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



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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Amendment 03 (xx-Dec-2019) .......................................................................................... 13 
Summary of previous amendments ................................................................................... 15 
Protocol summary .............................................................................................................. 20 
1 
Introduction ....................................................................................................................... 29 
1.1 
Background ............................................................................................................ 29 
1.2 
Purpose .................................................................................................................. 31 
2 
Study objectives and endpoints ......................................................................................... 31 
3 
Investigational plan ........................................................................................................... 33 
3.1 
Study design........................................................................................................... 33 
3.2 
Rationale for study design ..................................................................................... 36 
3.3 
Rationale for dose, regimen, route of administration and duration of treatment ... 40 
3.4 
Rationale for choice of comparator ....................................................................... 43 
3.5 
Purpose and timing of interim analyses/design adaptations .................................. 44 
3.6 
Risks and benefits .................................................................................................. 44 
4 
Population .......................................................................................................................... 47 
4.1 
Inclusion criteria .................................................................................................... 47 
4.2 
Exclusion criteria ................................................................................................... 49 
5 
Treatment ........................................................................................................................... 51 
5.1 
Study treatment ...................................................................................................... 51 
5.1.1 
Investigational and control drugs .......................................................... 51 
5.1.2 
Additional treatment .............................................................................. 52 
5.2 
Treatment arms ...................................................................................................... 52 
5.3 
Treatment assignment and randomization ............................................................. 52 
5.4 
Treatment blinding ................................................................................................. 53 
5.5 
Treating the participant .......................................................................................... 54 
5.5.1 
Participant numbering ........................................................................... 54 
5.5.2 
Dispensing the study drug ..................................................................... 55 
5.5.3 
Handling of study and additional treatment .......................................... 55 
5.5.4 
Instructions for prescribing and taking study treatment ........................ 56 
5.5.5 
Permitted dose adjustments and interruptions of study treatment ........ 57 

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5.5.6 
Rescue medication ................................................................................ 57 
5.5.7 
Concomitant medication ....................................................................... 58 
5.5.8 
Prohibited medication ........................................................................... 58 
5.5.9 
Emergency breaking of assigned treatment code .................................. 61 
5.6 
Study completion and discontinuation ................................................................... 62 
5.6.1 
Study completion and post-study treatment .......................................... 62 
5.6.2 
Discontinuation of study treatment ....................................................... 63 
5.6.3 
Withdrawal of informed consent ........................................................... 64 
5.6.4 
Lost to follow-up ................................................................................... 65 
5.6.5 
Early study termination by the sponsor ................................................. 65 
6 
Visit schedule and assessments ......................................................................................... 66 
6.1 
Screening and disclosure process .......................................................................... 73 
6.1.1 
Psychological readiness and follow up at screening (
 
) ..................................................................................................... 74 
6.1.2 
Source of genotyping, genotype result and genetic disclosure ............. 75 
6.1.3 
Screening lab tests ................................................................................. 76 
6.1.4 
Assessment of brain amyloid status at screening .................................. 76 
6.1.5 
Assessment of unimpaired cognition at Screening: Diagnostic 
Verification Form .................................................................................. 77 
6.1.6 
Other screening Considerations ............................................................ 77 
6.2 
Screen failures, demographics/other baseline characteristics ................................ 79 
6.2.1 
Information to be collected on screening failures ................................. 79 
6.2.2 
Participant demographics/other baseline characteristics ....................... 80 
6.2.3 
Treatment exposure and compliance ..................................................... 80 
6.3 
Efficacy .................................................................................................................. 80 
6.3.1 
MCI due to AD or dementia due to AD (MCI/dementia) criteria 
assessment ............................................................................................. 82 
6.3.2 
API Preclinical Composite Cognitive (APCC) battery ......................... 83 
6.3.3 
Mini Mental State Examination (MMSE) ............................................. 84 
6.3.4 
Repeatable Battery for the Assessment of Neuropsychological 
Status (RBANS) .................................................................................... 84 
6.3.5 
Raven’s Progressive Matrices ............................................................... 85 
6.3.6 
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SOB) ............. 85 
 
........................................ 86 
6.3.8 
Everyday Cognition Scale (ECog) ........................................................ 86 
 
 87 
 
 87 

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13.3 
Liver and renal event and laboratory trigger definitions and follow-up 
requirements ........................................................................................................ 137 
14 Appendix 2: Role of study partner and key site personnel ............................................ 140 
 144 
16 Appendix 4: Recruitment methods .................................................................................. 145 
17 Appendix 5: A testing strategy with option for dose regimen modification and two 
endpoints .......................................................................................................................... 146 
17.1 
Design and definitions ......................................................................................... 146 
17.2 
The closed multiple testing procedure ................................................................. 147 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 31 
 
 41 
Table 5-1 
Prohibited medication ........................................................................... 58 
Table 5-2 
Restricted treatments ............................................................................. 60 
Table 6-1 
Assessment schedule ............................................................................. 67 
Table 6-2 
Steps required around genetic testing and disclosure ........................... 75 
Table 6-3 
Adapted assessment schedule for roll over participants from 
Screening 1 to Screening 3 .................................................................... 79 
Table 7-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 103 
Table 9-1 
Schedule of pre-planned Interim analyses .......................................... 120 
Table 13-1 
Clinically notable vital signs ............................................................... 135 
Table 13-2 
Abnormal laboratory values leading to participant exclusion ............. 135 
Table 13-3 
Liver Event and Laboratory Trigger Definitions ................................ 137 
Table 13-4 
Follow-up requirements for liver events and laboratory triggers ........ 137 
Table 13-5 
Specific Renal Alert Criteria and Actions ........................................... 139 
Table 16-1 
Referral source of participants ............................................................ 145 
Table 17-1 
Closed test for the standard design option .......................................... 147 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 33 
Figure 3-2 
Screening parts ...................................................................................... 35 
Figure 6-1 
Flow of screening steps ......................................................................... 73 
Figure 13-1 
Abnormal ECG measurements leading to exclusion alerts ................. 135 
Figure 15-1 
Body surface area, Rule of Nines ........................................................ 144 

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List of abbreviations 
AA 
 
Alzheimer’s Association 
Aβ  
 
Amyloid-beta 
ACR 
 
Albumin Creatinine Ratio 
AD 
 
Alzheimer’s Disease 
ADP 
 
Adaptation Decision Point 
ADNI 
 
Alzheimer’s Disease Neuroimaging Initiative 
AE 
 
Adverse Event 
AIBL 
 
Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing 
Alb 
 
Albumin  
ALP 
 
Alkaline Phosphatse  
ALT 
 
Alanine Aminotransferase 
APCC  
API Preclinical Composite Cognitive Battery 
API 
 
Alzheimer's Prevention Initiative 
APOE  
Apolipoprotein E 
AOPE4  
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  
German Health Authority (Bundesinstitut für Arzneimittel und Medizinprodukte) 
BP 
 
Blood Pressure 
Bpm 
 
Beats per minute  
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 
CHMP  
Committee for Medicinal Products for Human Use 
CIs 
 
Confidence Intervals 
CNAR  
Censoring Not At Random 
CNS 
 
Central Nervous System 
ConMed 
Concomitant Medication 
CPK 
 
Creatine Phospho Kinase 
CPO 
 
Country Pharma Organization 
CRA 
 
Clinical Research Associate 
CRF 
 
Case Report/Record Form (paper or electronic) 
CRP 
 
C-Reactive Protein 
CSF 
 
Cerebrospinal fluid  
C-SSRS 
Columbia Suicide Severity Rating Scale 

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CYP3A4/2C 
Cytochrome P450 3A4 / 2C 
DAR 
 
Dose Administration Record 
DCF 
 
Diagnostic Classification Form 
DDI 
 
Drug-Drug-Interaction 
DMC 
 
Data Monitoring Committee 
DMI 
 
(RBANS) Delayed Memory Index 
DNA 
 
Deoxyribonucleic Acid 
DRM 
 
Dose Regimen Modification 
DTI 
 
Diffusion Tensor Imaging 
DVF 
 
Diagnostic Verification Form 
EC 
 
Ethics Committee 
ECG 
 
Electrocardiogram 
ECog 
 
Everyday Cognition scale 
eCRF  
Electronic Clinical Report Form 
eCSSRS 
Electronic Columbia Suicide Severity Rating Scale 
EDC 
 
Electronic Data Capture 
EMA 
 
European Medicines Agency  
EoS 
 
End of Study  
EoT 
 
End of Treatment 
EU 
 
European Union  
FAS 
 
Full Analysis Set 
FDA 
 
Food and Drug Administration 
FIH 
 
First-in-human 
FLAIR   
Fluid-Attenuated Inversion Recovery 
fMRI 
 
functional Magnetic Resonance Imaging 
FWER  
Family Wise type I Error Rate 
GCP 
 
Good Clinical Practice 
GDS 
 
Geriatric Depression Scale 
γ-GT 
 
Gamma Glutamyl Transferase 
GRE 
 
Gradient Echo 
HA 
 
Health Authorities 
Hb  
 
Hemoglobin 
HbA1C  
Glycated Hemoglobin 
HDL 
 
High Density Lipoproteins 
HIV 
 
Human Immunodeficiency Virus 
HM 
 
Homozygote for APOE-4 
HMs 
 
Homozygotes for APOE4 
HT 
 
Heterozygote for APOE-4 
HTs 
 
Heterozygotes for APOE4 
IA  
 
Interim Analysis 
IN  
 
Investigator Notification 
INR 
 
International Normalized Ratio 
IB  
 
Investigator’s Brochure 
ID  
 
Identification  
ICF 
 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 

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IEC 
 
Independent Ethics Committee 
IMI 
 
(RBANS) Immediate Memory Index 
IRB 
 
Institutional Review Board 
IRB/IEC 
Institutional Review Board/ Independent Ethics Committee 
IRT 
 
Interactive Response Technology 
Kg  
 
Kilogram 
LCD 
 
Liquid Crystal Display  
LOAD   
Late Onset Alzheimer’s Disease 
LDH 
 
Lactate Dehydrogenase 
LDL 
 
Low Density Lipoprotein 
LDR 
 
Lower Dose Regimen 
LFT 
 
Liver Function Test 
LLOQ  
Lower Limit of Quantification 
LSM 
 
Least Square Means 
LP  
 
Lumbar Puncture 
MAP 
 
Master Analysis Plan 
MAR 
 
Missing at Random 
MCI 
 
Mild Cognitive Impairment 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEMS  
Medication Event Monitoring System 
mEoS  
Modified End of Study 
Mg 
 
Milligram 
mL 
 
Milliliter 
mm 
 
Millimeter 
MMRM  
Mixed Model Repeated Measure 
MMSE  
Mini‑Mental State Examination 
MNAR  
Missing Not At Random 
MRI 
 
Magnetic Resonance Imaging 
mTEC  
Modified Treatment Epoch Completion 
NACC  
National Alzheimer’s Co-ordination Center 
NFL 
 
Light-chain Neurofilaments 
Ng  
 
Nanogram 
NIA 
 
National Institute of Aging 
NOAEL  
No Observed Adverse Effect Level  
NPI 
 
Neuropsychiatric Inventory 
NPI-Q  
Neuropsychiatric Inventory Questionnaire 
NYHA   
New York Heart Association 
PAC 
 
Progression Adjudication Committee 
PCR 
 
Protein Creatinine Ratio 
P-Tau  
Phosphorylated-Tau 
p.o. 
 
Oral (per os) 
PD 
 
Pharmacodynamic 
PET 
 
Positron Emission Tomography 
Pgp 
 
P-Glycoproteins 
PH 
 
Proportional Hazards 
PK 
 
Pharmacokinetics 
PPW 
 
Premature Participant Withdrawal 

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PT-INR  
Prothrombin Time-International Normalized Ratio 
q.d. 
 
Quoque die (once each day) 
QOL-AD 
Quality‑of‑Life in Alzheimer’s disease 
QM 
 
Quality Management 
QTcF 
 
Fridericia QT correction formula 
RAS 
 
Randomized Analysis Set 
RBANS  
Repeatable Battery for the Assessment of Neuropsychological Status 
RBC 
 
Red Blood Cells 
RNA 
 
Ribonucleic Acid 
SAP 
 
Statistical Analysis Plan 
SAE 
 
Serious Adverse Event 
SAF 
 
Safety Analysis Set 
SC 
 
Study Coordinator 
sCr 
 
serum Creatinine 
SD 
 
Standard Deviation 
SMQ 
 
Standardized MedDRA Query  
SNRIs  
Serotonin Norepinephrine Re-uptake Inhibitors  
SOB 
 
Sum of Box 
SOC 
 
System Organ Class 
SOP 
 
Standard Operating Procedure  
SSRI 
 
Selective Serotonin Re-uptake Inhibitor 
STAI-AD 
State Trait Anxiety Inventory for AD 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
SUVR  
Standardized Uptake Ratio  
TdP 
 
Torsades de Pointes 
TBL  
 
Total Bilirubin 
TEC 
 
Treatment Epoch Completion 
THC 
 
Tetra-Hydro-Cannabinoid 
TI  
 
Therapeutic Index 
TSH 
 
Thyroid Stimulating Hormone 
TTE 
 
Time-To-Event  
ULN 
 
Upper Limit of Normality 
USM 
 
Urgent Safety Measure 
UTE 
 
Unsatisfactory Therapeutic Effect 
VolMRI  
Volumetric Magnetic Resonance Imaging 
Vs  
 
Versus 
WBC 
 
White Blood Cells 
WHO 
 
World Health Organization 
WoC 
 
Withdrawal of Consent 

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Glossary of terms 
Assessment 
A procedure used to generate data required by the study. 
Control drug 
Drugs(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 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 
100 mg once a day, 75 mg twice a day) 
Electronic Data Capture 
(EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. 
EDC includes the use of Electronic Case Report Forms (eCRFs) which 
are used to capture data transcribed from paper source forms used at 
the point of care. 
eSource 
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits.  
eSource combines source documents and case report forms (eCRFs) 
into one application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as 
appropriate. 
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained (e.g. prior to starting any of the procedures 
described in the protocol) 
Epoch 
A portion of the study which serves a specific purpose. Typical epochs 
are: screening/recruitment, wash-out, treatment, and follow-up 
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.” 
Medication pack number 
A unique identifier on the label of each investigational drug package 
Participant number  
A unique number assigned to each participant upon signing the 
informed consent  
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. 
Randomization number 
A unique identifier assigned to each randomized participant, 
corresponding to a specific treatment arm assignment 
Premature participant(s) 
withdrawal (PPW) 
Point/time when a participant exits from the study prior to the planned 
completion of all investigational treatment administration and/or 
assessments 

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Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a 
dataset, a spreadsheet or even hard-coded data, such as paper or 
eSource. 
Study drug/ treatment 
Any single drug or combination of drugs administered to the participant 
as part of the required study procedures; includes investigational drug 
(s), placebo/comparator active drug run-ins or background therapy 
Study Treatment 
Discontinuation (TD) 
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 
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 continue in the study any longer, and does not allow 
any further collection of personal data 

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Amendment 03 (7-Jan-2020) 
Amendment rationale 
This amendment documents, for completeness, the changes regarding follow-up of 
participants after early termination of the study according to the Investigators 
Notifications distributed between July-2019 and December-2019. 
 
The changes related to discontinuation of treatment with CNP520 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 299 (mTEC).  
• The following assessments were no longer required: MRI, PET and Lumbar Puncture 
for CSF samples. 
2. Modified End of Study visit 301 (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 
v02 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 
post-treatment assessments demonstrated reversal of the worsening in key measures of 
cognition after CNP520 treatment discontinuation. The unblinded 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: 
This protocol amendment documents the final set of cumulative modifications after the 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: specified timing of the mEoS visit with respect to the mTEC visit 
• Section 3.5 and 5.4: Additional post-treatment interim analysis after treatment termination 
• Section 6: Timing of mEoS visits 
• Table 6-1: Assessment Schedule for the mEoS visit 301 is modified accordingly. 
• 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 5.6.5 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 
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.  
Summary of previous amendments  
To date, two global amendments and one local amendment to the original protocol have been 
released with their respective rationale described below: 
Amended Protocol v02 (18-Dec-2018) 
Amended Protocol v01.01DE (01-Oct-2018) 
Amended Protocol v01 (01-Nov-2017) 
Amendment 2 (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 13Nov2018. Other changes to the protocol include change in 
dose adaptation strategy by introducing 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 along with a decline in cognition starting in the first 3 to 6 
months of treatment. The protocol is therefore amended to include an additional cognitive 
assessment with RBANS at the 3 month visit, as well as the NPI-Q at 3 and 6 months and every 
6 months thereafter.  
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 doses of CNP520 in this study, 
50 mg and 15 mg, achieve 86% and 68% median reduction of CSF Aβ, respectively.  

