing 
of the following null-hypotheses: 
H01I: The primary active treatment arm does not differ from matching placebo with regard to 
the distribution of time to first diagnosis of MCI or dementia due to AD; 
and 
H02I: The primary active treatment arm does not differ from matching placebo in the APCC 
time profile.  

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The analysis models and methods will be the same as for described in Section 9.4 for the Final 
Analysis. An appropriate multiplicity correction procedure will be applied for testing two 
endpoints at two time points, the interim and the final analysis. 
The main purpose of the IA is futility. Nevertheless, since this involves unblinding of data on 
the primary endpoints, a small portion of the overall significance level alpha of 5% will be spent 
to control the type-I error rate using a Bonferroni split. The underlying idea is to set the hurdle 
very high such that an early stopping due to overwhelming efficacy is extremely unlikely. Early 
stopping rules for efficacy will refer primarily to the overwhelming efficacy on the TTE 
endpoint. For APCC, the rules will also take into account the status of the additional data 
generated to support APCC. In addition, overwhelming efficacy on APCC will need to be 
supported by at least a trend on TTE. 
The IA will be based on available data on the two primary parameters: time to diagnosis of 
MCI/dementia due to AD and the APCC. The IA is planned to be conducted in each cohort as 
early as possible when a sufficient number of events (e.g. 75% of expected number of events) 
have been observed to make analysis meaningful, but the latest 2 years before the projected end 
of the study.  It is planned to schedule the cognition IA based on a blinded review of data for 
the primary endpoints. 
As a consequence, changes in APCC from Baseline to earlier points in time than month 60 will 
be investigated at the IA. The exact endpoint will depend on the amount of data available at the 
point in time of the cognition IA. The analysis will be based on a longitudinal MMRM model 
and a contrast based on time point after and including year 3. The exact hypotheses to be tested, 
especially for the APCC, decision rules for futility, and all other details of the cognition IA will 
be pre-specified and be outlined in the DMC charter and the statistical analysis plan. 
9.7 
Multiplicity adjustment 
Cohort II 
The design for Cohort II of the study has been adapted based on competitor results and new 
scientific evidence and literature results in 2018. The adaptation at that point was strategic and 
not driven by data from the ongoing studies using CNP520. The decision has been taken to 
allow flexibility with regards to the dose regimen. Since the decline in cognitive performance 
and increase in psychiatric events demonstrated in other BACE inhibitors were observed within 
a few months of treatment start, it is anticipated that a potential DRM would occur early in the 
course of the trial. As a consequence, the exposure to the initial CNP520 dose will be limited 
in time and short in duration compared to the overall long-term exposure to the LDR.  
All proposed doses and regimens (leading to long-term BACE inhibition of at least 50%) are 
expected to show similar range of clinical efficacy. Potential treatment effects are expected to 
be driven by the long-term exposure of the final selected dose (see Section 3.3). Dose regimen 
modification will be driven by observation of symptomatic worsening in cognition and/or 
increase in neuropsychiatric events. As a consequence, it is assumed that DRM will not 
introduce an anticonservative bias. 
Regardless of the actual dose regimen, the total sample size will remain the same, as well as the 
ratio of 3:2 for active:placebo. In addition, the statistical analysis will not depend on the dose 