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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 incorporated into the 
protocol. Such dose regimen modification (DRM process) 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. While the protocol previously included an adaptive design allowing a 
dose reduction from the current 50 mg to 15 mg once daily dose, this amendment removes the 
original adaptation process since these two doses are deemed to be too close in terms of CSF 
Aβ lowering and replaces it with the DRM. 
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 the protocol based on Urgent Safety Measure (USM) dated 
13Nov2018 
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): 
• Table 6-1: addition of RBANS at 3 month, NPI-Q at 3 and 6 months and every 6 months 
thereafter.  
Section 1 - Background: Adding results from other BACE inhibitors 
Dose Regimen Modification (DRM) changes to the protocol 
• Section 3.1 Addition of Dose Regimen Modification (DRM)  
• Section 3.2: Addition of Dose Regimen Modification 
• Section 3:3:  Rationale for potential Lower Dose Regimen (LDR) if DRM is activated  
• Section 3:5:  Updated parameters for Interim analyses, frequency of DMC meetings and 
potential for DRM 
• Section 5.1.1: Describing process and documentation to activate the DRM 
• Section 9: Description of dose regimen and primary treatment arms for final primary 
analysis with or without DRM 
• Section 9.4 Description of primary analysis with and without DRM 
• Section 9.6 DRM added to regular DMC safety evaluation 
• Section 9.7 Partial conditional error rate approach removed. Description and rationale for 
closed testing procedure to address situation with and without DRM added. Handling and 
rationale for not accounting for DRM in statistical testing approach. Discussion of 
potential impact of DRM on type-1 error rate 
• Section 9.8 Discussion of potential impact of DRM on power and sample size 
• Section 3, 9 and 17: Removed reference to the ADP, replaced by DRM adaptation of the 
dose regimen only 
• Appendix 5: Description of partial conditional error rate approach to deal with ADP 
removed. Description of hypothesis with and without DRM added 

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Other changes to the protocol 
• Section 2: Addition of exploratory analyses for APOE genotyping, brain amyloid 
measurements and concordance between baseline CSF and PET results for elevated 
amyloid criteria 
• Section 4.1 and 4.2: Additional clarification for eligibility criteria 
• Section 5.1.2: Defines specific radiotracers to be used in select countries 
• Section 5.2: Describing process and documentation to activate the DRM. 
• Section 5.4: Removes blinding instructions during ADP 
• Section 5.5: Clarification of Participant numbering, Treatment assignment, dispensing and 
guidance dose adjustments/interruptions of study treatment  
• Section 5.5.7 and 5.5.8, Table 5-1 and Table 5-2: Clarification and additional examples of 
restricted and prohibited treatments 
• Section 5.6.3 Incorporate the new definition related to withdrawal of consent and personal 
data  
• Table 6-1: Clarification on footnotes 
Rules for repeating MMSE during screening (at visit 101 and visit 103)  
Tau PET and LP added at PPW/TEC, relax request for amyloid PET upon PPW/EoS  
adding optional phone call for compliance check at week 6 
• Table 6.2: Addition of source of genotyping, genotype result and genetic disclosure 
• Section 6.1.5: Moving the Diagnostic Verification assessment of unimpaired cognition 
from Baseline to Screening 
• Section 6.1.6.1: Description of extension of 12-week timeframe in screening period 
• Section 6.1.6.2: Description on adapted screening flow for roll over participants from 
API015A2201J study 
• Section 6.4.4.4: Local measurement of CSF cell count restricted to CNS-related safety 
concern in participant 
• Section 6.5.2: Additional clarification on amyloid measurement method 
• Section 7.2:  Paper SAE reporting updated to electronic (eSAE)  
• Section 7.7: clarification of use of the short eC-SSRS self-assessment PRO version 
• Section 8.1: Removes the use of central analytics organization for data review 
• Section 8.5: Clarifies handling and transfer of adjudication data 
• Section 8.4: Ad Hoc meetings for DMC increase frequency as needed 
• Section 9.4.4 Sub-group analysis 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 
• Appendix 1: Provides additional guidance on ECG, liver, and renal trigger alerts 
• Appendix 4: Clarifies participant referral process 

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• Correction to tau PET addition wording in Amendment 1 rationale: Include tau PET at 
screening, month 24 and month 60, to assess neurofibrillary tangles burden as a secondary 
endpoint (expected at the subset of sites that can access the tau tracer and have the 
required imaging capability) 
 
Germany-specific local amendment 01 to protocol v01 (v01.01DE)  
Amendment rationale  
The current amendment to protocol version 01 addresses the changes required by BfArM dated 
31 August 2018. No other changes are captured. 
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 together with these Germany specific changes. 
Changes to the protocol – marked as “for Germany only” 
Germany specific changes according to BfArM response: 
• Section 5.6.2: Adding clarification on discontinuation in case participant loses capacity to 
consent. 
• Table 6-1: New footnote 44 for interim safety check at week 6 in Germany only  
• Section 6.4.1, Section 6.4.2 and Section 7.7: Adding cross reference to Table 6-1 to clarify 
applicability of interim safety check at week 6.  
• Section 7.7: Clarify the C-SSRS is a self-reported Web version 
• Section 10.2: Specify that local regulations in Germany require the participant to be 
discontinued in case of loss of capacity to consent 
Amendment 1  
Amendment rationale  
The original study protocol v00 is amended to: 
Align with recent CNP520 IB update (Edition 4 released 25-Aug-2017) reflecting new data 
from: 
• (I) GLP embryo-fetal development studies : CNP520 is not genotoxic nor teratogenic 
therefore male contraception is no longer required   
• (II) 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. Concomitant medications associated with Torsades de Pointes are allowed, but 
timing of the triplicate ECGs is adjusted to expected Tmax of CNP520 
• Include tau PET at screening, 24 month and 60 month, mandatory in subset of sites to 
assess neurofibrillary tangles burden as a secondary endpoint (mandatory at the subset of 
sites that can access the tau tracer and have the required imaging capability) 

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Addressed the comments from the FDA on original protocol (feedback received 12-Apr-2017): 
• Highlighted the rationale for a blinded dose adaptation  
• Described visit window, multiplicity testing strategies and clarified timing of Interim 
Analyses  
Incorporate additional clarifications required by investigators, health authorities and ethics 
committees on: Data privacy (audio-recordings, skin photographs), rater qualification, etc… 

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ongoing participants have completed their month 60 assessment and (2) 
the overall targeted number of events has been reached (see Section 
3.3), whichever is later. The expected maximal duration for an individual 
participant is 96 months (8 years). The CNP520 50 mg dose arm is 
designated as the primary active arm, i.e. the active arm used for 
comparison with placebo in the primary analyses. 
The study will be conducted with a randomization ratio of 2:1:2 (CNP520 
50 mg: 15 mg: placebo). This study will allow a dose regimen 
modification (DRM) of the CNP520 doses. Based on the Data Monitoring 
Committee (DMC) recommendation and/or other data from studies 
becoming available for CNP520 or other BACE inhibitors, either the 50 
mg dose arm will be maintained as the primary active arm and the initial 
study design will remain unchanged, or the dose of CNP520 in both 
active arms will be replaced by a single lower dose regimen (LDR).   
The study is broadly categorized into 3 periods as Screening epoch, 
Treatment epoch and Follow-up epoch.  
 
Screening 
As part of informed consent process, participants will be informed of the 
risk of developing symptoms of Alzheimer’s disease in relation to age, 
APOE4 genotype, and brain amyloid status. Participants may receive 
disclosure of their individual test results for APOE genotyping and brain 
amyloid status (the latter optional for HMs). Screening will include several 
visits, separable into two parts: screening part I and screening part II.  
Screening part I will include the less invasive assessments and those 
expected to lead to highest screen failure, i.e. participants will have their 
APOE genotype assessed. After genetic counseling and disclosure, 
participant may take a few days to reflect on this information, before 
continuing to screening part II. A follow up will take place two to seven 
days post genetic disclosure. 
Screening part II starts after the reflection period, and contains safety 
assessments, various cognitive and neuropsychological scales, brain 
MRI scan, and mandatory either amyloid PET scan or a lumbar puncture 
to verify eligibility of HTs based on brain amyloid status. Although HMs 
are eligible regardless of their brain amyloid elevation, they will also 
undergo a PET scan or a lumbar puncture during screening (HMs can opt 
out of amyloid disclosure). Another reflection period may take place after 
amyloid disclosure. A follow up will take place two to seven days post 
disclosure and prior to baseline (see Section 6.1).  At the subset of sites, 
tau PET will be the last assessment prior to randomization. 
Altogether, the screening period from signature of ICF#B  is expected to 
last about 12 weeks. The screening period can be extended on a case-
by-case basis to accommodate scheduling.  
Treatment  
During the treatment period, participants who are randomized to the 
study will receive the investigational treatment or placebo for variable 
treatment duration: at least 60 months, and up to an expected maximum 
of 96 months.  
Participants will return to the study site every three months for drug 
dispensing. The measurements to assess efficacy endpoints are 
performed month 3, month 6 the first year and then every six months, and 
include various cognitive and neuropsychological scales with input from 
the study partner. 

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Safety related assessments (e.g. eCSSRS, physical, skin and 
neurological evaluations, laboratory tests, electrocardiograms (ECGs) 
brain MRI scans 
 AD biomarkers and tau PET (at 
the subset of sites that can participate) are conducted according to the 
schedule shown in Table 6-1. 
Voluntary assessments include amyloid PET scans, Lumbar Puncture
 
 
Follow-up  
The Follow-up visit will be scheduled 12 weeks after the last study drug 
administration. Participants will undergo efficacy and safety related 
assessments, as described in the assessment schedule. Participants will 
be discharged from the study after the Follow-up visit. 
Population 
The study will enroll cognitively unimpaired individuals who are between 
the ages of 60-75 years with at least one APOE4 allele (HMs or HTs) 
and, if HTs, with evidence of elevated brain amyloid.  
Approximately 2000 participants will be randomized in approximately 180 
centers worldwide. 
Key Inclusion criteria 
(refer to Section 4.1 for 
exhaustive details) 
Screening part I: Participants eligible for inclusion must fulfill all of the 
following criteria prior to scheduling the genetic disclosure. 
1. Written informed consent must be obtained before any assessment is 
performed as part of the study, including consent to receive 
disclosure of their risk estimates to develop clinical symptoms of AD 
based on their APOE genotype and, if HTs, with evidence of elevated 
brain amyloid. 
2. Male or female, age 60 to 75 years inclusive, at the time of signing 
the informed consent. To ensure that no more than 20% of 
participants in the age group 60-64 years are randomized across the 
whole recruitment period, a site level process will be implemented.  
3. 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. 
history of vasomotor symptoms), or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or 
tubal ligation. 
4. Intellectually, visually and auditorily capable, fluent in, and able to 
read, the language in which study assessments are administered 
(e.g. completion of at least six years of regular schooling or sustained 
employment or equivalent local level of knowledge). 
5. Mini-Mental State Examination (MMSE) total score ≥ 24(can be 
based on documented result obtained within the previous 3 months). 
6. Willing to have a study partner throughout the study. 
NB. Buccal swab, genetic disclosure, and corresponding 2-7 day follow-
up do not need to be repeated if already performed within the 
API015A2201J study (roll-over participants).  
Screening part II: Participants eligible for inclusion must fulfill all of the 
following criteria prior to randomization based on the results from the 
screening test procedures. 
7. Carrier of at least one ε4 allele of the APOE gene (inclusion #7a): 
• 
HMs with elevated or not elevated brain amyloid.  
OR 

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• 
HTs with elevated brain amyloid (inclusion #7b) (as measured in 
CSF collected via lumbar puncture or by amyloid PET imaging).  
 
Note: In cases where both lumbar puncture (CSF) amyloid and 
amyloid PET imaging tests are performed, at least one should be 
indicative of elevated brain amyloid.  
8. Cognitively unimpaired at screening visit as defined by : 
• 
Score of 85 or greater on the RBANS delayed memory index 
score  
AND 
• 
CDR global score of 0  
with two special exceptions: 
­ 
If the RBANS delayed memory index score is between 70 and 
84 (inclusive) AND the global CDR = 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. 
9. 
Having a study partner who agrees to participate in the study and 
who is intellectually, visually, and auditorily capable, and fluent in, 
and able to read, the language in which study assessments are 
administered. 
Additionally, the study partner must be capable of and willing to: 
• 
Accompany the participant to visits that requires the input of 
the study partner 
• 
Meet the definition of a “study partner” as described in 
Appendix 2 
Key Exclusion criteria 
(refer to Section 4.2 for 
exhaustive details) 
Screening part I: Participants will be excluded if they fulfill any of the 
following criteria prior to scheduling the genetic disclosure. 
1. 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,  current 
alcohol/drug abuse or dependence, or dependence within the last two 
years or history of traumatic brain injury associated with loss of 
consciousness and ongoing residual transient or permanent 
neurological signs/symptoms including cognitive deficits, and/or 
associated with skull fracture 
2. 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), or unstable angina. 

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3. 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. 
4. Current treatment with Cholinesterase Inhibitors (ChEIs) and/or 
another AD treatment (e.g. memantine). 
5. Clinically relevant depigmenting or hypopigmenting conditions (e.g. 
albinism, vitiligo) or active / history of chronic urticaria in the past 
year.  
6. Score “yes” on item four or item five of the Suicidal Ideation section of 
the Columbia Suicide Severity Rating Scale (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 2 years prior to screening. 
7. Lacking psychological readiness to receive APOE genotype / amyloid 
status results, as assessed based on investigator’s judgement 
supported by the  pre-disclosure rating scales: 
• 
Geriatric Depression Scale (GDS short form) total score > 6.  
• 
Six Item Subset Inventory of the modified State Trait Anxiety 
Inventory (STAI-AD) total score >17. 
8. Use of other investigational drugs prior to screening until: 
• 
Small molecules: after five half-lives, or within 30 days until 
the expected pharmacodynamic effect has returned to 
baseline, whichever is longer 
• 
Biologicals: blood concentration has returned to baseline (or 
below serological responder threshold) for antibodies 
induced by active immunotherapy; or five half-lives for 
monoclonal antibodies or other biologicals 
9. Treatment  
• 
in the four weeks prior to randomization with any drug or 
treatment known for the 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 treatment like 
tamoxifen, systemic immunosuppressive drugs like 
methotrexate or 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 drugs with the exception of 
those described in Table 5-2. 
10. Current chronic treatment (> three months) with : 
• 
Strong CYP3A4 inducers or strong CYP3A4 inhibitor;  
• 
Drugs with a narrow therapeutic index known to be primarily 
metabolized by CYP2C or CYP3A isoenzymes, and sensitive 
P-gp substrates (. 

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11. Violations of concomitant medication restrictions as described in 
Section 5.5.8 
12. Donation or loss of 400 mL or more of blood within eight weeks prior 
to screening blood sampling and/or Lumbar Puncture if applicable. 
13. Contraindication or intolerance to MRI investigations 
Screening part II: Participants fulfilling any of the following criteria based 
on results from the screening test procedures will be excluded 
14. A positive drug screen, 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. 
15. Previous participation in a CNP520 study with more than three month 
exposure to active treatment. 
16. Significantly abnormal laboratory results at screening, meeting the 
exclusionary alert values as described in the Appendix 1 (Table 13-3) 
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. 
17. Current significant ECG findings as reported by from 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 
18. 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, stroke, cerebrovascular disease as evidenced 
by multiple lacunar infarcts ≤ 20 mm or single infarct > 20 mm, 
evidence of cerebral contusion, encephalomalacia, aneurysms, 
vascular malformation, subdural hematoma or space-occupying 
lesions). 
19. If PET scans are scheduled for this participant: Total dosimetry 
above the acceptable exposure in the country when combining the 
previous or planned Nuclear Medicine Radiology exposure and the 
scheduled study PET scan(s).  
20. If CSF sampling is scheduled for this participant: Contraindication 
to lumbar puncture, e.g. low platelet count, abnormal prothrombin 
time international normalized ratio (PT-INR), history of back 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. 
Investigational and 
reference therapy 
• 
CNP520 15 mg 
• 
CNP520 50 mg 
• 
(potential for a lower dose of CNP520 6 mg) 
• 
Arm #1: CNP520 capsule p.o. for q.d. administration at 50 mg (or 
LDR) 

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• 
Arm #2: CNP520 capsule p.o. for q.d. administration at 15 mg (or 
LDR) 
• 
Arm #3: Placebo to CNP520 capsules p.o. for q.d. administration 
Both CNP520 dosage strengths will be provided as similar size and 
appearance (hard gelatin capsules) for oral administration (p.o.) once 
daily (q.d.) or once weekly (LDR)  
Placebo: 
• 
Matching placebo to CNP520 will be provided as capsules of similar 
size and appearance. 
Participants will be dispensed medication supplies for 3-month treatment 
with CNP520 50 mg or placebo for oral intake administration for the 
duration of the Treatment Epoch. 
All study treatments, including placebo, must be stored according to the 
storage conditions specified on the medication labels (do not store above 
25°C). 
Efficacy assessments 
Diagnosis of MCI due to AD or dementia due to AD  
MMSE (included in APCC) 
RBANS (included in APCC) 
Raven’s Progressive Matrices - subset (included in APCC) 
Clinical Dementia Rating Scale (Global score and Sum of Boxes  
Everyday Cognition Scale (ECog) 
volumetric brain MRI and PET scans 
Safety assessments 
Physical (including skin) and Neurological examination: 
• Vital signs 
• Height and Weight 
• Laboratory evaluations 
• 
Hematology 
• 
Clinical Chemistry 
• 
Urinalysis 
• Electrocardiogram (ECG) 
• Dermatological Assessments: 
• 
Skin evaluation 
• 
Pruritus  
• Safety brain MRI scans 
• Adverse events (including dermatological) and serious adverse events 
• Columbia-Suicide Severity Rating Scale (eC-SSRS) 
Other assessments 
AD Biomarkers: 
• 
Imaging biomarkers 
• 
Volumetric MRI 
• 
Diffusion tensor and diffusion weighted Imaging 
 
 

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• 
PET scans (amyloid and tau at subset of sites) 
• 
Fluid biomarkers: 
• 
CSF-based biomarkers (Aβ, tau, p-tau, NFLs, others) 
• 
Blood-based biomarkers (serum, plasma, blood for Aβ, NFLs 
 
Data analysis 
The final analysis will occur once the overall targeted number of events of 
498 for the study has been reached and all participants have completed 
their month 60 assessments or PPW. 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 general, efficacy analyses will be conducted on the FAS and safety 
analyses on the SAF. 
In the situation of no DRM of CNP520 dose, the primary active arm is the 
50 mg and the secondary active arm is the 15 mg. In case of DRM in 
both active treatment arms, the primary active arm will be defined by 
pooling arm #1 and #2. The primary analysis will contrast the primary 
active arm vs. placebo.  
There are two primary endpoint variables: TTE (time to first diagnosis of 
MCI due to AD or dementia due to AD) and the APCC test score. 
Success of the trial will be determined by a positive result in at least one 
primary endpoint on the primary active arm to be used for the primary 
analysis vs. placebo. 
The primary analysis to address the primary objective comprises 
statistical tests of hypotheses of both primary endpoints. The statistical 
tests will compare the primary active arm of the investigational treatment 
vs. placebo at the appropriate α-level. These elementary primary 
analyses are embedded in the overall testing procedure. 
To control the overall family-wise type I error rate (FWER) an appropriate 
multiplicity adjustment procedure using a closed testing strategy will be 
applied to the analyses of the primary efficacy variables. The procedure 
will take into account testing two endpoints, two active arms vs. placebo,  
and the IA on primary endpoints. 
For the primary active arm of the investigational drug, the following two 
null hypotheses will be tested corresponding to the two primary 
endpoints: 
H01(1): The primary active arm does not differ from placebo with regard to 
the distribution of time to first diagnosis of MCI due to AD or 
dementia due to AD; 
H02(1): The primary active arm does not differ from placebo in the mean 
change from baseline to month 60 in the APCC test score. 
The corresponding alternative hypotheses are: 
HA1(1): The primary active arm differs from placebo with regard to the 
distribution of time to first diagnosis of MCI due to AD or dementia 
due to AD; 
HA2(1): The primary active arm differs from placebo in the mean change 
from baseline to month 60 in the APCC test score. 
In a similar way, H01(2) and H02(2) and corresponding alternative 
hypotheses are defined for the secondary active arm.  
Time-to-event 
After the target overall number of events has been reached and after all 
participants have completed their month 60 visit or PPW, the team will 

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agree on the exact cut-off date/point for the final analysis. The final TTE 
analysis will include data until the cut-off point in the study. Any data 
collected after this cut-off point will not be used for the primary analysis of 
TTE. That means specifically that only confirmed events collected up to 
the data cut-off point will be counted. Confirmation information collected 
after the cut-off point to confirm an earlier (meaning before the cut-off 
point) adjudicated diagnosis of MCI or AD due to dementia will not be 
taken into consideration. As a consequence, the observation will be 
censored at the last date prior to cut-off point that the TTE endpoint was 
evaluated, and the unconfirmed diagnosis will not be counted as an event 
in the primary analysis.  
The primary analysis of the TTE endpoint will be based on a Cox 
proportional hazards (PH) model including treatment arm as a factor and 
adjusted for important baseline covariates.  
Terms will be included for the following effects:  
• 
treatment arm 
• 
baseline value of the APCC test score 
• 
age group (60-64 years, 65-75 years) 
• 
region (North America, Europe, Asia, Other) 
• 
genotype (HM, HT).  
APCC 
The final primary analysis of the APCC score will use data from all 
participants in the FAS.  
The primary analysis of the APCC score will be performed using a 
longitudinal model for the change from baseline: the mixed model 
repeated measure (MMRM).  
An unstructured covariance matrix will be assumed, and the model will 
include the following baseline covariates as fixed effects: 
• 
treatment arm 
• 
time as the discrete variable scheduled (mapped) visit window 
• 
baseline value of the APCC test score 
• 
age group (60-64 years, 65-75 years) 
• 
Region (North America, Europe, Asia, Other) 
• 
Genotype (HM, HT).  
and the following interaction terms: 
• 
treatment arm × visit window 
• 
baseline APCC test score × visit window 
The adjusted least square means (LSM)s of change scores for each 
treatment arm, the difference between the LSMs (active vs. placebo), the 
2-sided p-values (unadjusted for multiplicity) and associated confidence 
intervals (CIs) comparing the active and placebo LSMs, will be calculated 
from the MMRM analysis and presented for each visit. 
In addition to these primary analyses, sensitivity and supportive analyses 
are planned. 
Descriptive summary tables will be provided by treatment for AEs, safety 
MRI and other safety parameters based on the SAF. 
Key words 
Randomization, Placebo controlled, Parallel – group, APOE4 allele, 
homozygotes, heterozygotes, amyloid positive, preclinical Alzheimer’s 
Disease (AD) and Aβ lowering  

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1 
Introduction 
1.1 
Background  
There is high unmet medical need for effective prevention and treatment of Alzheimer’s disease 
(AD), one of the most prevalent neurological disorders among older people (i.e., >60 years of 
age) worldwide.  
The amyloid cascade hypothesis states that deposition of amyloid-beta (Aβ) is a very early event 
in the pathogenesis of AD starting a decade or longer before the first clinical symptoms. Aβ 
aggregates in oligomers and plaques that ultimately lead to neurodegeneration and dementia of 
the Alzheimer type (Selkoe and Hardly 2016). Strategies that target decreasing Aβ, e.g. through 
inhibition of Beta-site-APP cleaving enzyme-1 (BACE-1), an enzyme involved in the 
processing of the amyloid precursor protein (APP), have emerged as potential disease-
modifying treatments (Vassar et al 2014; Jonsson et al 2012)  
The development of drugs targeting amyloid focuses increasingly on the earlier stage of AD, 
i.e. mild cognitive impairment (MCI) and preclinical AD, a newly defined stage of AD which 
reflects current evidence that measurable changes in brain biomarkers may occur years before 
symptoms appear (Sperling et al 2011). It is presumed that benefits of a disease-modifying 
therapy targeting amyloid will be greatest during these early stages. If one or more forms of Aβ 
play an early role in the development of AD, and if an appropriate treatment is safe, tolerated 
and started early enough in the disease course, this treatment could have a profound clinical and 
public health impact by helping to slow down or prevent the progression of AD. 
The study CNP520A2202J is designed to provide efficacy, safety and tolerability data for 
CNP520 compared to placebo in people at risk for the onset of clinical symptoms of AD.  
The Apolipoprotein E (APOE) gene is associated with Aβ clearance, aggregation, and 
deposition (Liu et al 2013), and carriers of the Apolipoprotein E ε4 allele (APOE4) are at greater 
risk for late-onset AD (Bonham et al 2016) with an increased accumulation of Aβ starting at an 
earlier age (Jansen et al 2015). The population for this trial will include cognitively unimpaired 
participants at increased risk for the onset of clinical symptoms due to AD, based on their age 
and APOE genotype (APOE4 homozygotes (HMs) and heterozygotes (HTs)), with the further 
requirement of elevated brain amyloid for HTs. Most of these participants are considered to be 
in a stage of preclinical AD, i.e., they are at particularly elevated risk of developing AD 
dementia but do not have overt symptoms and do not meet criteria for MCI or dementia (Reiman 
et al 2009; Sperling et al 2011).  
This study will complement the ongoing CAPI015A2201J (also called “Generation Study 1”) 
study which focuses on the APOE4 HMs population. Both studies employ the same two primary 
outcomes: time-to-event (TTE) with event defined as diagnosis of MCI due to AD and/or 
dementia due to AD), and the Alzheimer’s Prevention Initiative (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 late-onset 
AD (Langbaum et al 2014). 

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CNP520 
CNP520 is an orally active BACE-1 inhibitor with approximately three-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 a 
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 months exposure, conducted in healthy adults ≥60 years of age. Clinical data 
generated to date have been collected in a total of 422 subjects that have been administered 
CNP520 (n = 335) or 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 APOE ε4 allele.  
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 
month appeared to be safe and well tolerated.  
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 once a day (q.d). Aβ40 
concentrations in CSF decreased by 91% compared to baseline after three month exposure at 
CNP520 85 mg q.d.  
CNP520 undergoes predominantly an oxidative metabolism via CYP3A4/5. Following three 
months of multiple dose administration of up to 85 mg CNP520 q.d., the mean terminal-half 
life was approximately 150 hours. CNP520 showed good brain penetration, indicated by 
cerebrospinal fluid (CSF) concentrations similar to the unbound plasma concentrations with 
both single and multiple dose administration. 
Further details are provided in the CNP520 Investigator’s Brochure (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). 
• LY3202626 did not indicate a change in cognitive performance over the duration of the 
trial (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) 

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Although CNP520 and the drugs being tested by other pharmaceutical companies all belong to 
the same class of drugs (BACE inhibitors), each drug has a unique safety profile. Encouraging 
results obtained with elenbecestat at a dose that results in a 57% lowering of CSF Aβ 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 CNP520 on cognition, global clinical 
status, and underlying AD pathology in people at risk for the onset of clinical symptoms of AD. 
The study will assess progression to clinical symptoms in participants treated with CNP520 
compared to placebo. 
2 
Study objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Primary Objectives 
Endpoints  
To demonstrate the effect of CNP520 vs 
placebo on time to diagnosis of MCI due to AD 
or dementia due to AD, whichever occurs first 
during the course of the study.  
Time to the first event with event defined as the 
first confirmed diagnosis of MCI due to AD or 
dementia due to AD. 
To demonstrate the effect of CNP520 vs 
placebo on cognition using APCC 
Change from baseline to month 60 in APCC 
score.  
Key Secondary Objectives 
To demonstrate the effects of CNP520 vs 
placebo on global clinical status  
Change from baseline to month 60 in Clinical 
Dementia Rating Scale - Sum of Boxes (CDR-
SOB) score.  
Secondary Objectives 
 
To demonstrate the safety and tolerability of 
CNP520 vs placebo 
Frequencies, changes from baseline, Kaplan-
Meyer estimates when applicable of : 
• 
Adverse events  
• 
Skin events based on a centralized 
dermatological monitoring  
• 
Safety findings from brain structural MRI 
central reader  
• 
Laboratory tests 
• 
Vital signs 
• 
ECG findings  
• 
Prospective suicidality assessment 
(ideation and behavior) from the self-
reported Columbia Suicide Severity Rating 
Scale eC-SSRS. 
To demonstrate the effects of CNP520 vs 
placebo on cognition using Repeatable Battery 
Change from baseline to month 60 in total 
RBANS score and individual neurocognitive 
domain index scores. 

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for the Assessment of Neuropsychological 
Status (RBANS) 
To demonstrate the effects of CNP520 vs 
placebo on function  
Change from baseline to month 60 in total 
score of the Everyday Cognitive (ECog) scale: 
ECog-subject and ECog-informant. 
To demonstrate the effects of CNP520 vs 
placebo on brain atrophy  
Change from baseline to month 24 and to 
month 60 on volume of brain regions as 
measured by volumetric MRI. 
To demonstrate the effects of CNP520 vs 
placebo on AD-related biomarkers  
Change from baseline to 24 and 60 months on: 
• 
neurofibrillary tangle burden as measured 
by standardized uptake ratio (SUVR) of 
PET scans with tau tracer 
• 
amyloid deposition as measured by SUVR 
of tracer PET scans  
• 
CSF/blood levels of Aβ40, Aβ42 
• 
neurodegeneration as measured by CSF 
levels of total tau and phosphorylated tau 
and NFL in blood/CSF 
Collected only in participants who consented to 
additional voluntary procedures  

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The DRM activation will follow the allocation of 2:1:2 across the three treatment arms, resulting 
in an overall randomization ratio of 3:2 for CNP520 (arm #1 and #2) vs placebo. 
The planned total number of randomized participants will not exceed n = 2000.  
Screening  
The proposed recruitment methods are described in Appendix 4. As part of the consenting 
process, participants will be informed of the risk estimate of developing symptoms of 
Alzheimer’s disease in relation to age, APOE4 carriage, and brain amyloid status. As part of 
the Screening process (ICF#B) participants will consent to receive disclosure of their individual 
test results for APOE genotyping and brain amyloid status.  
Screening will include several visits and will be split into two parts: screening part I and 
screening part II (see Figure 3-2).  
A preliminary informed consent (ICF#A) may be used for APOE genotyping only, in order to 
enable building a local database as described in Appendix 4 scenario 4. In such cases, 
genotyping under ICF#A (where applicable) takes place before screening part I. Screening part 
I starts with ICF#B (where applicable) and will include the less invasive assessments and those 
expected to lead to highest screen failure. Interactive Response Technology (IRT) is contacted 
and participant registered as in screening after signing ICF#B. After genetic counseling and 
disclosure, participant may take a few days to reflect on this information before continuing to 
screening part II. A follow up will take place two to seven days post genetic disclosure (see 
Section 6.1.1 for details).  
Screening part II starts after the first reflection period, and contains safety assessments, various 
cognitive and neuropsychological scales, brain MRI scan, and mandatory either amyloid 
Positron Emission Tomography (PET) scan or a lumbar puncture (LP) to verify eligibility of 
HTs based on brain amyloid status (see Section 6.1.4 for details and tracers). Although HMs 
are eligible regardless of their brain amyloid status (elevated/not elevated), they will also 
undergo a PET scan or a lumbar puncture during screening (HMs can opt out of amyloid 
disclosure). A follow up will take place two to seven days post amyloid disclosure and prior to 
baseline visit (see Section 6.1 for details). At the subset of sites, tau PET will be the last 
assessment prior to randomization. Another reflection period may take place after amyloid 
disclosure. 

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Figure 3-2 
Screening parts 
 
Altogether, the screening period (part I and part II, including reflection periods when required) 
is expected to last about 12 weeks. The screening period can be extended on a case-by-case 
basis to accommodate scheduling. In such case see Section 6.1 for guidance on assessments to 
be repeated to ensure continued eligibility during extended screening.  
The assessments to be performed are listed in the assessment schedule (Table 6-1) and include 
assessments to be performed by the investigator/study site personnel, participant and study 
partner (see definition of study partner and role of key study site personnel in Appendix 2).  
Treatment  
Participants who are randomized to the study will receive the investigational treatment or 
placebo for variable treatment duration: at least 60 months, and up to an expected maximum of 
96 months (see Section 3.3). 
During the treatment period participants will return to the study site every three months for drug 
dispensing. The measurements to assess efficacy endpoints are performed at 3 months and 6 
months during the first year and then every six months, and include various cognitive and 
neuropsychological scales with input from the study partner. 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 obtain by telephone interview. 
Safety related assessments will include regular standard assessments (e.g. eC-SSRS, vital signs 
physical evaluation, laboratory tests, electrocardiograms (ECGs)), as well as specific 
assessments related to potential CNS or other safety assessment requirements (skin photographs 
and pruritus evaluation, neurological evaluations, brain MRI scans for monitoring of 
cerebrovascular pathology and detection of ARIA) are conducted according to the schedule 
shown in Table 6-1. Brain MRI scans will be read centrally at the Imaging Central Review 
Vendor, with safety reports provided to the Investigators and Novartis Medical Monitor. 
Guidance to the Investigators in case of new findings is provided in Section 13.2.  

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 and AD biomarkers; and tau PET scans (expected at the subset 
of sites that can participate) are performed according to the schedule shown in Table 6-1. 
Voluntary assessments, include amyloid PET scan and/or lumbar puncture (for biomarkers 
 
) 
. 
At each visit, the Investigator will assess the participant for the presence of MCI or dementia 
using pre-specified criteria described in Section 6.3.1. 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, CNS biomarkers and clinical endpoints, throughout 
the study. The main purpose of the planned IAs will be safety monitoring and futility. If, at the 
time of the primary endpoint IA (see Section 3.5), futility is not met, the sponsor will plan an 
open-label extension study with CNP520 to be initiated after individual participants complete 
the double-blind phase of the study.  
Follow-up  
The Follow-up mEoS visit will be scheduled after the mTEC visit. Participants will undergo 
efficacy and safety related assessments, as described in the assessment schedule (Table 6-1). 
Participants will be discharged from the study after the Follow-up visit. 
Voluntary AD-related biomarker assessments 
Voluntary participation to undergo lumbar puncture for CSF collection and/or PET AD-
biomarker assessments is also expected. Additional CSF collection or amyloid PET scans will 
be proposed to participants as follows: 
• At screening: the alternative method to the one used to determine their amyloid status 
(CSF or PET), provided this alternative method is available. 
• Post-baseline at years 2 and 5: Follow-up assessments with the method(s) used at 
screening. 
3.2 
Rationale for study design  
The design of this study addresses the primary objectives, which are to assess the effect of 
CNP520 vs placebo on clinical progression of AD (i.e. time to diagnosis of MCI due to AD or 
dementia due to AD and cognition) in cognitively unimpaired participants at risk for the onset 
of clinical symptoms. This study design therefore implements an event driven design intended 
to treat individual participants until the overall targeted number of events of 498 has been 
observed. In addition, the design takes into account the minimum treatment duration of 60 
months required to assess the APCC endpoint at the end of 5 years.  

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Study population 
In order to select individuals with a greater likelihood of progressing to the diagnosis of MCI 
due to AD or dementia due to AD in a reasonable time frame, the study will enroll cognitively 
unimpaired individuals who are between the ages of 60 to75 years with at least one APOE4 
allele (HMs or HTs) and if HTs, with evidence of elevated brain amyloid (FDA 2012 Draft 
Guidance for Industry: Enrichment Strategies for Clinical Trials to Support Approval of Human 
Drugs and Biological Products; US Department of Health and Human Services, Food and Drug 
Administration Draft Guidance for Industry (2018), Early Alzheimer’s disease, Development 
Drugs for Treatment on the Clinical Investigation of Medicines for the Treatment of 
Alzheimer’s Diesease and other Dementias. 
APOE4 carriers are estimated to represent about 25 to 30% of the general population and are at 
higher risk of developing symptoms of Late Onset Alzheimer’s Disease (LOAD) than people 
who are non-carriers of the ε4 allele (Jansen et al 2015). The ε4 allele has been associated with 
reduced Aβ clearance, increased Aβ accumulation, increased Aβ-induced neurotoxicity, 
inflammation, reduced energy metabolism, impairment in mitochondrial function, aspects of 
metabolism, and other processes relevant to AD risk (Liu et al 2013). APOE4 carriers have 
greater fibrillar amyloid deposition than age-matched non-carriers and accelerated age-
dependent cognitive decline and the amount of amyloid deposition in preclinical AD individuals 
and rate of cognitive decline, respectively, are directly associated with ε4 gene dose (Reiman et 
al 2009).  
The risk of progression to MCI due to AD or dementia due to AD increases with age (Genin et 
al 2013). HMs are at particularly high risk (~30-55%) to develop clinical symptoms due to 
Alzheimer’s disease by age 85 (Qian et al 2017). No further enrichment beyond genotype and 
age will apply to the HM population. HTs in the age range 60 to75 years have a 20-25% lifetime 
risk for AD by age 85. In order to identify a population with a comparable risk and a similar 
progression rate to HMs within the same age range, HTs will be further enriched for the 
presence of elevated brain amyloid at screening.  
Longitudinal data from prospective cohort studies are not yet available to accurately determine 
risk estimates for developing dementia due to AD in cognitively unimpaired APOE4 HTs with 
elevated brain amyloid. However, the risk estimates were approximated based on the following: 
• the estimated life-time risk by age of 85, in the HTs (~20-25%) or HMs (~30-55%) is 
independent of amyloid status ;  
• proportion of non-elevated amyloid individuals among HTs (50%) and HMs (20%) at age 
of 60 to 75 years (Jansen et al 2015); and,  
• the low overall risk (estimated 10%) of dementia due to AD in amyloid-negative subjects. 
Using these assumptions, enrichment by elevated amyloid status increases the risk in APOE4 
HTs to ~30-40%.  