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regimen, but will in any case compare active treatment (all CNP520) versus matching placebo. 
The primary analysis will not be adjusted for the potential DRM. Although these major design 
features will not change in case of DRM, it is acknowledged that the potential change in dose 
regimen may introduce additional variation and bias.   
General 
The primary analyses will consist of testing hypotheses related to the two investigational drugs, 
respectively. Active treatment arms will be compared vs. matching placebo. Since the placebo 
control includes only data from the matching placebo arms, these are considered as independent 
comparisons to support independent conclusion about success or failure of the trial with respect 
to the two investigational drugs. As a consequence, an adjustment of the type one error for the 
multiple testing across the two cohorts is not needed.  
To ensure control of the family-wise type I error rate within cohorts, the testing of the null 
hypotheses on the main endpoints will be done by a gatekeeping procedure based on the 
graphical approach to sequential rejective multiple test procedures (Bretz et al 2009, Maurer et 
al 2011) that combine hierarchical and simultaneous testing based on the Bonferroni inequality. 
The testing procedure is fully determined by an initial weighted graph where the elementary 
hypotheses are represented by vertices with associated weights representing the local 
significance levels. The weight associated with a directed edge between any two vertices 
indicates the fraction of the (local) significance level at the initial vertex (tail) that is added to 
the significance level at the terminal vertex (head) if the hypothesis at the tail is rejected. 
Together with the algorithm as specified by Bretz et al (2009) for sequentially updating the 
graph after rejection of a hypothesis, this approach controls the family-wise type I error rate 
strongly at level α. 
As shown by Bretz et al (2009) the test decisions are independent of the order of rejection. If in 
a step of the algorithm more than one hypothesis can be rejected, the choice of the hypothesis 
H0i does not influence the total set of hypotheses that eventually can be rejected. The initial 
graph and the algorithm unequivocally define the testing strategy. 
There are two primary efficacy variables and one key secondary which will be included in the 
multiple testing strategy. This yields to 3 statistical hypotheses which are as follows:  
H01: The primary active treatment arm does not differ from matching placebo with regard to 
the distribution of time to first diagnosis of MCI or dementia; 
H02: The primary active treatment arm does not differ from matching placebo in the mean 
change from Baseline to Month 60 in the APCC test score; 
H03: The primary active treatment arm does not differ from matching placebo in the mean 
change from Baseline to Month 60 in the CDR-SOB score; 
where Η01, Η02 are the primary null hypotheses, Η03 is the key secondary null hypothesis which 
are included in the multiple testing strategy. 
In addition to that, there are two hypotheses which will be tested at the cognition interim 
analysis: 
H01I: The primary active treatment arm does not differ from matching placebo with regard to 
the distribution of time to first diagnosis of MCI or dementia due to AD;  

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and 
H02I: The primary active treatment arm does not differ from matching placebo in the APCC 
time profile. 
All tests will be two-sided. A small portion (a thousandth) of the overall significance level alpha 
of 0.05 (5%) will be spent to control the type-1 error rate across final and IA using a Bonferroni 
split. The two hypotheses of the cognition IA will, therefore, not be included in the graphical 
approach to adjust for multiplicity. An alpha of 0.00004 will be spent for testing of H01I and an 
alpha of 0.00001 will be spent for testing of H02I. Thus, an alpha of 0.04995 can be spent for 
testing the above specified 3 hypotheses using the graphical approach. The alpha will be split 
unequally (80% vs. 20%) across the two hypotheses on the two primary endpoints. Hence, an 
alpha of 0.03996 will be spent for testing of H01 and an alpha of 0.00999 will be spent for testing 
of H02. 
Significance levels α1 = 0.03996 and α2 = 0.00999 (and α3 = 0) are initially defined such that 
they sum up to α = 0.04995.  
The procedure is as follows: Test the hypotheses H0i, i = 1, 2, 3 each at its local significance 
level αi. If a hypothesis H0i can be rejected, reallocate its level to other hypotheses according to 
a pre-specified rule represented by an initial weighted graph. Update the reallocation weights 
in the reduced graph and repeat the testing step for the remaining, non-rejected hypotheses with 
the updated local significance levels. This possibility leads to further rejected null hypotheses 
with the updated local significance levels. The procedure is repeated until no further hypothesis 
can be rejected.  
The reallocation of the local alpha levels is fully determined by the initial graph of the multiple 
testing strategy.  
Initial graph for CAD106: 
 

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Initial graph for CNP520: 
 
Motivation for this test procedure: These graphs are motivated by the following general 
considerations. 
The hypotheses Η01 and Η02 on the primary outcomes are considered to be more important than 
the hypothesis Η03 on the key secondary outcome. Thus, the significance levels are split in a 
way that Η01 and Η02 have larger initial significant levels. Once a null-hypothesis on the primary 
endpoints is rejected, the local initial significance level is passed on to the remaining hypothesis 
on the same level (primary) and/or or to the hypothesis in the lower level according to the 
portions specified in the graph.  
Implementation of the test procedure (example):  
If Η02 is rejected, the associated level α2 is split equally into 2 parts. One half is passed on to 
Η01, the other half is passed on to the hypothesis Η02. This leads to the local levels α1 updated  = α1 
+ ½ α2 = 0.03996 + ½ * 0.00999 = 0.04496 and α3 updated  =  ½ α2 = 0.00500. 
Table 9-2 
Local levels up to second level Part I 
 