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Design features 
During the treatment duration, it is expected that at least 30% of the participants in the placebo 
group, either HMs or elevated amyloid HTs, will be diagnosed with MCI due to AD or dementia 
due to AD. The majority of the diagnoses are expected to be MCI due to AD. These assumptions 
of event rates are based on exploration of multiple longitudinal cohorts in observational studies. 
To ensure that a sufficient proportion of participants progress towards a diagnosis of MCI / 
dementia due to AD during the trial, the study will recruit no more than approximately 20% of 
participants in the age group 60-64 years. A site level process will be implemented to ensure 
these younger participants are enrolled throughout the recruitment period (see Section 5.5.1).  
Randomization across treatment arms will be stratified by age group, genotype, method used to 
determined brain amyloid elevation in HT and geographic region. The method used to derive 
the amyloid status may result in populations with slightly different AD risk estimates. 
Stratification by the method will secure proper balance of treatment allocation in related 
subgroups. 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. 
The screening assessments will be performed in sequential steps to minimize the number of 
participants exposed to invasive procedure (CSF sampling) or to procedures requiring 
transportation to other center (MRI, amyloid PET). Genotyping (APOE) and amyloid 
counseling and disclosure will be made available to all screened participants. The proposed 
flow of the screening steps is provided in Figure 6-1. 
Eligibility of HTs will require confirmation of an elevated amyloid status, which can be 
obtained using either an amyloid PET scan or a lumbar puncture to measure concentration of 
P-tau and Aβ in CSF (see Section 6.1.4). This allows flexibility depending on medical practice 
(acceptability of lumbar punctures) and availability of amyloid radiotracers at the site (see 
Section 6.5.3.2 for allowed amyloid radiotracers).  
Dose regimen modification 
The study will be conducted with a randomization ratio of the original once daily regimen dose 
arms 50 mg: 15 mg: placebo of 2:1:2. The unequal randomization will maximize the collection 
of safety information on the high dose of 50 mg. Non clinical and clinical data to date suggest 
that both CNP520 15 mg. and 50 mg once daily doses have an acceptable safety profile. Both 
doses are expected to lead to CSF Aβ lowering > 50% as well as the potential LDR if activated 
(refer to dose rationale in Section 3.3). The CNP520 50 mg once daily dose arm is designated 
as the primary active arm, i.e. the active arm used for comparison with placebo in the primary 
analyses. Data collected for the 15 mg dose arm will then be used to increase the knowledge on 
safety, biomarkers, and to explore clinical efficacy of the low CNP520 dose regimen and 
investigate the dose-response relationship.  
In case of DRM activation, the primary active arm will be defined by pooling the two active 
treatment arms. The primary objective of the study will compare effects of the overall long-
term exposure to CNP520 through the whole study duration across the dose regimens used 
versus placebo.  

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The testing procedure will cover both cases within the same approach (see Section 9.7). The 
planned total number of randomized participants will be approximately 2000.   
The potential bias caused by the procedure of the DRM such as potential un-blinding of 
investigators or participants will be operationally managed. In general, the following principles 
will be applied to the study to maintain the integrity and to avoid or control operational bias of 
any kind: (I) modification of the dose regimen is pre-planned and pre-specified in the Statistical 
Analysis Plan, (II) adaptation is kept to a minimum of two options for the LDR, (III) 
modification will be recommended by an independent DMC based on the pre-defined and 
specified options within the DMC charter and/or new data for CNP520 or other BACE 
inhibitors, (IV) the modification is restricted to the dose regimen, main design features like the 
total sample size, the randomization ratio, and the testing procedure remain unchanged. The 
DMC charter outlines the information channels for the release of DMC reviews. The amount of 
information about decisions following DMC recommendations to be shared with any persons 
involved in the study conduct will be pre-defined in the DMC charter and documented 
accordingly.  
This design strategy allows maximizing both the potential benefit to participants as well as the 
amount of benefit/risk information for selection of the recommended target dose regimen of 
CNP520. The decision to introduce the option for DRM and to remove the original potential for 
adaptation 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 will be determined by a positive result in at least one endpoint.  
The main primary endpoint is defined as time to first diagnosis of MCI due to AD or dementia 
due to AD. 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 8.5).  
The alternative primary endpoint, APCC test score, will allow examination of drug effects using 
a continuous measure of cognition from unimpaired throughout the mild impairment stages 
expected to occur in the study. Although there is no currently validated cognitive test sensitive 
to the initial stages of impairment, the APCC test was developed based on data from multiple 
longitudinal observational cohorts in cognitively unimpaired individuals at baseline in the target 
age-range (Langbaum et al 2014). It 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 sensitivity to detect and track cognitive decline in preclinical AD 

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(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. Individual assessments selected for inclusion 
in the APCC test battery are described in Section 6.3.2.  
Secondary endpoints  
Clinical Dementia Rating (CDR) is a global measure widely used in clinical research in AD, 
the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is an 
established clinical tool used to assess the neuropsychological status, and the Everyday 
Cognition scale (ECog) is a measurement of daily function and evaluation of memory concerns 
completed by both the participant and informant. The Clinical Dementia Rating – Sum of Box 
(CDR-SOB) score, RBANS total score, and ECog participant/informant (i.e. study partner) 
scores 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 Section 6.3).  
The study will also investigate the effects of CNP520 on the underlying AD pathology (e.g. 
amyloid and neurodegeneration: Aβtau, P-tau, NFLs in blood/CSF) assessed by additional 
biomarker data based on voluntary consent to lumbar punctures. 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 CNP520 to modify the 
course of the disease. These AD biomarker data will be also used to assess CNS activity (target 
engagement and downstream effects) at the CNS interim analysis (IA) (see Section 3.5). 
Furthermore, biomarker data would potentially allow assessment of the effect of CNP520 vs 
placebo on preclinical stage 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 one), 
abnormal amyloid and neuronal injury markers (stage two), and abnormal amyloid and neuronal 
injury markers and subtle cognitive changes (stage three). 
APOE4 has been linked to development of cerebral amyloid angiopathy (CAA, Greenberg et al 
2014). BACE inhibitors such as CNP520 might have potential to reduce vascular amyloid load 
and to therefore have beneficial effects on CAA and ultimately reduce the risk for microbleeds. 
Appropriate monitoring with T2/fluid-attenuated inversion recovery (FLAIR) and T2* gradient 
echo (GRE) MRI sequences will be implemented to monitor for these events.  
3.3 
Rationale for dose, regimen, route of administration and duration 
of treatment  
Dose 
Two dose strengths of CNP520 (50 mg once daily and 15 mg once daily) are used in this study.  
The targeted doses were selected based on the safety and tolerability as well as CSF Aβ lowering 
results obtained in the first-in-human (FIH) study CNP520X2101 and the three-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 

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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, and the 15 mg dose achieves 60% of CSF Aβ lowering in 90% of the subjects. 
The corresponding median CSF Aβ lowering are 86% and 68% for 50 mg and 15 mg, 
respectively.  
Genetic data suggest that a life-long 30% reduced Aβ production 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 a greater inhibition may 
be required to demonstrate efficacy.  
While both doses achieve a substantial effect on lowering Aβ (moderate and strong), these two 
doses have non-overlapping exposure distributions.  
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 no-observed-adverse-effect-level (NOAEL) provide substantial coverage. The predicted 
safety margins Area Under Curve (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).  

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time-limited exposure to a higher dose is not expected to impact potential effect of the treatment 
(i.e. delay the progression to clinical symptoms). 
Treatment duration 
Based on the mechanism of action of the investigational drug, no short-term benefit is expected, 
particularly in the preclinical stage of AD. It is expected that if the investigational drug delays 
the underlying pathological or pathophysiological disease processes, these changes will emerge 
only gradually over time. As discussed in the CHMP Guideline ( CHMP draft Guideline on the 
Clinical Investigation of Medicines for the Treatment of Alzheimer’s Disease and other 
Dementias, 2018) prevention trials require long treatment durations, typically of at least five 
years.  
In this study, participants will be treated for at least 60 months (five years) up to an expected 
maximum of 84 months (seven years). The minimum treatment duration of 60 months was 
chosen based on the likelihood of detecting (1) a 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. The expected maximum treatment duration for an 
individual is 96 months based on the TTE and recruitment assumptions (Section 9.8).  
The relationship between the treatment duration and the overall targeted number of 498 events 
needed for adequate power is further explained in Section 9.8. 
The process of study completion will be initiated when the overall targeted number of events 
for the final primary analyses is anticipated. In practice, the number of events will be monitored 
regularly in a blinded fashion throughout the course of the study while participants are being 
followed in the treatment epoch to estimate the time point when the required events (see Section 
9.4.1) will occur.  
The process of study completion comprises scheduling the end of treatment for each participant. 
At end of treatment visit Treatment Epoch Completion (TEC) or Premature Participant 
Withdrawal (PPW) each participant will commence the 12-week Follow-up until study 
completion (End of Study (EoS) visit).  
The expected drop-out rate for the study is approximately 30% over 5 years, corresponding to 
a yearly rate of about 6.9%. While there are no similar trials recently conducted that may 
directly inform the design assumptions, previous studies in a more progressed population 
(Petersen et al 2005; Feldman et al 2007; Doody et al 2009; Doody et al 2014) and a recent 
meta-analysis on cardiovascular endpoint trials (across 25 trials, Rodriguez et al 2015) support 
this number.  
3.4 
Rationale for choice of comparator  
Placebo will be used in a double-blind fashion. The use of a placebo control is considered 
essential to ensure study validity and allow for appropriate assessments of safety and tolerability 
data as well as efficacy data. No active comparator is used in this study as there is no treatment 
currently available for preclinical AD or to delay onset of clinical symptoms of AD. 

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3.5 
Purpose and timing of interim analyses/design adaptations  
The main purpose of the planned Interim Analyses (IA) will be safety monitoring, dose 
adaptation, and assessment of either futility or overwhelming efficacy, with the potential 
consequence of discontinuing one active treatment arm or the whole study. 
Interim analyses (also refer to Section 9.6 for details) and data review by the DMC are pre-
planned as follows: 
• Regular safety reviews (semi-annually, with an increased frequency as needed to 
appropriately evaluate the safety/tolerability profile of the current doses of CNP520 and 
the recommendation to maintain or modify the dose regimen via DRM):  
• Safety and tolerability parameter evaluation including the assessment of potential 
worsening of cognition on active study drug based on selected clinical endpoints (RBANS 
and CDR-SOB). The initial regular safety reviews during the recruitment period will also 
serve the purpose of potential design adaptation.. 
• Two Interim analyses to assess:  
• Futility based on CNS activity using some or all of  the following biomarkers:  
a. Volumetric MRI: hippocampal volume 
b. CSF: Aβ, tau, p-tau 
c. PET : tau tangles  
d. NFL in blood / CSF 
• Primary efficacy parameters (TTE and APCC test score) to assess futility or early 
stopping due to overwhelming efficacy.  
• An additional post-treatment IA was conducted by an independent team to assess the need 
for continued follow-up of participants after treatment termination.  
3.6 
Risks and benefits  
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 with 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 spontaneously. No dose-dependent AEs were identified.  
In Study CCNP520X2102, with the longest exposure duration so far (i.e. three months exposure 
in subjects ≥60 years of age at up to 85 mg daily, with a 1-month follow-up after last dose), 
there was no indication for an imbalance in AE incidence between CNP520 and placebo in any 
of the system organ classes (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 

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with generalized pruritus of moderate severity leading to discontinuation on CNP520 85 mg. 
Data from monthly dermatological assessments did not raise safety concerns. There were no 
clinically relevant alterations of laboratory tests, vital signs, ophthalmological assessments 
(visual acuity/field) or ECG data or any indication of systematic changes over time or as a 
function of dose. 
There was also no indication of impaired neurological function during the study and after one 
month 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.  
A pooled concentration-effect analysis of Holter- and 12-lead-ECG QT data from the first-
inhuman study (CCNP520X2101), the 3-month safety and tolerability study (CCNP520X2102) 
and the Japanese ethnic sensitivity study (CCNP520X1101) was performed. No 
QTcF prolongation was observed in the pooled analysis (for further details refer to CNP520 IB).  
Good Preclinical Practice (GLP) embryo-fetal development studies for CNP520 have been 
completed and CNP520 is not genotoxic and not teratogenic; 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 preliminary data, exposure to concomitant medications that are CYP3A4 
substrates may be reduced when treatment with CNP520 is initiated. Importantly, the effect of 
autoinduction on systemic exposure of CNP520 is not considered to be clinically relevant since 
there was no decrease in exposure over three months of treatment. 
No efficacy data have been generated to date. However, pharmacodynamic data have 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 tolerated (750 
mg) and 95% after multiple dosing (2 weeks) at the highest dose tested (300 mg q.d.). Aβ40 
concentrations in CSF decreased by 91% compared to baseline after three month exposure at 
CNP520 85 mg q.d. Similar changes in Aβ40 concentrations in CSF after CNP520 
administration were obtained for carriers of the APOE ε4 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 cognitive decline in pre-
clinical AD stages of the disease offers potentially important benefits.  
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, 
BACE inhibition, were associated with an increase in neuropsychiatric symptoms, along with 

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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. 
The Generation studies (current study and CAPI015A2201J study) focus exclusively on APOE4 
carriers who may benefit more from CNP520 based on their higher risk for amyloid 
accumulation leading to progression to symptomatic stages of AD. Presence of the APOE4 
allele has been linked to increased amyloid-β secretion in vitro 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 the 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. 
Risks of the procedures such as lumbar punctures, MRI and amyloid PET will be minimized by 
appropriate training, standardized procedures and close clinical monitoring.  
The study requires participants to receive disclosure of their APOE genotype results and the 
corresponding risk estimates for developing AD. In addition, the individual results of amyloid 
status at screening (elevated / not elevated) will be communicated to APOE4 HTs. They will 
also be proposed to HMs (although not a criteria for eligibility, so they may choose to forgo the 
disclosure of the result). Individuals with high levels of emotional distress before undergoing 
genetic testing are more likely to have emotional difficulties after disclosure (Green et al 2009; 
Green et al 2014). Therefore, the study has specific criteria to exclude participants whose scores 
on screening assessments indicate lack of psychological readiness to receive their individual 
risk estimates for developing AD (based on age, APOE4 genotype and amyloid status).  

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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 as 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 increase in psychiatric symptoms, 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 doses do not provide an 
appropriate risk/benefit, they will recommend to lower the dose which is one of the criteria for 
activation of DRM. The recommendation from each DMC meeting is 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 v02 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. 
4 
Population 
The study population will consist of cognitively unimpaired male and female participants at 
risk for the onset of clinical symptoms of AD, based on their age (60 to 75 years of age 
inclusive), APOE genotype (carrier of at least one ε4 allele) and, if HTs, evidence of elevated 
brain amyloid based on amyloid PET imaging or CSF testing at screening. It is expected that 
approximately 25-30 % of the general population without dementia are APOE4 carriers, of 
which about 50% are expected to have elevated brain amyloid (Jansen et al 2015) in this age 
group. Approximately 2000 participants will be randomized at approximately 180 centers 
worldwide. 
4.1 
Inclusion criteria 
Screening part I: Participants eligible for inclusion must fulfill all of the following 
criteria prior to scheduling the genetic disclosure. 
1. Written informed consent must be obtained before any assessment is performed as part of 
the study, including consent to receive disclosure of their risk estimates to develop clinical 
symptoms of AD based on their APOE genotype and, if HTs, their evidence of elevated 
brain amyloid status. 
2. Male or female, age 60 to 75 years inclusive, at the time of signing the informed consent. 
To ensure that no more than 20% of participants in the age group 60-64 years are 
randomized across the whole recruitment period, a site level process will be implemented 
(see details in Section 5.5.1).  

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3. 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. history of vasomotor symptoms), or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation.  
4. Intellectually, visually and auditorily capable, fluent in, and able to read, the language in 
which study assessments are administered (e.g. completion of at least six years of regular 
schooling or sustained employment or equivalent local level of knowledge). 
5. Mini-Mental State Examination (MMSE) total score ≥ 24 (can be based on documented 
result obtained within the previous 3 months). 
6. Willing to have a study partner (see definition Appendix 2 for definition of study partner) 
throughout the study. 
Screening part II: Participants eligible for inclusion must fulfill all of the following 
criteria prior to randomization based on results from the screening test procedures 
7. Carrier of at least one ε4 allele of the APOE gene (inclusion #7a): 
• HMs with elevated or not elevated brain amyloid 
OR 
• HTs with elevated brain amyloid (inclusion #7b) (as measured in CSF collected via 
lumbar puncture or by amyloid PET imaging). 
Note: In cases where both lumbar puncture (CSF) amyloid and amyloid PET imaging tests 
are performed, at least one should be indicative of elevated brain amyloid (see specific 
situations described in Section 6.1.4).  
8. Cognitively unimpaired at screening visit as defined by: 
• Score of 85 or greater on the RBANS delayed memory index score (DMI) 
AND 
• CDR global score of 0  
with two special exceptions: 
• If the RBANS DMI score is between 70 and 84 (inclusive) AND the global CDR 
= 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 DMI 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. 
9. Having a study partner (Appendix 2) who agrees to participate in the study and who is 
intellectually, visually, and auditorily capable, and fluent in, and able to read, the language 
in which study assessments are administered. 
Additionally, the study partner must be capable of and willing to: 
• Accompany the participant to visits that requires the input of the study partner 
• Meet the definition of a “study partner” as described in Appendix 2.  

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4.2 
Exclusion criteria 
Participants fulfilling any of the following criteria are not eligible for inclusion in this study. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible participants. 
Screening part I: Participants will be excluded if they fulfill any of the following criteria 
prior to scheduling the genetic disclosure.  
1. 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, current alcohol/drug abuse or dependence, 
or dependence within the last two years, or history of traumatic brain injury associated 
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. 
2. 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), or unstable angina. 
Note: the available Investigator Guide provides guidance on the interpretation of 
laboratory tests for HBV and HCV. 
3. 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. 
4. Current treatment with Cholinesterase Inhibitors (ChEIs) and/or another AD treatment 
(e.g. memantine). 
5. Clinically relevant depigmenting or hypopigmenting conditions (e.g. albinism, vitiligo) or 
active / history of chronic urticaria in the past year.  
6. Score “yes” on item four or item five of the Suicidal Ideation section of the Columbia 
Suicide Severity Rating Scale (eC-SSRS patient-reported outcome), 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 2 years prior to screening. 
7. Lacking psychological readiness to receive APOE genotype / amyloid status results, as 
assessed based on investigator’s judgment supported by the pre-disclosure rating scales: 
• Geriatric Depression Scale (GDS short form) total score > 6.  

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• Six Item Subset Inventory of the modified State Trait Anxiety Inventory (STAI-AD) 
total score >17. 
8. Use of other investigational drugs prior to screening until: 
• Small molecules: after five half-lives, or within 30 days until the expected 
pharmacodynamic effect has returned to baseline, whichever is longer 
• Biologicals: blood concentration has returned to baseline (or below serological 
responder threshold) for antibodies induced by active immunotherapy; or five half-
lives for monoclonal antibodies or other biologicals 
9. Treatment: 
• in the four weeks prior to randomization with any drug or treatment known for the 
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 treatment like tamoxifen, systemic 
immunosuppressive drugs like methotrexate or 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 drugs with the exceptions of those described in Table 5-2 
10. Current chronic treatment (> three months) with (see Table 5-1, expanded list is available 
as an Investigator Guide): 
• Strong CYP3A4 inducers or strong CYP3A4 inhibitors;  
• Drugs with a narrow therapeutic index known to be primarily metabolized by CYP2C 
or CYP3A isoenzymes, and sensitive P-gp substrates  
11. Violations of concomitant medication restrictions as described in Section 5.5.8. 
12. Donation or loss of 400 mL or more of blood within eight weeks prior to screening blood 
sampling and/or Lumbar Puncture if applicable  
13. Contraindication or intolerance to MRI investigations. 
Screening part II: Participants fulfilling any of the following criteria based on results 
from the screening test procedures will be excluded 
14. A positive drug screen, 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. 
15. Previous participation in a CNP520 study with more than three month exposure to active 
treatment. 
16. Significantly abnormal laboratory results at screening, meeting the exclusionary alert 
values as described in the Appendix 1 Table 13-2 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. 
17. Current significant ECG findings as reported by central reader that are assessed as 
clinically significant by the investigator  (e.g. sustained ventricular tachycardia, significant 

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second or third degree atrioventricular block without a pacemaker, long QT syndrome or 
clinically meaningful prolonged QT interval). QTc interval > 500 ms is exclusionary. 
18. 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), stroke, cerebrovascular disease as 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). 
19. If PET scans are scheduled for this participant: Total dosimetry above the acceptable 
exposure in the country when combining the previous or planned Nuclear Medicine 
Radiology exposure and the scheduled study PET scan(s).  
20. If CSF sampling is scheduled for this participant: Contraindication to lumbar puncture, 
e.g. low platelet count, abnormal prothrombin time international normalized ratio (PT-
INR), history of back 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. 
5 
Treatment 
5.1 
Study treatment 
5.1.1 
Investigational and control drugs 
CNP520 
• CNP520 15 mg 
• CNP520 50 mg  
In case of DRM, new study medication and/or an 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 three treatment arms using the 
currently dispensed medication packs may be implemented until updated LDR medication 
packs are available at sites. 
CNP520 dosage strengths will be provided as similar size and appearance (hard gelatin capsules) 
for oral administration (p.o.) in bottles supplied for at least three months of treatment.  
Placebo 
• Placebo to CNP520 will be provided as capsules of similar size and appearance in bottles 
supplied for at least three months of treatment.  

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An overage is included in all bottles to account for logistical constraints with visit scheduling.  
All study treatments, including placebo, must be stored according to the storage conditions 
specified on the medication labels (do not store above 25°C) and in accordance with regulations 
governing investigational medicinal products and local regulations.  
5.1.2 
Additional treatment 
If PET scans are scheduled, other study treatments include: 
• an amyloid PET radiotracer: 18F-florbetapir, 18F-flutemetamol, or 18F-florbetaben 
according to local regulations, (e.g. 18F-florbetaben only in Germany and 18F-florbetaben 
or 18F-flutemetamol only in Canada) and,  
• a tau PET radiotracer (18F-flortaupicir (AV-1451), MK-6240 or PI-2620) at a subset of 
sites that can access a tau radiotracer and have the required imaging capability and where 
locally permitted (e.g. applicable for USA and Canada with 18F-flortaucipir only). 
It is expected that each site will use only one of the amyloid PET and one of the tau PET 
radiotracers. 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 
Participants will be randomized at visit 201 after the pre-dose assessments have been completed. 
Participants will be assigned to one of the three arms with unequal randomization (2:1:2).  
• Arm #1: CNP520 50 mg capsule for. p.o. administrationor CNP520 LDR if DRM is 
activated 
• Arm #2: CNP520 15 mg capsule for p.o. administrationor CNP520 LDR if DRM is 
activated 
• Arm #3: Placebo to CNP520 capsules for p.o. administration 
If DRM is activated: 
• All participants already assigned to an active treatment arm (Arm #1 or Arm #2) will be 
transitioned from CNP520 50 mg or 15 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 #3 will be transitioned to matching Placebo for 
LDR. 
5.3 
Treatment assignment and randomization  
At baseline visit (visit 201), all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. 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 for the package(s) of study drug to be dispensed to the participant. 
The randomization number will not be communicated to the caller. 

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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and study site personnel. A 
participant randomization list will be produced by the IRT provider using a validated system, 
following an automated process. These randomization numbers are linked to the different 
treatment arms, which in turn are linked to medication numbers. The corresponding separate 
medication list(s) will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of medication 
numbers to packs containing the investigational drug(s). .  
Randomization will be stratified by: 
• Age: 60 to 64,  65 to 75 
• Region: North America, Europe, Asia, Other  
• Genotype: HM, HT 
• Method used to determine amyloid status (only for HT):  PET,  CSF  
In case both methods were used, the one indicating elevated amyloid will be captured, 
and if both results indicated elevated amyloid, then PET method will be considered 
for stratification. 
These factors will be entered by the site into the IRT at randomization call.  
Rationale for stratification factors is provided in Section 3.2. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Group. 
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 performing the assessments, and data analysts will remain blind to 
the identity of the treatment from the time of randomization until database lock, using the 
following methods:  
1. 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: 
 
 
• DMC members and unblinded statisticians and programmers in charge of the interim 
DMC outputs and Interim analysis (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.  
 

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All other data with potential for unblinding (typically markers of the treatment effect) 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. 
2. Although the randomization list will NOT be communicated to them, the following 
personnel will be considered as unblinded due to the results post-baseline: 
• AD biomarker analysts (Aβ, tau and p-tau in CSF and Aβ in plasma, NFLs in 
CSF/blood) 
• Analysts at the Imaging CROs (amyloid PET, tau PET) 
3. The identity of CNP520 will be concealed by the use of an identical matching placebo 
capsule and identical packaging, labeling, schedule of administration, appearance, taste 
and odor. 
Unblinding will only occur in the case of participant emergencies (see Section 5.5.9), and after 
the completion of the study.  
5.5 
Treating the participant 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
5.5.1 
Participant numbering  
Each participant is uniquely identified in the study by a combination of center number and 
participant number. This is the only number assigned to the participant throughout the study. 
The center number (4 digits) is assigned by the sponsor to the investigative site.  
Upon signing the informed consent form (ICF), the participant is assigned the next sequential 
3-digit number by the investigator. At each site, the first participant is assigned participant 
number 
, and subsequent participants are assigned consecutive numbers (e.g. the second 
participant is assigned participant number 
; the third participant is assigned participant 
number 
). Once assigned to a participant, it will not be reused and all participants will keep 
the participant number from screening onwards. 
If preliminary informed consent ICF#A is used, the same unique participant number will be 
used e.g. for buccal swab central lab requisition form. For example, if the site number is 
 
then the participant numbers should be assigned: 
, etc. 
Furthermore, participants who will start screening after consent under ICF#B, will keep the 
same participant number.  
In case of re-screening a new number will be assigned sequentially by the site.  
The investigator or study site personnel will contact the IRT once the participant has signed 
ICF#B to provide the requested identifying information for the participant to be registered. The 
site must select the Case Report Form (CRF) book with a matching participant number from 
the Electronic Data Capture (EDC) system to enter data.  
IRT provides an alert at screening, to help each site to manage a ratio of maximum 20% of 
participants randomized in the age group 60 to 64 years. Ideally, priority should be given to 

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to contact the investigator if the participant is unable for any reason to take the study treatment 
as prescribed. 
5.5.5 
Permitted dose adjustments and interruptions of study treatment  
Change in frequency of dosing by site or participant are not permitted. In case a daily dose was 
omitted, it can still be taken until approximately 6 hours after the usual once daily administration 
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 one 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.  
In the case that one or more dose(s) are missed, study treatment should resume as soon as 
possible. Any missed doses should be recorded on the Dosage Administration eCRF page. Also 
see Section 5.6.2 for reasons to discontinue or suspend study treatment. 
Investigational treatment should be suspended for participants: 
• who no longer have 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 they are taking medications listed in Table 5-1 leading to temporary 
suspension of investigational treatment (e.g. for an acute condition) 
• develop a condition/decision leading to suspension of  study treatment at any time for any 
reason  
• who request temporary suspension of study treatment 
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 
progression has been confirmed as meeting criteria for dementia due to AD (McKhann et al 
2011). Symptomatic treatments for AD (such as ChEIs or memantine) can be prescribed, in 
addition to the investigational treatment, only as per the approved label of the drug (i.e., only 
after the diagnosis of dementia due to AD and not during the preclinical or MCI stages). Once 
these medications are introduced, their dosage should not be adjusted in the six weeks preceding 
a clinical evaluation (see Table 5-2). 
Other CNS-active medications to control behavioral changes are allowed with restrictions as 
specified in Table 5-2.  

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Use of symptomatic treatment for AD must be recorded on the Concomitant medications / 
Significant non-drug therapies in the eCRF. 
5.5.7 
Concomitant medication 
The investigator must instruct the participant to notify the study site (by telephone and during 
study visits) about any new medications he/she takes after study enrollment. All medications, 
procedures and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the participant was enrolled into the study must be recorded in 
the concomitant medications / significant non-drug therapies eCRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. 
Treatment for pruritus 
In case of occurrence of pruritus, additional investigations and treatment should be performed 
as per local standard of practice. Treatment may include liberal uses of local emollients or oral 
anti-histamines. No other specific active treatment is recommended in the absence of 
inflammation/rash. If the pruritus is accompanied by an associated skin lesion/rash, a 
photograph will be taken for centralized dermatological assessment and topical steroids may be 
used. Systemic steroids should be reserved for cases of severe rash or other associated systemic 
symptoms. For moderate or severe pruritus referral to a specialist is recommended.  
For further information in relation to skin reaction and or pruritus, refer to Section 6.4.6.2. 
5.5.8 
Prohibited medication 
Use of the treatments listed in Table 5-1 is NOT allowed after the start of investigational drug. 
Treatment with any drug or treatment known for its potential to cause major organ system 
toxicity, i.e. drugs that may require periodic safety monitoring of a specific organ or body fluid.  
• Chronic use (> three months) of (extensive list of the drugs covered below is available as 
an Investigator Guide): 
• strong CYP3A4 inducer or a strong CYP3A4 inhibitor is prohibited due to the 
potential effect on CNP520 exposure. 
• narrow therapeutic index drugs known to be primarily metabolized by CYP2C or 
CYP3A isoenzymes, and sensitive P-gp substrates are prohibited, since CNP520 may 
be a weak inducer of CYP3A4 and consequently potentially also of CYP2C9 and P-
Glycoproteins (P-gp).  
• In addition, CNS-active drugs are generally prohibited except if listed and used within the 
restricted conditions specified in Table 5-2.  
Table 5-1 
Prohibited medication 
Medication 
Prohibition period 
Action taken during 
treatment phase 
Any drug or treatment known for its 
potential to cause major organ 
Pre-dose see Exclusion 
criteria #9 
Any use: Discontinue 
investigational treatment, 

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Medication 
Prohibition period 
Action taken during 
treatment phase 
system toxicity, i.e. drugs that require 
safety 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 immunosuppressive biological 
medicines for rheumatic diseases or 
multiple sclerosis  
Whole study duration 
(Treatment and Follow-
up epochs) 
continue monitoring participant 
at scheduled study visits until 
PPW or EoS 
Strong CYP3A inducer (e. g. 
carbamazepine , phenytoin, 
rifampicin , St John’s wort)  
Pre-dose see Exclusion 
criteria #10 
Whole study duration 
(Treatment and Follow-
up epochs) 
Acute use: allowed, no action 
(continue study treatment and 
visits) 
Chronic use (> three months): 
Discontinue investigational 
treatment, continue monitoring 
participant at scheduled study 
visits until Premature 
Participant Withdrawal (PPW) 
or End of Study (EoS) 
Strong CYP3A inhibitor (e.g. 
clarithromycin, grapefruit juice, 
itraconazole) 
Pre-dose see Exclusion 
criteria #10 
Whole study duration 
(Treatment and Follow-
up epochs) 
Acute use: Suspend 
investigational treatment; 
continue monitoring the 
participant at scheduled study 
visits, resume investigational 
treatment upon discontinuation 
of the strong CYP3A4 inhibitor 
Chronic use (> three months): 
Discontinue investigational 
treatment, continue monitoring 
participant at scheduled study 
visits until Premature 
Participant Withdrawal (PPW) 
or End of Study (EoS) 
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 (digoxin, talinolol). 
Pre-dose see Exclusion 
criteria #10 
Whole study duration 
(Treatment and Follow-
up epochs) 
Acute use: Suspend 
investigational treatment; 
continue monitoring the 
participant at scheduled study 
visits, resume investigational 
treatment upon discontinuation 
of the drug with narrow TI.  
Chronic use: 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 
Pre-dose see Exclusion 
criteria # 9 
Whole study duration 
(Treatment and Follow-
up epochs) 
Acute use: Suspend 
investigational treatment; 
continue monitoring the 
participant at scheduled study 
visits, resume investigational 

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Medication 
Prohibition period 
Action taken during 
treatment phase 
otherwise specified in Table 5-2 
below 
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 
Table 5-2 
Restricted treatments 
Medication 
Restrictions / action to be taken during treatment 
phase 
Anti-coagulants 
Anti-coagulant treatments are allowed.  However, 
when appropriate, review the International 
normalized ratio (INR) level and adjust dosage 
according to the prescribing information. 
CNS active drug: Cholinesterase 
inhibitor or memantine (permitted only 
after diagnosis of dementia due to AD 
and not during the preclinical or MCI 
stage). 
If initiated during the study (see Section 5.5.6) , 
maintain a stable dose in the six weeks prior to 
clinical evaluations 
CNS active drug: 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 administration 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). 
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 or fMRI (as 
applicable). 
CNS active drug: 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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Medication 
Restrictions / action to be taken during treatment 
phase 
CNS active drug: 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 administration 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). 
Resting state fMRI need not be performed during 
MRI examinations. 
CNS active drug: 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 six weeks prior to 
clinical evaluation. 
CNS active drug: Chronic or acute 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 that 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 
Emergency breaking of assigned treatment code 
In general, circumstances that might lead to emergency breaking of an assigned treatment code 
are uncommon. One unusual circumstance in which the breaking of an assigned treatment code 
might be necessary is when a participant requires emergency surgery and the anesthesiologist 
needs to know all medications to which the participant has been exposed in order to make proper 
decisions about treatment and support during the surgery. 

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Emergency code breaks must only be undertaken when it is required in order to treat the 
participant safely. Most often, study 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 Novartis monitor for the site and the 
Study Team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 
• study drug name (if available) 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.  
In case of emergency code breaking, the participant can continue attending the study visits and 
perform the protocol-required assessments until EoS but he/she cannot resume study treatment. 
If an extension is implemented, he/she may be eligible after a full assessment has been 
performed, condition has resolved and causality to study drug ruled out by the investigator or 
the DMC. 
5.6 
Study completion and discontinuation  
5.6.1 
Study completion and post-study treatment 
The study will be considered completed when all the following conditions are met: 
1. Target number of events has been reached  
2. All individual participants have performed their scheduled month 60 or the PPW visit 
3. All participants have completed their Follow-up visit 
Assuming the Target number of events was reached, the Treatment Epoch will complete 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 PPW/TEC column will be 
completed unless they were performed in the timeframe specified in footnote 37 to Table 6-1. 
Upon study completion (assuming futility was not met), participants may have the opportunity 
to enter an extension under a separate study, if eligible.  

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5.6.2 
Discontinuation of study treatment 
Participants may voluntarily discontinue the investigational treatment for any reason at any time. 
In case of permanent discontinuation or temporary suspension from study treatment, 
participants are encouraged to continue attending study visits and remain in the study. IRT 
should be notified of treatment discontinuation so that no further drug resupply is planned for 
this participant. 
Participants who progress to MCI/dementia due to AD should continue on the 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. 
• Withdrawal of Informed Consent (participant wish, see Section 5.6.3) 
• In the unlikely event of Pregnancy (see Section 7.6) 
• Use of prohibited treatment leading to discontinuation of treatment as per Table 5-1 or 
meeting criteria for treatment discontinuation with restricted medications listed in Table 5-
2 
• Any other protocol deviation or situation that results in a significant risk to the 
participant’s safety 
• Meeting the criteria for discontinuing the investigational treatment due to: 
• 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, laboratory tests, vital signs or ECG (Appendix 1).  
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 5-1 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. 

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Participants who discontinue the investigational treatment should NOT automatically be 
considered withdrawn from the study unless they explicitly withdraw their consent. They are 
expected to continue attending study visits according to protocol assessments as planned in the 
assessment schedule (with exception of drug dispensing and drug administration). 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 5.6.4.  
Missed or rescheduled visits or assessments should not lead to automatic discontinuation. 
Assessments required upon discontinuation from treatment epoch are detailed in the “PPW” 
column in the assessment schedule (Table 6-1) should be completed and recorded in the eCRF. 
The investigator must determine the primary reason for the participant’s discontinuation of 
study treatment and record this information on the Dosage Administration eCRF.  
Participants must be followed for 12 weeks after their last administration 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 assessments (EoS).  
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment, and also register the visits with no treatment dispensed until PPW/TEC and 
EoS. 
5.6.3 
Withdrawal of informed consent  
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore 
and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand 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.  
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the participant’s study withdrawal should be made as detailed in the 
assessment Table 6-1, PPW visit. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a participant’s samples until their time of withdrawal) according to 
applicable law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.  

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For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
5.6.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant cannot be considered as lost to follow-up 
until the time point of his/her scheduled EoS visit has passed. 
5.6.5 
Early study termination by the sponsor  
Novartis may terminate the trial for reasons related to the benefit/risk assessment of treatment 
for participants in the study, or for regulatory or medical reasons (including slow enrollment) 
in consultation with the DMC. In the event that the study is terminated early, the HAs and 
IRBs/ECs will be informed on reasons for early termination and the process to prematurely 
withdraw the participants. 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. 