Local level for Η01 
Local level for Η03 if Η01 
rejected 
Local level for Η03 if Η01 
not rejected 
Η02 not rejected 
0.03996 
0.03996 
0 
Η02 rejected  
0.04496 
0.04995 
0.00500 
Table 9-3 
Local levels up to second level Part II 
 
Local level for Η02 
Local level for Η03 if Η02 
rejected 
Local level for Η03 if Η02 
not rejected 
Η01 not rejected 
0.00999 
0.00500 
0 
Η01 rejected  
0.00999 
0.04995 
0.03996 
For all analyses included in the graphical approach, summary tables will present unadjusted p-
values; the adjustment will be applied in the discussion of the results. 

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9.8 
Sample size calculation 
The trial will involve the assessment of efficacy for two investigational treatments. The primary 
analysis will compare each active investigational treatment arm to matching placebo, i.e. only 
the placebo arm from the same cohort will be used. For the first cohort a number of 430 
participants in the active treatment arm CAD106 and 260 in the matching placebo group were 
calculated; for the second cohort a number of 390 in the active treatment arm CNP520 and 260 
in the corresponding placebo arm. In total, 1340 participants will be randomized into the study.  
Unbalanced randomization 
In order to optimize recruitment, an unbalanced randomization ratio of 3:2 is selected. Slight 
over-allocation to CAD106 is done with a 5:3 randomization ratio to account for expected 10% 
of participants who will not develop serological response. 
Type I error rate alpha and power 
The family-wise type I error rate α will be 5% within each cohort (rate of any false positive 
decision, i.e. at least one Null-Hypothesis is rejected although all were true). The overall α of 
5% will be split between the two primary hypotheses as follows: An alpha of 4% will be chosen 
to test the hypothesis H01 on the time to first diagnosis of MCI or dementia due to AD; an alpha 
of 1% will be chosen to test the hypothesis H02 on the APCC score. A small portion of a 
thousandth of the error rates will be spent (Bonferroni split) to account for multiplicity due to 
the IA on primary endpoints. Since the portion will be very small (Section 9.7), this has been 
ignored for power calculations. 
Since two primary null hypotheses and one hypothesis on the key secondary endpoint will be 
tested simultaneously, a graphical approach (Bretz et al 2009, Maurer et al 2011) will be used 
to adjust for multiplicity. Tests of hypotheses will be two-sided. The details of the multiplicity 
adjustment and the multiple testing strategy are outlined in Section 9.7.  
Sample size calculations were mainly driven by power considerations for the primary endpoint 
time to diagnosis of MCI due to AD or dementia due to AD, based on the variable follow-up 
time of 5 to approximately 8 years, with initially recruited participants followed for longer. The 
power, i.e. the probability to detect a true difference between treatment arms, was set to be at 
least 80% for this analysis.  
Simulations 
In addition to standard sample size calculations using the package PASS 2008, the sample size 
calculation of the trial has been supported by simulations.  Further details are described in the 
Sample Size documentation. 