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6 
Visit schedule and assessments 
A preliminary step may be performed to obtain a buccal swab for APOE genotyping to be 
recorded in the local site database using the dedicated ICF#A. (refer to Appendix 4) 
Table 6-1 lists all of the assessments and indicates with an “x” when the visits are performed. 
Participants must be seen for all visits during the designated period, or as close to it as possible. 
Scheduled study visits during the treatment epoch may require multiple visits spread over 
different days that should be scheduled within the ±4-week window (exception for the cognitive 
assessments at month 3 
, see Table 6-1, footnote 45). Missed or 
rescheduled visits or assessments should not lead to automatic discontinuation. Upon study drug 
discontinuation, all dispensed investigational product should be reconciled.  
Participants are encouraged to continue attending study visits even after study drug 
discontinuation. After the Early Termination of the treatment per the 11 July 2019 USM 
notification, mEoS visits can be scheduled any time after receipt of the Follow-up #2 
notification but no later than 15-Mar-2020, and may be converted to a phone call in case of 
logistical constraints. 
All adverse events and concomitant medications should be reconciled on the eCRF prior to End 
of Study (EoS). 

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Table 6-1 
Assessment schedule 
Epoch 
Screening2 
Treatment 
Visit Name Scr1 Scr2 Scr3 Scr4 Scr5 Scr6 Scr7 Bas Y1Q1 
39 
Y1Q2 Y1Q3 Y1Q4 Y2Q1 Y2Q2 Y2Q3 Y2Q4 Y3Q1 Y3Q2 Y3Q3 Y3Q4 
Visit Numbers 101 
102 
103 
104 
105 
106 
107 
201 
202 
203 
204 
205 
206 
207 
208 20940 210 
211 
212 
213 
Weeks 
 
 
 
 
 
 
 
 
13 
26 
39 
52 
65 
78 
91 
104 
117 
130 
143 
156 
Main study Informed consent 
(ICF#B) 
X3,4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion criteria 
S 
  
S5 
  
  
  
  
S5  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history/current 
meds/AD family history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
APOE Genotype (buccal 
swab) may be done as a 
preliminary step using ICF#A 
X6 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs7 
X 
  
  
  
  
  
  
X(S44) 
X 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
MMSE 
X8 
  
X8 
  
  
  
  
X9 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Electrocardiogram (ECG)15 
  
X14 
  
  
  
  
  
  
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Physical / Skin / Neurological 
Exam 
  
S 
  
  
  
  
  
(S44) 
S16 
S16 
 
S16 
  
S16 
  
S16 
  
S16 
  
S16 
MCI / Dementia Diagnostic 
Verification18/ Classification 
  
  
X 33 
  
  
  
  
 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
RBANS (APCC)19,20 
  
  
X 
  
  
  
  
X9 
X9,45 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Raven's (APCC)19,20 
 
 
X 
  
  
  
  
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 

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Epoch 
Screening2 
Treatment 
Visit Name Scr1 Scr2 Scr3 Scr4 Scr5 Scr6 Scr7 Bas Y1Q1 
39 
Y1Q2 Y1Q3 Y1Q4 Y2Q1 Y2Q2 Y2Q3 Y2Q4 Y3Q1 Y3Q2 Y3Q3 Y3Q4 
Visit Numbers 101 
102 
103 
104 
105 
106 
107 
201 
202 
203 
204 
205 
206 
207 
208 20940 210 
211 
212 
213 
Weeks 
 
 
 
 
 
 
 
 
13 
26 
39 
52 
65 
78 
91 
104 
117 
130 
143 
156 
CDR, ECog19,21,20,18 
  
  
X 
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
MRI (safety, volMRI, 
) 
22,20 
  
  
  
X23 
  
  
  
  
  
X 
  
X 
  
  
  
X 
  
  
  
X 
Amyloid PET22,20 
  
  
  
  
X11,23
,24 
  
  
  
  
  
  
  
  
  
  
X25 
  
  
  
  
Tau PET26 
  
  
  
  
  
  
X27 
  
  
  
  
  
  
  
  
X 
  
  
  
  
Drug Dispensing and 
Administration28 
  
  
  
  
  
  
  
X29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE/ConMeds  
As needed 
eC-SSRS 
X 
  
X10 
  
  
  
X10 
Every visit  including unscheduled visits (44) 
Laboratory evaluations 
  
X14,34 
  
  
  
  
  
  
X 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Lumbar puncture22,35,36,25 
  
  
  
  
X24,23 
  
  
  
  
  
  
  
  
  
  
X25 
  
  
  
  
Biomarker Plasma/Serum 
  
  
  
  
X 
  
  
  
X 
 X 
 
X 
  
  
  
X 
  
  
  
X 

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Epoch 
Treatment 
Visit Name Y4Q1 Y4Q2 Y4Q3 Y4Q4 Y5Q1 Y5Q2 Y5Q3 Y5Q4 Y6Q1 Y6Q2 Y6Q3 Y6Q4 Y7Q1 Y7Q2 Y7Q3 Y7Q4 Y8Q1 Y8Q2 Y8Q3 PPW/TEC 
Visit Numbers 214 
215 
216 
217 
218 
219 
220 22140 22241 22341 22441 22541 22641 22741 22841 22941 23041 23141 23241 
29942 
Weeks 169 
182 
195 
208 
221 
234 
247 
260 
273 
286 
299 
312 
325 
338 
351 
364 
377 
390 
403 
415 
Vital Signs7 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
MMSE 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Electrocardiogram (ECG) 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Physical / Skin / 
Neurological Exam 
  
S16 
  
S16 
  
S16 
  
S16 
  
S16 
  
S16 
  
S16 
  
S16 
  
S16 
  
S16 
MCI / Dementia 
Diagnostic Classificaton18 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
RBANS (APCC), Raven's 
(APCC)19,20 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
CDR, ECog19,21,20,18 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
MRI (safety, volMRI, 
) 
22,20 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X37 
Amyloid PET22,20 
  
  
  
  
  
  
  
X25 
  
  
  
  
  
  
  
  
  
  
  
X25, 37 
Tau PET26 
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
X37 
Drug Dispensing and 
Administration28 
X 
X 
X 
X 
X 
X 
X 
X 
X38 
X38 
X38 
X38 
X38 
X38 
X38 
X38 
X38 
X38 
X38 
  
AE/SAE/ConMeds 
As needed 
eC-SSRS 
Every visit including unscheduled visits 
Laboratory evaluations 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 

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µ Lab result must contain information from the 2 alleles 
6.1.3 
Screening lab tests 
In addition to the regular laboratory tests described in Section 6.4.4, the following test will be 
performed during screening: 
• A buccal swab for APOE genotyping will be analyzed (under ICF#A as applicable) to 
determine APOE genotype and will also be stored for re-analysis with different assays / 
methods across all participants once the recruitment is completed  to support the 
development of a potential companion diagnostics test if needed.  
•  A urine drug screen will be performed for confirmation of eligibility and may be repeated 
once for the purpose of inclusion of participants who initially test positive but are not 
suspect of having engaged in drug abuse / use of illicit substances. 
• A urine sample for analysis of creatinine, total albumin, total protein and their respective 
ratios. 
• A serology screening to test for Lyme disease (boreliosis), Hepatitis B and C (including 
reflex confirmation in case of positive IgG results), syphilis, and HIV may be performed if 
a previous result is not available from past 12 months as 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. 
6.1.4 
Assessment of brain amyloid status at screening 
The last step of the qualifying assessments at screening will confirm brain amyloid status 
(elevated/not elevated). During the accumulation of amyloid into plaques in the brain of 
participants at risk for AD, the levels of several form Aβ species and tau / p-tau will change in 
the CSF collected by a lumbar puncture; and amyloid plaques will be detected by the amyloid 
PET radiotracers. The study allows either method for confirmation of brain amyloid status, 
which is required for enrollment of the HTs. For HMs the procedure is also mandatory even 
though elevated amyloid status is not required for eligibility. In exceptional circumstances, 
HMs can be enrolled in case of a contra-indication to lumbar puncture if no PET tracer is 
available. For APOE4 homozygote participants who opt out from amyloid disclosure, the 2 to 
7 days follow up post amyloid disclosure is not applicable.  The lumbar puncture CSF assay 
selected for the study will allow to run real time quantitative analysis of several forms of Aβ 
and tau / p-tau concentrations in the CSF. .. The lumbar puncture will be performed according 
to specific procedures described in the Laboratory Manual. The CSF samples collected  will be 
sent to a central laboratory, where the selected validated assay will be used. The cut-off value 
to determine the amyloid status as elevated/not elevated will depend on the assay selected. The 
results will be provided to the clinical site. The remainder of the CSF collected will be frozen 
and stored as screening AD-related biomarker sample in all participants (even if they do not 
consent to further post-baseline CSF collection, or screen failed after the lumbar puncture was 
performed). The assessment of elevated brain amyloid from the central lab is required to 
document eligibility for APOE4 HTs. 

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6.1.6.1 
Screening extensions 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 Section 6.1.6 for potential
re-screening in case of temporary conditions).
•
Any screening (including Baseline) assessment supporting eligibility criteria must be
performed within 12 weeks before the date of randomization. Assessments that are
collected again during screening/baseline per Table 6-1, 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 or
lumbar puncture to verify brain amyloid levels are valid without any limitation and do no
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 Baseline pre-dose, CDR is only collected once a V103 and needs to be
repeated beyond 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 6.3.4 for
APCC requirements during Screening.
6.1.6.2 
Adapted screening flow for roll over participants from API015A2201J 
study 
Table 6-3 describes assessments completed in API015A2201J study optimized for roll over 
participants. Concomitant Medications and Medical History have to be re-entered on eCRF and 
checked for any changes since API015A2201J interview.  Similarly, V101 pre-disclosure scales 
& AD Baseline characteristics need to be re-entered in Virgil. Source data should document 
date of genotype disclosure in API015A2201J.  

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• Diagnosis of MCI due to AD or dementia due to AD 
• MMSE (also contributing to APCC) 
• RBANS all domains (also contributing to APCC) 
• Raven’s Progressive Matrices – subset (also contributing to APCC) 
• Clinical Dementia Rating Scale (Global score and Sum of boxes)  
 
 
• Everyday Cognition Scale (ECog) 
 
 
 
 
 
 
Cognitive testing must be administered by a clinician/rater certified by the rater training 
program of the dedicated Cognition vendor, including regular re-training. The selected raters 
will complete a pre-qualification survey.  Criteria for granting “pre-qualification” status is based 
on their 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.  
If not available from previous 3 months documentation, the initial MMSE at the first Screening 
visit may be administered by a non-certified rater using a paper version of the MMSE (not 
transcribed to Virgil in such case). 
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 the cognitive and 
other test results (i.e. using a separate user ID on the Virgil® tablet) and should not be the 
Physician completing the DVF.  
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 objectives (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, beside the audio recordings 
that will not be transferred to Novartis but destroyed after the end of the study. 
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 
must record the events as per instructions given in Section 7.1 and Section 7.2 of the protocol.  
Paper versions are available in case of technical issue.  

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6.3.1 
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 due to AD (Albert et al 2011) 
or dementia due to AD (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. 
However, with the six month visit intervals for cognitive assessments and potentially rapid 
progression in the participants at risk for clinical symptoms of AD, 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, 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), measures of daily function and measure of 
subjective/observer memory concerns (ECog – both informant [study partner] and participant 
versions), and other assessments (e.g. 
 MRI or other safety tests as needed). The 
investigator or deputy physician (sub-investigator) will complete the DCF on the Virgil® tablet 
with a narrative supporting his assessment. 
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 detail in a specific charter.  
The adjudication process will be triggered by: 
• A change in diagnostic status as captured on the DCF on the Virgil® tablet; or 
• Any increase from baseline on the global CDR score until a 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 cognitively unimpaired 
to MCI / 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 six-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). However, full cognitive assessments will only 
be conducted at the next scheduled visit to be scheduled at least four months from the previous 
cognitive assessment visit. 
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 /dementia due to AD made at any time other than a six-monthly cognitive 
assessment visit will not trigger the adjudication process. The process will be triggered at the 
next cognitive assessment visit when the investigator updates the DVF or the results of cognitive 
assessments supporting the diagnosis as described above.  
The adjudication process is briefly described below and further details can be found in the PAC 
charter (see Section 8.5). After the adjudication process has been triggered at a given visit, it 
will be repeated at the next scheduled cognitive assessment visit six months later to confirm the 
diagnostic classification. Once the diagnosis has been confirmed, the date of the initial visit that 
triggered the adjudication will be used to establish the event date for the TTE analysis. The 
event date and final diagnosis from the PAC will be captured in the database and used for 
analysis. 
The PAC diagnoses will be communicated to the sites. If the PAC and the investigator do not 
agree on diagnosis, the PAC diagnosis will be used for analysis purposes. 
No submitted cases will be re-adjudicated unless additional information provided by the site 
has a potential impact on the adjudication of the case. 
6.3.2 
API Preclinical Composite Cognitive (APCC) battery  
The APCC score will be derived from the following seven tests performed as part of the 
cognitive scales administered during the study (see Table 6-1 Assessment schedule) 
• MMSE: 
• Orientation to Time 
• Orientation to Place 
• RBANS: 
• List Recall 
• Story Recall 
• Coding 
• Line Orientation 

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• Raven’s Progressive Matrices – subset  
All scales used to derive the APCC test score (RBANS, MMSE and Raven’s) will be 
administered twice during screening: first to assess inclusion (V101 and/or V103) 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 CDR and RBANS is required during screening to 
confirm unimpaired cognition (see Section 6.1.6.1), 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 2 for details on assessment from study partner and conditions of 
administration/presence at visits. 
6.3.3 
Mini Mental State Examination (MMSE) 
The MMSE is a brief, practical clinician reported outcome that examines cognitive status 
(Folstein et al., 1975). It evaluates orientation, memory, attention, concentration, naming, 
repetition, comprehension, and the ability to create a sentence and copy two intersecting 
pentagons. 
The test consists of five sections (orientation, registration, attention, recall, and language) with 
a total score ranging from zero 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 zero to five) will be used. MMSE will be performed at Screening part I first (by 
regular site personnel, no certification required) and then at baseline pre-dose and every 6 
months by a certified rater. If MMSE is not available from previous 3 months source data, it 
should be collected a V101. If it is administered by a non-certified rater (allowed at V101 only) 
record on a paper form, do not upload to Virgil. If administered by a certified rater at V101 on 
Virgil, then no need to repeat at V103. 
During the study, the test 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.  
6.3.4 
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 cognitively 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 

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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) 
The RBANS Delayed Memory index score is used as an inclusion criterion, together with the 
CDR global score, to ensure selection of participants with unimpaired cognition at screening. 
With a normal mean score of 100 and standard deviation (SD) of 15, the 85 and 70 cut-offs for 
inclusion correspond to 1SD and 2SD below the normal mean, respectively. Participants who 
score between 85 and 70 will be considered suitable for the study only if their CDR global score 
is zero, confirming the absence of any clinically-detectable memory decline. 
RBANS comes in four different versions labeled A, B, C, D. Form B will be used at screening 
(and repeat screening, if needed), while Form A will used at baseline, Form D at month 3 and 
Form C at month 6.  Subsequent visits during the Treatment Phase will follow the pattern: Form 
D, B, A, C / D, B, A, C and so on.  
6.3.5 
Raven’s Progressive Matrices  
Raven’s Progressive Matrices (Raven et al 2000) is a non-verbal, multiple choice measure of 
general ability and reasoning using a visual modality. It was designed to be culturally nonbiased, 
as neither language nor academic skills are required to answer items successfully. The test 
requires conceptualization of spatial design and numerical relationships with varying levels of 
difficulty. For each item a participant is asked to identify the missing component to complete a 
pattern.  
Although all components of the Raven’s Progressive Matrices Set A and Set B will be assessed, 
in order to calculate the APCC test score, only a subset of items from Sets A and B will be used 
(items A2, A4, A8, B1-B6), with a total score from zero to nine. 
The Raven’s will be administered using a paper-based stimulus booklet, results being captured 
on the Virgil® tablet.  
6.3.6 
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 

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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 zero 
to three, with greater scores indicating greater disease severity. CDR-SOB scores range from 
zero to 18 with greater scores indicating greater disease severity. 
Clinician judgment of MCI due to AD or dementia due to AD and/or a change in the global 
CDR score (until the established diagnosis of dementia) will trigger the adjudication process 
(see Section 8.5). 
6.3.8 
Everyday Cognition Scale (ECog) 
The ECog scale measures cognitively-relevant everyday abilities and is comprised of 39 items 
covering six 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 the participant (ECog-subject) 
and his/her study partner (ECog-informant). All questionnaires will be completed in the 
language most familiar to the respondent, at the scheduled study visit. The participant should 
be given sufficient instruction, space, time and privacy to complete the questionnaire on the 
tablet. The study coordinator (SC) should check the responses to the questionnaire for 
completeness and encourage the participant to complete any missing responses 
Within each domain, ability to perform a specific task is rated on a five-point scale ranging 
from: 1) no difficulty, 2) mild difficulty, 3) moderate difficulty, 4) severe difficulty, or 5) unable 
to do.  
The total score for the 39 items ranges from 39 to 195, with greater scores indicating worse 
daily function. The study will include a modified version of the ECog scale to measure a static 
state (not a change), assessed at regular, six month intervals to minimize recall bias. 
Details on the study partner characteristics (relationship and frequency of interaction) are also 
captured on the ECog-informant.  

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6.4.1 
Physical (including skin) and neurological examination  
Physical and neurological examinations will be performed by a qualified clinician at visits 
specified in Table 6-1. Any findings are to be recorded as unscheduled assessment/AE, as per 
Investigator judgement.  
Physical examination will include an examination of general appearance, skin (and skin 
reactions), neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities and vascular.  
Neurological examinations will include mental status, cranial nerve 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 (see Section 6.4.6 for further 
information on dermatologic findings). 
6.4.2 
Vital signs 
Vital signs include blood pressure, pulse, and temperature (using site equipment) measurements. 
Systolic and diastolic blood pressure and radial pulse rate will be assessed after the participant 
has rested in the sitting position for at least three minutes. The vital signs data will be recorded 
on the corresponding eCRF pages, unless marked for source documentation only in Table 6-1.  
6.4.3 
Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured at screening. In addition, weight will be measured at all 
visits where vital signs are measured.  
6.4.4 
Laboratory evaluations 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collections, shipment of samples, and reporting of results by the central laboratory are provided 
to investigators in the Laboratory Manual. 
Please refer to Section 6.1.3 for additional laboratory tests required at Screening. 
6.4.4.1 
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 will be measured. 
In addition if clinically warranted for participants treated with anti-coagulants, prothrombin 
time international normalized ratio (PT/INR) may be measured for assessment of coagulation 
at screening and repeated, if required. 