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Different sources of evidence have been used to identify reasonable assumptions for sample 
size calculations. Results from the literature on the lifetime risk and the risk in the age group of 
interest to develop AD (Jansen et al 2015, Genin et al 2011) have been used as a starting point 
to understand the expected event rate in the planned study population. Up to now, there are no 
published results available about the expected time course of the novel endpoint APCC. Hence, 
longitudinal data from different available cohort studies has been evaluated and used as main 
source of evidence to simulate trial data: 
• Data from three cohort studies of aging and dementia at the Rush Alzheimer’s Disease 
Center (the Rush Alzheimer’s Disease Center’s Religious Orders Study [ROS], Memory 
and Aging Project [MAP], or the Minority Aging Research Study [MARS]); 
• longitudinal data from the National Alzheimer’s Coordinating Center (NACC), Washington 
University which specifically included a sub-group of APOE4 homozygotes in the age range 
of 60-75 years. 
The cohort data has been used to develop models to describe time to first diagnosis of MCI 
due to AD and dementia due to AD as well as for the time course of APCC. The distribution 
of baseline APCC, age and other characteristics from the Rush cohort have been used to 
simulate the target population. A number of 100 simulated trials have been used to investigate 
the power under different assumptions, as for instance on the age distribution. An age 
distribution of 1:2:2 for the age groups 60-64, 65-69, and 70-75 has been chosen which 
reflects the quota of 20% of participants in the lower age group. The observed event rate in 5 
years in the simulated trials was about 35%-40% which is in line with the assumption on the 
event rate in 5 years in the target population of 25 to 35% without enrichment for older ages 
and up to 40% in a population with age distribution of 1:2:2 (as described above).  
In Cohort II, it is assumed that all proposed active dose regimens leading to at least 50% BACE 
inhibition, are equally efficacious with regards to the primary clinical endpoints, and that a 
potential mild symptomatic worsening in cognition under active high doses of CNP520 will not 
impact long-term treatment effect (TTE or 5 years outcome of the APCC) of a long-term lower 
dose regimen not causing worsening in cognition. Hence, the following calculations apply to 
all potential dose regimen scenarios as described in this protocol. 
Sample size calculation based on the primary endpoint time to MCI due to AD 
or dementia due to AD 
The sample size calculation for the Time-to-event endpoint, i.e. for time to first diagnosis of 
MCI due to AD or dementia due to AD has been based on the following assumptions: 
• 60 to 96 months observation period,  
• 40% of participants experiencing an event in the control group for each cohort in 5 years 
observation period, 
• a hazard ratio of 0.67 in favor of the active treatment group, 
• 30% drop-out rate over 5 years (corresponding to a yearly drop-out rate of about 6.9%), 
• α = 4%, two-sided test. 
 Power and sample size have been investigated for the comparison versus matching placebo 
using a Logrank test (Lakatos) with PASS 2008, a Cox PH model in simulations, and 

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additionally, the Schoenfeld formula (Schoenfeld 1983). Based on the above-mentioned 
assumptions and a randomization ratio of 3:2 (active versus placebo), a total sample size of 650 
participants (390 participants in the active treatment arm and 260 in placebo) will be 
randomized into each cohort of the study.  
Assuming a treatment effect of HR = 0.67, 218 observed events are needed to reach at least 80% 
power in the comparison versus matching placebo based on the Schoenfeld formula, but the 
power for the comparison versus matching placebo may be higher using the Cox PH model 
adjusting for important prognostic factors in the primary analysis. In case of an assumed HR of 
0.67, the target number of events needed for each comparison of the active investigational 
treatment versus matching placebo is 218 for each investigational treatment. Hence, the final 
analysis of a cohort will be scheduled when the target number of at least 218 events has been 
observed within the cohort. Based on PASS 2008 and the above listed assumptions, the target 
number of 218 events will be observed when the last randomized participant will reach 5 years 
follow-up time. Assuming a smaller treatment effect of HR = 0.7, the target number of 275 
events would be needed to reach at least 80% power in the comparison versus matching placebo 
based on the Schoenfeld formula. 
Sample size and power calculations for TTE using the two-sided Logrank test (Lakatos) have 
been performed with PASS 2008 Version 08.0.11. 
Power calculations based on the primary endpoint APCC 
Power calculations for the APCC have been based on the same simulated trials as for the TTE 
endpoint for the comparison of each active investigational drug arm vs. matching Placebo. 
Hence, the above mentioned assumptions also apply to calculations for APCC. The following 
additional assumptions for the power calculations based on the change from baseline to Month 
60 in APCC are underlying the calculations for APCC:  
• Target power of 80%,  
• α = 1%, two sided test. 
The total sample size of n = 650 participants per cohort, with n = 390 participants in the active 
treatment arm and n = 260 in the placebo arm is sufficient to detect an effect size of 0.33 in the 
comparison of change from baseline to Month 60 on APCC in the active treatment arm versus 
matching Placebo using a simple t-test with a power of 80%. Results from simulations indicate 
that using a longitudinal model and adjusting for prognostic factors will increase power to detect 
an effect size of 0.33.  
Sample size and power calculations for APCC using the two-sided t-test have been performed 
with nQuery Advisor 7.0.  
Overall power 
The overall power to detect a true treatment effect in at least one of the two endpoints on each 
of the investigational drugs is higher as compared to the power calculated for the single 
endpoints. The power increase due to testing two hypotheses depends on the relationship 
between the two endpoints.  

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On the other side, the overall power will be lower as calculated above due to multiple futility 
IAs. The actual loss in overall power will depend on the rules for stopping due to futility and 
the operating characteristics of these rules. The rules will be specified in the DMC charter and 
analysis plan. The operating characteristics of the rules will be assessed, and rules will be 
defined such that power loss will be limited. 
9.9 
Power for analyses of key secondary variables and target 
engagement of CAD106 
Summary of assumptions for the power calculations based on the change from baseline to 
Month 60 in CDR- SOB score are the following: 
• Sample size of the treatment group is 390, sample size of the control group (matching 
placebo) is 260 
• treatment effect size of 0.33 ,  
• Drop-out rate 30% over 60 months, 
• Two sided two sample t-test. 
The distribution of CDR-SOB and also the distribution of the change from baseline in CDR-
SOB to Month 60 are expected to be right-skewed. A two-sample t-test is expected to result in 
more conservative power estimates in such situations as compared to other approaches such as 
the Mann-Whitney U test. Power calculations for the key secondary endpoint are based on the 
multiplicity adjustment strategy described in Section 9.7.  
The different scenarios in the multiplicity adjustment strategy described in Section 9.7 will 
result in the appropriate relocated alpha level to be used for the power calculation for this key 
secondary outcome. Thereby, it is assumed that the hypothesis test statistics for the two primary 
null hypotheses (H01 for the TTE endpoint and H02 for the APCC score) and the key secondary 
null hypothesis (H03 for the CDR-SOB score) are independent from each other. For each of the 
three possible scenarios, the following power calculations were made: 
1. H01 is rejected, H02 is rejected. The alpha levels for H01 and for H02 are both relocated for 
testing H03, i.e. the local level for H03 is α3 = 4.995%. The sample size of 390 vs 260 
participants for active treatment vs. matching placebo group will have a conditional power 
of 93% to detect a clinically meaningful reduction corresponding to an effect size of 0.33 
in CDR-SOB between active investigational treatment and matching placebo. 
2. H01 is rejected and H02 is not rejected. The alpha level for H01 is relocated for testing 
H03, i.e. the local level for H03 is α3 = 3.996%. The sample size of 390 vs 260 participants 
for active treatment vs. matching placebo group will have a conditional power of 91% to 
detect a clinically meaningful reduction corresponding to an effect size of 0.33 in CDR-
SOB between active investigational treatment and matching placebo. 
3. H01 is not rejected and H02 is rejected. Half of the alpha level for H02 is relocated for 
testing H03, i.e. the local level for H03 is α3 = 0.5%. The sample size of 390 vs 260 
participants for active treatment vs. matching placebo group will have a conditional power 
of 73% to detect a clinically meaningful reduction corresponding to an effect size of 0.33 
in CDR-SOB between active investigational treatment and matching placebo. 
The sample size calculations were performed using nQuery Advisor 7.0.  