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6.4.4.2 
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, creatinine, creatine phosphokinase (CPK), C-reactive protein (CRP), 
Vitamin B12, folate, gamma-glutamyl transferase (γ-GT), lactate dehydrogenase (LDH), 
cholesterol (total / LDL / HDL), triglycerides, lipase, α-amylase, alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), glycated hemoglobin (HbA1c), blood urea nitrogen 
(BUN), uric acid, and thyroid stimulating hormone (TSH) 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 because of findings on previous MRI scans.  
6.4.4.3 
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 
laboratory 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. 
6.4.4.4 
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. 
6.4.5 
Electrocardiogram (ECG) 
ECGs will be centrally evaluated. Full details of all procedures relating to the ECG collection 
and reporting will be contained in the technical manual, which is provided to the site by the 
centralized ECG vendor. 
Twelve-lead standard ECGs will be recorded in triplicate (one minute apart) after participants 
have been resting in the supine position for at least 10 minutes. The ECGs should be scheduled 
approximately 2.5 hours post CNP520 drug administration on site (Section 5.5.4). If the LDR 
is 50 mg once weekly and the dosing day corresponds to the visit day then the scheduled is 
maintained otherwise, the ECG should be taken preferably at the same time of the day than 
earlier visits.  
The Fridericia QT correction formula (QTcF) should be used for clinical decisions. 
Electrocardiograms will be obtained as designated in the Table 6-1, if applicable.  
The ECG readings will be sent automatically to the centralized ECG vendor. Findings at 
screening, considered as clinically significant and meeting alert values, in the opinion of the 
investigator, must be discussed with the Novartis Medical Monitor before administration of 
investigational treatment. 

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Each ECG tracing must be labeled with study number, participant initials, participant number, 
date and time, and filed in the study site source documents. For any ECGs with participant 
safety concerns, two additional ECGs must be performed to confirm the safety finding and 
copies forwarded to the central ECG laboratory for assessment. 

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6.4.7 
Safety brain MRI scans 
Safety MRI will include the following sequences: 
• 3D T1-weighted, structural T1 MPRAGE/IR-FSPGR/TFE (with acceleration) (also used 
for volumetric MRI, see Section 6.5.3.1. Note that this sequence will be captured twice at 
each scan, and may need a repeat in case of motion) 
• Axial FLAIR (for general ascertainment of brain abnormalities including Amyloid Related 
Imaging Abnormality-Edema (ARIA-E) and for white matter lesions) 
• Axial T2 Star/Gradient echo (GRE) (to assess Amyloid Related Imaging Abnormality-
Hemorrhages (ARIA-H), including superficial siderosis, and other hemorrhages) 
• Axial PD/T2: surrogate to FLAIR with better sensitivity in infratentorial regions  
• Axial Diffusion-Weighted Imaging (for assessment of recent infarcts and white matter 
integrity examination). Diffusion Tensor Imaging (DTI) may be performed at specific 
sites. 
• Only in case of certain new findings on other sequence or at request of DMC: T1-
weighted MRI with Gd-contrast. 

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In relation to previously reported risks for other compound from the same class, regular skin 
examinations and centralized dermatological monitoring to assess skin reactions, are 
implemented.  
Given the imbalance of pruritus observed in a previous study with CNP520, dermatological AE 
page and scales for itch and sleep disturbances are planned to capture those AEs in a systematic 
way. Management of pruritus is described in Section 6.4.6.2.  
Other safety assessments are standard for clinical trials in populations of older individuals. 
6.5 
Other assessments 
6.5.2 
AD biomarkers 
Since biomarker data have the potential to unblind individual participants, the results will be 
imported into a restricted database with controlled access and managed as described in Section 
5.4. The results of the CSF biomarkers completed after baseline will not be disclosed to the 
participant nor to the investigator.  
Blood-based biomarkers 
Blood samples will be collected to explore blood biomarkers including gene expression 
associated with the treatment response to CNP520, respectively, and the pathophysiology of 
AD and/or associated diseases. Serum and plasma samples will be collected at time points of 
the safety labs blood draws. Samples will be prepared and shipped according to procedures 
described in the Central Laboratory Manual. 

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Diffusion tensor and diffusion weighted Imaging 
Diffusion weighted imaging will be acquired in all participants in order to be able to assist in 
assessment of recent infarcts. Diffusion weighted imaging will also be used to assess white 
matter integrity and in sites where it is technically feasible Diffusion Tensor imaging will also 
be added for this purpose. Further details will be given in the imaging manual. 
6.5.3.2 
PET scans 
PET scanning will be performed on a PET scanner meeting requirements specified in the PET 
Imaging manual. Procedural details will be provided to the participating PET imaging sites 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, but 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 specified for each radio-
tracer will be specified in the PET procedure imaging manual. 
The approximate scanning time, during which the participant will be lying on his or her back, 
will be 20 to 30 minutes, depending on the PET tracer. Participants will be supervised during 
each PET scan. CT scans will 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 biomarker data have the potential to unblind individual participants, the SUVR 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 scans 
Cerebral amyloid burden and the effect of experimental treatment on cerebral amyloid will be 
assessed using specific amyloid PET radiotracers.  
Amyloid PET scans will be performed at each timepoint year 2 and year 5 provided an amyloid 
PET scan with the same PET tracer was performed at screening. At screening at least one 
amyloid measurement method (lumbar puncture or PET) is required for eligibility. Consenting 
for a second method of amyloid measurement at screening is voluntary. The same radiotracer 
(either 18F-florbetapir, 18F-flutemetamol, or 18F-florbetaben) will be used for all scans of given 
participant.  

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Date, time, batch, volume, and radiation dose of the radiotracer injection (according to the 
Imaging Manual) and any AEs occurring at the PET center will be recorded on the eCRF. For 
eligibility, a qualitative read will be performed by a central reader.  
For biomarkers assessment, cerebral-to-reference region standard uptake value ratios (SUVRs) 
will be calculated for scans obtained at screening, month 24 and month 60, using pre-defined 
and automatically generated cerebral and reference regions-of-interest.  
The quantitative SUVR results of the amyloid PET scans will not be disclosed to the site.  
Tau PET scans 
Tau PET, where available and locally permitted. (e.g. applicable for USA and Canada with 18F-
flortaucipir only), will be performed to detect the effect of experimental treatment on 
neurofibrillary tangle burden. The same radiotracer (either 18F-flortaupicir (AV-1451), MK-
6240 or PI-2620) will be used for all scans of a given participant. Corresponding documentation 
will be submitted. 
Tau PET scans are expected at screening, month 24 and month 60 for participants from the 
subset of sites that can access the selected tau PET tracer and have the required imaging 
capability (i.e. tau PET scans are not required at sites without this access and/or capability). 
Date, time, volume, batch, and dose of tau tracer, and any AEs occurring at the PET center and 
within the following 24 hours will be recorded. 
SUVR measurements will be calculated in pre-defined cerebral and reference regions, which 
will be predefined based on their ability to detect and track AD-related tangle burden in 
independent observational data sets. 

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7 
Safety monitoring 
7.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign including abnormal laboratory findings, symptom or disease) in a participant 
after providing written informed consent for participation in the study until EoS. Therefore, 
an AE may or may not be temporally or causally associated with the use of the investigational 
product. Similarly any untoward medical occurrence associated with genetic or amyloid 
disclosure in this study will be captured as an AE. 
In addition, all reports of intentional misuse and abuse of the product are also considered an 
adverse event irrespective if a clinical event has occurred.  
The occurrence of any adverse events must be sought for by non-directive questioning of the 
participant at each visit during the study. Adverse events also may be detected when they are 
volunteered by the participant during or between visits, or through physical examination 
findings, laboratory test findings or other assessments. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information: 
The severity grade 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 adverse events must 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) must be recorded. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study drug, the interventions required 
to treat it, and the outcome. 

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Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the medicinal product that is identified between 
IB updates will be communicated as appropriate, for example, via an investigator Notification 
or an Aggregate Safety Finding. New information might require an update to the informed 
consent and has then to be discussed with the participant. 
The investigator must also instruct each participant to report any new adverse event (beyond 
the protocol observation period) that the participant, or the participant’s personal physician, 
believes might reasonably be related to study treatment. This information must be recorded in 
the investigator’s source documents; however, if the AE meets the criteria of an SAE, it must 
be reported to Novartis. 
Laboratory test results 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• They induce clinical signs or symptoms 
• They are considered clinically significant 
• They require therapy  
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
screening or the previous visit, or values which are considered to be non-typical in participant 
with underlying disease. Investigators have the responsibility for managing the safety of 
individual participants and identifying adverse events. Alert ranges for laboratory will be listed 
in the central laboratory manual. 
Refer to Section 7.8 for additional guidance on adverse events that may be related to genetic or 
amyloid disclosure, refer to Section 7.9 for additional guidance on major life events and to 
Section 6.4.6.2 for additional guidance on pruritus.  
7.2 
Serious adverse events  
7.2.1 
Definition of SAE  
An SAE is defined as any adverse event [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) 

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• 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, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention. 
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 it were more severe (please refer to 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 (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
7.2.2 
SAE reporting  
To ensure participant safety, every SAE, regardless of causality to study treatment or to genetic 
or amyloid disclosure, occurring after the participant has provided informed consent and until 
30 days after the last study visit/EOS or PPW must be reported to Novartis safety within 24 
hours of learning of its occurrence. Any SAEs experienced after the 30 day period after the last 
study visit/EOS or PPW should only be reported to Novartis safety 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 occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
Information about all SAEs (either initial or follow up information) is collected and recorded 
in English in the electronic Serious Adverse Event Report (eSAE) Form within the Oracle 
Clinical/Remote Data Capture (OC/RDC) system (whenever available and/or feasible) or on 
the paper SAE Report Form that should be used as back-up, especially in cases where there is 
no feasibility of the use of an eSAE Form. The investigator must assess the relationship of each 
SAE to CNP520.  

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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 folder. Each re-occurrence, 
complication, or progression of the original event must 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 Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Drug Safety and Epidemiology 
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 study 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 has to be followed.  
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as (S)AE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages 
Every liver laboratory trigger or liver event as defined in Section 13.3 should be followed up 
by the investigator or designated personal at the trial site as summarized below. Detailed 
information is outlined in Table 13-3 and Table 13-4  in Appendix 1. 
For the liver laboratory trigger: 
• Repeating the liver function test (LFT) within the next week to confirm elevation. 
• These LFT repeats must 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 LFTs must 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 must be reported on the Liver CRF pages. 
• If the elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• For the liver events: 

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• Repeating the LFT to confirm elevation as appropriate 
• Discontinuation of the investigational drug if appropriate 
• Hospitalization of the participant 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, 
consultancy of a hepatologist, based on investigator’s discretion. All follow-up 
information, and the procedures performed must be kept as source and recorded on 
appropriate CRF pages, including the liver event overview CRF pages. 
7.4 
Renal safety monitoring  
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 
• Serum event: 
• confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to baseline 
during normal hydration status 
• Urine event 
• new onset (≥1+) proteinuria; confirmed by doubling in the urinary albumin-creatinine 
ratio (ACR) or urinary protein-creatinine ratio (PCR) (if applicable) 
• new onset (≥1+), hematuria or glycosuria  
Please refer to Table 13-5 in Appendix 1 for complete definition of renal laboratory triggers 
and renal events. Every renal laboratory trigger or renal event as defined in Table 13-5 in 
Appendix 1 should be followed up by the investigator or designated personnel at the trial site.  
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 (European Medicines Agency (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. 

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Table 7-1 
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 
Fertility control and pregnancy reporting  
Participants eligible for this study will be 60 to 75 years of age, with women of childbearing 
potential being 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 as described 
in Table 6-1, including unscheduled visits. 
A validated shorter version 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. Since this algorithm 
is dynamic, it cannot be administered on a paper form. 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. 
If, at any time the score is “yes” on item four or item five of the Suicidal Ideation section of the 
eC-SSRS (and if at Screening, the ideation occurred in the past 6-months) or “yes” on any item 
of the Suicidal Behavior section, the participants must be referred to a psychiatrist for further 
assessment and/or treatment if the investigator is not a certified psychiatrist. The decision on 
whether the investigational treatment should be discontinued is to be taken by the Investigator 
in consultation with the psychiatrist to whom the participant is referred. 
Based on investigator judgement of the participant’s ability to complete the eC-SSRS on their 
own, eg. in case of progression to dementia, the supplemental C-SSRS data eCRF page may be 
completed instead with input from the study partner. 
In addition, all life-threatening events must be reported as SAEs. For example, if a participant 
answers “yes” to one of the questions in the Suicidal Behavior section, an SAE must be reported 
if the event was life-threatening. All events of “Non-Suicidal Self-Injurious Behavior” 
(question also included in the Suicidal Behavior section) should be reported as AEs and 
assigned the appropriate severity grade.  
All SAEs relating to suicidal behavior must be reviewed by the DMC. 

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The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs 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 data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/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 CRFs 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 study site personnel will enter the data required by the protocol into the Electronic 
Data Capture (EDC) system. Designated study site personnel will not be given access to the 
system until they have been trained.  
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 study site personnel. The investigator must certify that the 
data entered into the eCRFs 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 study team will review the data entered into the eCRFs by study site personnel 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 
study site personnel are required to respond to the query and confirm or correct the data.  
Concomitant medications entered into the database will be coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomic Therapeutic 
Chemical classification (ATC) classification system. Concomitant procedures, nondrug 
therapies and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology. 
Since the study includes specific genotyping requirement as APOE4 HTs and HMs at inclusion, 
the results of the genotyping performed at the central laboratory will be provided to the site and 
be part of the source documents for the participant. Results will also be sent electronically to 
Novartis. 
Results for brain amyloid status from CSF Aβ and/or amyloid PET scans will be communicated 
to the site to confirm eligibility of HTs. The result (elevated/non elevated) will be captured in 
the eCRF. 

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• Enhance safety monitoring 
• Suspend treatment with current dose(s) of CNP520.  In this case, the sponsor may switch 
participants to the LDR by activating the DRM.  
• Stop the trial in case of (1) unexpected safety issues, (2) futility at pre-planned one of the 
two IAs, or (3) outstanding efficacy at one pre-planned IA on primary efficacy endpoints.  
The safety parameters to be checked will be guided by potential and theoretical compound and 
class risks as described in the DMC charter, applicable until treatment termination.  
The DMC may also assess any potential relationship (i.e. temporal) between exposure data for 
CNP520 with the occurrence of a particular AE of interest at the participant level if required, 
or identify signs or signals of safety concerns within the study and across studies with data from 
the API015A2201J study Cohort II with CNP520. 
The DMC will also receive all SAEs and specific reports (including CDR, RBANS, MMSE and 
, centralized safety MRI scans, and volMRI), and any other reports as described in the 
DMC charter or requested ad hoc at any time by the DMC. The DMC may then access the 
treatment codes as provided in the DMC closed reports for each participant, to assess the 
relationship to study medication and assess criteria for suspension or design modification as 
described in the DMC Charter.  
The DMC will be provided with individual participant’s data, 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 external 
independent statistician.  
8.5 
Progression Adjudication Committee (PAC) 
A process for the adjudication of MCI/dementia diagnoses will be implemented with an external 
PAC managed by the Cognition vendor. Details of the diagnostic criteria are described in 
Section 6.3.1 and a description of the PAC members, role, and function will be described in the 
PAC charter applicable until treatment termination. The same PAC membership and operating 
rules that apply for the API015A2201J study will also apply for this study as well. 
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 in the PAC charter. 
The PAC will be provided with the available participant data to assess for possible progression 
and potential confounding factors for the events received for adjudication.  
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 
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: 

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• 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 and/or amyloid disclosures)) and making recommendations regarding changes or 
adjustments  
• Providing summary reports to the DMC prior to each data review meeting summarizing 
any findings related to the safety monitoring of genetic and/or amyloid disclosures.  
The DMAG will be composed of recognized academic experts, as described in the DMAG 
Guidelines. 
9 
Data analysis 
The final analysis will occur once the overall targeted number of events for the study has been 
reached and all participants have completed their month 60 assessments.  
In general, data will be reported by treatment arms of interest and by visit as applicable. 
Summaries including only baseline data, may also include a total group (All participants). In 
case of no DRM, treatment arms of interest are the originally defined treatment arms #1 to #3. 
In case of DRM, summaries will show the following treatment arms of interest: the pooled 
active treatment arms (Arm #1 and Arm #2) and placebo (Arm #3). In addition, summaries may 
also include the sub-group of participants randomized to any of the two active treatment arm 
after the DRM, i.e. those who started on the LDR. 
In general, descriptive statistics (mean, median, standard deviation, minimum, and maximum) 
will be presented for continuous variables . The number and percentage of participants in each 
category will be presented for categorical variables. 
The primary treatment arms for efficacy analysis will include the following participants based 
upon whether or not the DRM will be implemented.  
• In the case that the DRM does not occur, the 3 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 1:1. 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 #1, 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, namely 2:1:2 for Arm #1: Arm #2: Arm #3. The primary placebo arm 
(Arm #3) consists of all the participants who have been randomized to Arm #3 and 
received placebo regardless of DRM. The primary active arm (pooled Arm #1 and Arm 
#2) consists of the following participants  
1. those who received CNP520 50 mg once daily dose followed by CNP520 LDR (those 
who were originally randomized to Arm #1, and subsequently switch to the lower 
dose regimen) and  
2. those who received CNP520 15 mg once daily dose followed by CNP520 LDR (those 
who were originally randomized to Arm #2, and subsequently switch to the lower 
dose regimen) and  
3. those who received CNP520 LDR dose only (those who were randomized to active 
treatment arm after the DRM).  

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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 Full analysis set (FAS) will consist of all randomized participants who started 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.  
All efficacy analyses will be conducted on data from all participants in the FAS. All safety 
analyses will be conducted on data from all participants in the SAF. 
9.2 
Participant demographics and other baseline characteristics 
Demographic variables and other baseline characteristics will be summarized for each treatment 
arm of interest and all participants (total). 
In addition, all relevant medical history will be summarized following the same approach. 
9.3 
Treatments  
In case of no DRM, for both doses of CNP520 and placebo, data for investigational drug 
administration will be summarized and listed. In case of DRM, summaries will contrast the 
treatment groups of interest and 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 ATC classification) 
and by treatment arm of interest, and be listed. 
9.4 
Analysis of the primary variables 
In case of no DRM, the primary active arm is the 50 mg active arm and the secondary active 
arm is the 15 mg active arm.  In case of DRM, the primary active arm will be defined by pooling 
of the two active treatment arms (Arm #1 and Arm #2), a secondary treatment arm will not be 
defined. The primary analysis will contrast the primary active arm vs. placebo. This primary 
comparison will be embedded into a closed testing procedure that will be applied to both 
scenarios, with and without DRM.  
There are two primary endpoint variables: time to first diagnosis of MCI due to AD or dementia 
due to AD and the APCC test score. Success of the trial will be determined by a positive result 
in at least one primary endpoint on the primary treatment arm dose to be used for the primary 
analysis vs. placebo.  
To control the overall family-wise type I error rate (FWER) an appropriate multiplicity 
adjustment procedure using a closed testing strategy will be applied to the analyses of the 
primary efficacy variables. The procedure will take into account testing two endpoints, two 
active arms vs. placebo and the IA on primary endpoints. This strategy to preserve the overall 
FWER at α = 5% (two-sided) is described in Section 9.7. 