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In the event that Novartis wants to perform testing on the samples that are not described in this 
protocol and not under the oversight of NCRAD biobank management (see Section 6.6.3.2), 
additional Institutional Review Board and/or Ethics Committee approval will be obtained. 
Special requirement for assessing the participant’s capability to consent 
Where required by the HA and/or EC/IRB, for participants who progressed to mild or early-
moderate dementia* (according to investigator’s judgement or confirmed by the PAC, whether 
dementia is due to AD or not), an additional process can be implemented to assess the 
participant’s capacity to consent prior to the post-treatment voluntary procedures (ie. lumbar 
puncture and/or PET scans at Week 104 and 260). This process will involve, a qualified person 
who will deliver the questionnaire “Assessment of capacity to consent to the participation in 
the Study CAPI015A2201J” that will be included as an Appendix to the approved local version 
of the Informed Consent Form. Adherence to this procedure will be documented in the local 
study files and the completed questionnaire archived as a source document with the Informed 
Consent. The verbatim answers from the participant to the following questions will be captured: 
1. Is your participation to the PET scans and the lumbar punctures voluntary? 
2. Can you tell me why the Study Doctor wants you to undergo a PET scan of your brain 
during the study? 
3. Can you tell me why the Study Doctor wants to take a sample of the cerebrospinal fluid 
during the study? 
4. Which side effects could appear while cerebrospinal fluid is being taken? 
The answers provided by the participant should demonstrate their capacity to understand the 
study requirements. The interviewer will determine the participant’s capacity to consent using 
his/her judgment on the validity on the answers provided and may inquire further to gather 
additional insight when necessary. 
Participants who do not demonstrate satisfactory understanding of the lumbar puncture and/or 
optional PET scans prior to Week 104 or 260, should not undergo these specific procedures 
they had consented to originally. Their study participation should nevertheless be continued if 
authorized by local regulations. Administration of investigational treatment, other voluntary 
less invasive procedures like blood sampling, and attending the protocol-specified visits can 
continue as planned.  
* Refer to Section 5.5.9 in case of progression to late-moderate or severe dementia.  
Re-consenting considerations  
In case of progression to cognitive impairment, capacity to consent should be assessed by the 
investigator based on the changes in cognitive status that are observed, such as MCI or dementia. 
Participants who progress to MCI (due to AD or other causes) or dementia (due to AD) with a 
diagnosis confirmed by the PAC (see Section 8.5) have to confirm their consent to continue 
taking study treatment. In case re-consent is not obtained, they should be encouraged to still 
continue attending study visits as long as they agree to do so. A specific section for re-
consenting to receive study treatment in such cases will be included in the ICF. 
Note: Refer to Section 5.5.9 in case of progression to late-moderate or severe dementia.  

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Upon signs of mild cognitive impairment, the investigator may consider appropriate discussion 
with the participant and the study partner to notify of this decline and assess the participant 
willingness to continue on treatment and/or attending study visits. Loss of capacity to consent 
will require involvement of family or institutionally authorized representative. Such 
consideration will be anticipated in the ICF, with specific signature for assent from the legal 
representative in such case, as appropriate per local regulations (e.g. for Germany, in case of 
loss of capacity to consent, the participant shall be discontinued from the study).  
In the event of a protocol and/or ICF amendment requiring the participant to re-consent, the 
investigator should use the above checklist (if applicable) and exert their judgment to assess 
ability to consent to the remaining study procedures and understanding any new risk 
information provided in the revised ICF. 
10.3 
Responsibilities of the Investigator and IRB/IEC  
Before initiating a trial, the Investigator/institution should obtain approval/favorable opinion 
from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
participant recruitment procedures (e.g., advertisements) and any other written information to 
be provided to participants. Prior to study start, the Investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with these 
documents and all of the instructions and procedures found in this protocol and to give access 
to all relevant data and records to the monitors, auditors, Quality Assurance representatives, 
designated agents of Novartis/the CRO, IRBs/IECs, and regulatory authorities as required. If 
an inspection of the clinical site is requested by a regulatory authority, the Investigator must 
inform Novartis/the CRO immediately that this request has been made. 
10.4 
Publication of study protocol and results  
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results. 
Trial data, blood, CSF, and imaging biomarker samples will also be stored for research purposes 
and participants will provide specific consent for such extended usage and option to share them 
with the scientific community under management from an independent committee. 
11 
Protocol adherence 
This protocol defines the study objectives, the study procedures, and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances should an 
Investigator collect additional data or conduct any additional procedures for any research related 
purpose involving any investigational drugs. 

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Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
All significant protocol deviations will be recorded and reported in the CSR. 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. Only amendments that are intended to eliminate an apparent immediate hazard 
to participants may be implemented immediately provided the Health Authorities are 
subsequently notified by protocol amendment and the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participants included in 
this study even if this action represents a deviation from the protocol. In such cases, the 
reporting requirements identified in Section 7 Safety Monitoring should be followed. 

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Vassar R, Kuhn PH, Haas C, et al. (2014) Function, therapeutic potential and cell biology of 
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Vernooij MW, van der Lugt A, Ikram MA, et al (2008) Prevalence and risk factors of cerebral 
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Weiss DS, et al (2004) The Impact of Event Scale-Revised. In J. P. Wilson, & T. M. Keane 
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Wahlund LO, Barkhof F, Fazekas F, et al (2001) A new rating scale for age-related white 
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