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9.4.1 
Primary Variable(s) 
Two primary variables will be used: 
• TTE, defined as the time to first confirmed diagnosis of MCI due to AD or dementia due 
to AD. TTE will be calculated as the time from randomization to the first confirmed 
diagnosis. For each event (confirmed diagnosis), the date of the initial investigator 
diagnosis will be used to establish the date of the event (neither the date of adjudication 
(see Section 6.3.1), nor 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 where the diagnostic classification has been assessed. Time to 
censoring date will be calculated from day 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 zero 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 analysis to address the primary objective comprises statistical tests of hypotheses 
of both primary endpoints. The statistical tests will compare the primary active arm of the 
investigational treatment vs. placebo at the appropriate α-level. These primary analyses are 
embedded as part of the overall testing procedure described in Section 9.7. 
For the primary active arm (1) of the investigational drug, the following two null hypotheses 
will be tested corresponding to the two primary endpoints: 
• H01(1): The primary active arm does not differ from placebo with regard to the distribution 
of time to first diagnosis of MCI due to AD or dementia due to AD; 
• H02(1): The primary active arm does not differ from placebo in the mean change from 
baseline to month 60 in the APCC test score; 
The corresponding alternative hypotheses are: 

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• HA1(1): The primary active arm differs from placebo with regard to the distribution of time 
to first diagnosis of MCI due to AD or dementia due to AD. 
• HA2(1): The primary active arm differs from placebo in the mean change from baseline to 
month 60 in the APCC test score. 
In a similar way, H01(2) and H02(2) and corresponding alternative hypotheses are also defined for 
the secondary active arm (2) in case of no DRM.  
Time-to-event 
After the target overall number of events has been reached and after all participants have 
completed their month 60 visit or PPW, the team will agree on the exact cut-off date/point for 
the final analysis. The final TTE analysis will include data until this cut-off point. Any data 
collected after this cut-off point will not be used for the primary analysis of TTE. That means 
specifically that only confirmed events collected up to the data cut-off point will be counted. 
Confirmation information collected after the cut-off point to confirm an earlier (meaning before 
the cut-off point) adjudicated diagnosis of MCI or AD due to dementia will not be taken into 
consideration. As a consequence, the observation will be censored at the last date prior to cut-
off point that the TTE endpoint was evaluated, and the unconfirmed diagnosis will not be 
counted as an event in the primary analysis.  
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.  
The primary analysis of the TTE endpoint will be based on a Cox proportional hazards (PH) 
model including treatment arm as a factor and adjusted for important baseline covariates.  
Terms will be included for the following effects:  
• treatment arm 
• baseline value of the APCC test score 
• age group (60 to 64 years, 65 to 75 years) at Baseline 
• region (North America, Europe, Asia, Other) 
• genotype (HM, HT) 
APCC 
The final primary analysis of the APCC score will use data from the FAS.  
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 
baseline covariates as fixed effects: 
• treatment arm 
• time as the discrete variable scheduled (mapped) visit window 
• baseline APCC test score 
• age group (60 to 64 years, 65 to 75 years) at Baseline 
• region (North America, Europe, Asia, Other) 

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• genotype (HM, HT)  
and the following interaction terms: 
• treatment arm × visit window 
• baseline APCC test score × visit window 
The adjusted least square means (LSM)s of change scores for each treatment arm, the difference 
between the LSMs (active vs placebo), 2-sided p-values (unadjusted for multiplicity) and 
associated confidence intervals (CIs), comparing the active and placebo LSMs, will be 
calculated from the MMRM analysis and presented for each visit. 
Visit windows used as a factor in the MMRM will correspond to all scheduled visits for which 
participant level data for the parameter was expected. Thus, all available data including data 
from visits after Month 60 will be used in the model. 
NOTE: While the method used to identify amyloid positive HTs is included as a level in the 
genotype stratification variable, it is not included in the abovementioned genotype factor in the 
primary analysis models for the two primary endpoints. The potential effect of the method is 
investigated separately as supportive analyses, specified in Section 9.4.4. 
9.4.3 
Handling of missing values/censoring/discontinuations 
9.4.3.1 
Primary endpoint time-to-diagnosis of MCI due to AD or dementia due 
to AD 
Primary analysis 
In general, an observation will be censored if no confirmed event has been observed prior to the 
TTE analysis cut-off point. 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 PH model) for the TTE endpoint assumes censoring at 
random for participants not having an event. 
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; 

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2. Missing data from participants that prematurely discontinued the treatment epoch due 
to an AE, death, or unsatisfactory therapeutic effect (UTE). 
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, 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 (60 to 64 years, 65 to 75 years) at Baseline 
• region (North America, Europe, Asia, Other) 
• genotype (HM, HT). 
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.  
9.4.3.2 
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. 
Primary analysis 
The primary analysis method (MMRM) for APCC will assume missing data to be MAR. 
Sensitivity analyses 
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. 
Sensitivity analyses will be conducted for the following scenarios in which 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 such missing data the following sensitivity analyses will be applied:  

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• 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 abovementioned reasons for 
missingness; 
• 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. 
• A further sensitivity analysis under a plausible missing not at random (MNAR) process 
will also be conducted. 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 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, 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. 
9.4.4 
Supportive analyses 
Censoring data after discontinuation of study drug 
A TTE comparison of the primary active arm of CNP520 vs. placebo will be performed on the 
FAS, taking into account whether a participant had continued, interrupted or permanently 
discontinued study-drug during the study. For this analysis, 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. 
The censoring date for each participant that did not have an event (i.e. a confirmed diagnosis) 
is defined as follows: 
1. For participants having completed the study: the last day of his/her final diagnosis 
assessment visit, that is at the final visit during the follow-up epoch when a diagnosis 
assessment occurred,  
2. For participants ongoing in the study 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). 
3. For participants who permanently discontinued from study drug, but still being followed 
up: The last day of a diagnosis assessment up to 12 weeks after the last day of study drug 
administration. Any data beyond the abovementioned 12 weeks will be excluded from this 
TTE analysis. 
For study drug interruptions lasting longer than 12 weeks, assessments of diagnostic 
classification during this period, but beyond the abovementioned 12 weeks will be excluded 
from the derivation of the TTE endpoint. Assessments subsequent to resuming drug 
administration (on-treatment) will be included in the derivation. 

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The first subsequent on-treatment assessment will then be used to define a change in diagnostic 
classification and the TTE as follows: 
1. If the result antecedent to the first excluded result was adjudicated as a change in 
diagnostic classification, then the subsequent on-treatment assessment result will serve as 
the confirmation assessment if it was also assessed as a diagnosis and the date of the 
antecedent assessment will serve as the event date. 
2. If the result antecedent to the first excluded result was not adjudicated as a change in 
diagnostic classification, then if the subsequent on-treatment assessment was adjudicated 
as a change in diagnostic classification and also confirmed subsequently, then it will serve 
as a confirmed adjudicated event, but the date of the event will be defined as the date of 
the first excluded result.  
Other analyses on the time-to-event endpoint 
A non-stratified log-rank test will be conducted to compare estimates of the hazard functions of 
the treatment arms.  
In order to understand the potential longitudinal difference in the rate of disease progression by 
genotype, a longitudinal Cox PH model will be implemented as an important primary 
supportive analysis. This will be done by including the additional interaction term treatment 
arm × genotype × visit window. 
Excluding data after discontinuation of study drug in APCC 
As with the primary analysis method (MMRM) for APCC, this analysis will assume missing 
data to be MAR. 
Within this analysis, the following data will be excluded (regarded as missing though it is 
available) and thus implicitly assumed to be MAR: 
• Data retrieved from participants remaining in the treatment epoch beyond 12 weeks after 
permanent study drug discontinuation 
• For intermediate study drug interruptions lasting longer than 12 weeks, off-drug APCC 
data during this period, but beyond the abovementioned 12 weeks. Assessments 
subsequent to resuming drug administration will be included in the analysis. 
In addition to this analysis, the same tipping point, controlled imputation and ‘copy reference’ 
sensitivity analyses as planned for the primary analysis will be conducted, but additionally 
excluding the off-treatment data to be missing as mentioned above. 
Other analyses on 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 includes the same factors, but also including the additional interactions (and 
underlying factors) 
• baseline hippocampal volume | visit window 
• genotype (HM, HT) | visit window | treatment 

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The primary analysis will be supported by an MMRM similar to the primary model, but using 
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. 
Potential drug-drug-interaction (DDI) 
Potential PD-mediated DDIs with frequent concomitant medications may include the use of 
cholinesterase inhibitors in terms of transient interaction with cognitive readouts.  
Treatment interaction with CNP520 will be assessed as follows: 
• Cholinesterase inhibitors (ChEIs): The primary efficacy analysis will be based on an 
intention-to-treat principle and will neither exclude participants who started ChEIs during 
the study, nor exclude time points from the analysis after start of ChEIs. 
• Sensitivity analysis will be carried out to investigate the role of concomitant 
cholinesterase therapy on the efficacy of CNP520, such as exclusion of time points from 
the analysis after initiation of ChEI therapy, or using this information as a stratification 
factor or as a time-varying covariate in the statistical models. 
Other supportive analyses 
In order to understand the possible difference in outcome due to the method of classifying 
amyloid status of HTs at baseline, a Cox PH model and MMRM model for APCC will be 
conducted. The models will include treatment arm as a factor, while adjusting for genotype and 
classification method (PET or CSF).  
Sub-group analyses 
Analyses similar to the primary 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 2018 Early Alzheimer’s disease: Developing Drugs for Treatment 
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. 
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 (amyloid and tau), Volumetric MRI, tau and p-tau in CSF. All of the secondary 
endpoints will be analyzed using longitudinal models such as a mixed measures repeated model 
(MMRM) for the CDR-SOB similar to the approach for the primary endpoint APCC with 
treatment as factor and adjusting for important covariates. 
9.5.1 
Efficacy variables 
Clinical Dementia Rating Scale (CDR) sum of boxes (SOB) 
A multiplicity adjustment will also be applied to the key secondary variable, as specified in 
Section 9.7. 

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The following null hypothesis will be tested for the selected dose within the framework of the 
multiple testing strategy:  
• H03(1): 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: 
• HA3(1): 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. It is planned to apply an MMRM adjusted for important 
factors similar to the approach for the primary analysis model as specified for the APCC. 
Further specifications will be given in the statistical analysis plan (SAP). 
The adjusted least square means (LSMs) for each treatment arm, the difference between the 
LSMs (active vs placebo), the 2-sided p-values (unadjusted for multiplicity) and associated 
confidence intervals (CIs) 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.  
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 in ECog total score will be presented over 
time. An analysis of change from baseline will be also performed using longitudinal MMRM 
model as described for APCC scores 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. An analysis of change from baseline will be also performed using a longitudinal 
MMRM model as described for APCC score in Section 9.4.2. 
 
 
9.5.2 
Safety variables 
All 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. 

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AEs, SAEs and Death 
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, and 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 arm. These descriptive summaries will be presented by laboratory test category, visit, 
and treatment arm. 
Shift tables will also be provided in which 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 arm. 
Vital signs 
Summary statistics of change from baseline values will be presented by vital sign parameter 
and treatment arm. Number and percentage of participants with clinically notable vital sign 
changes from baseline will be tabulated by treatment arm.  
Electrocardiogram (ECG) 
Summary statistics of change from baseline values will be presented by ECG parameter and 
treatment arm. Number and percentage of participants with clinically notable ECG 
abnormalities will be tabulated by treatment arm.  
Safety brain MRI scans  
Descriptive summaries will be provided by treatment arm for safety MRI data with special focus 
on ARIA and white matter disease. Number, intensity and location of microhemorrhages and 
white matter hyperintensities using the Wahlund scale (both as assessed by central MRI reader) 
will be tabulated. 

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Potential PD-mediated DDIs with frequent concomitant medications may include the use of 
medications which affect the coagulation/platelet function in terms of safety (e.g. increased 
incidence of ARIA-H). The effect of concomitant coagulation therapy and CNP520 on the risk 
of ARIA-H will be monitored by the DMC during the study, and analyzed by anticoagulant 
type and by their use during the study, using the information on timing of initiation and dose as 
time-varying covariates in the statistical TTE models. 

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9.6 
Interim analyses (IAs)  
The main purposes of the planned IAs are safety monitoring, dose adaptation and assessment 
of either futility or overwhelming efficacy with the potential consequence of discontinuing one 
active treatment arm or the whole study. Safety data from CNP520 in the API015A2201J study 
as well as learnings from external data which are expected to become available during the 
course of the study will also be considered for decision making by the DMC. All IAs will be 
conducted by an independent DMC based on unblinded data.  
Table 9-1 
Schedule of pre-planned Interim analyses 
 
Expected timing 
Main parameters under 
evaluation 
Regular Safety Review 
Semi-annual (and additional ad 
hoc reviews as needed) 
All safety data as determined by 
the DMC. 
CNS activity futility analysis  
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 and CSF and 
blood biomarkers 
Primary efficacy futility analysis 
Once approximately 75% of the 
target 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 as 
follows: 
1. Safety review: 
a. Regular semi-annual evaluation of safety parameters and worsening in cognition as a 
safety measure throughout the study duration  
b. During the recruitment period, safety and tolerability will also be assessed for a 
potential DRM. 
2. Review of CNS activity for futility based on the following biomarkers:  
a. Volumetric MRI: hippocampal volume  
b. CSF: Aβ, tau and p-tau  
c. PET : tau tangles  
d. NFLs in blood / CSF 
3. Review of primary endpoints (TTE and APCC test score) to assess futility or 
overwhelming efficacy 

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9.6.1 
Interim analysis for biomarkers of CNS activity 
CNS activity of CNP520 will be assessed by means of one unblinded interim analysis performed 
by the DMC for futility based on treatment difference from baseline in CSF (Aβ, tau, p-tau) and 
volumetric MRI (e.g. hippocampal volume) at 24 months. The unblinded IA will consist of a 
pooled analysis across studies API015A2201J (Cohort II) and CNP520A2202J, and also 
separated by genotype. Additional AD related biomarkers obtained at 24 months post-baseline 
may be used to support decision making.  
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 24 months post baseline. This preliminary sample size is based on exploration of 
the change over 24 months from the longitudinal data from Alzheimer’s disease Neuroimaging 
Initiative (ADNI) cohort data.  
The exact futility decision rules will be based on further investigation of internal and external 
data. Specific decision criteria, sample sizes and the exact timing of the analysis are under 
investigation and will be outlined in the DMC charter and pre-specified in the DMC master 
analysis plan (MAP) prior to the corresponding IA. 
The main purpose of this IA is futility. No alpha spending strategy will be employed. 
9.6.2 
Interim analysis for primary endpoints 
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.  
The analysis models and methods will be the same as for described in Section 9.4 for the Final 
Analysis of the primary endpoints. 
The main purpose of this IA is futility. Nevertheless, since this involves unblinding of data on 
the primary endpoints, a small portion of 1/1000 of the overall significance level alpha of 5% 
will be spent to control the type-I error rate using a Bonferroni split (that means 0.004% and 
0.001% for TTE and for APCC, respectively). The underlying idea is to set the hurdle very high 
such that an early stopping due to efficacy can only occur when an extremely large treatment 
effect is observed. Efficacy of APCC will be considered as overwhelming only if it is supported 
by at least a convergent trend on TTE and additional data generated outside of this trial 
supporting the clinical meaningfulness of the APCC. Decision on futility will also be based on 
meeting the futility rule for the TTE endpoint. The decision should be strengthened by 
consistent results for the TTE endpoint in a pooled futility analysis including also data from the 
API015A2201J trial as well as for the APCC. Stopping for futility based on APCC only is not 
foreseen.  

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The IA will be based on available data on the two primary parameters: time to first diagnosis 
of MCI/dementia due to AD and the APCC. The IA is planned to be conducted 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 at 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 the number of 
events (total across all treatment arms). 
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 IA on primary endpoints. 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 IA on primary endpoints will be pre-specified and be outlined in the DMC charter and 
the DMC MAP prior to the IA. 
9.7 
Multiplicity and adaptation adjustment 
Main strategy 
To ensure control of FWER of α = 5% (two-sided), the multiple testing procedure will account 
for the following:  
1. Testing hypotheses on two primary endpoints - H01(i) and H02(i), where i represents the two 
doses 
2. Testing two doses of CNP520 versus placebo - H0j(1) and H0j(2), where j represents the two 
primary variables 
The familywise error rate (FWER) due to testing the four hypotheses on two primary endpoints 
and two active doses will be controlled by the closed testing procedure (Marcus, et al 1976). 
For an intersection of two hypotheses, which test an active dose against placebo on the same 
endpoint, data of the two doses will be pooled across the two dose levels. This pool will be 
treated as a single “treatment group” to be tested against placebo. 
The multiplicity arising from testing two different endpoints (APCC and time-to-diagnosis) will 
be handled by a Bonferroni adjustment: At a global level, APCC will be tested at a level of 1% 
and time-to-diagnosis at a level of 4%. 
Combining these approaches of a Bonferroni adjustment and separate closed-testing procedures 
guarantees that the FWER is controlled at α = 5% (two-sided).  

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The fact that the protocol allows a DRM will not be accounted for in the statistical testing 
procedure. Strictly speaking, the option of the DRM is a pre-planned potential adaptation to the 
design, limited to the dose regimen and the definition of primary treatment arm, but keeping 
other design features and the statistical analysis strategy stable. The potential adaptation has 
been pre-specified based on current knowledge, not driven by data of the ongoing clinical 
program. Specifically, the selection of the dose regimen options (before and after DRM), has 
not been informed by blinded or unblinded data of the program. The total sample size, the 
number of treatment arms, the randomization ratio across arms, and the testing strategy will 
remain unchanged regardless of the DRM. Hence, it is assumed that bias due to DRM will be 
minimal and can be ignored in the statistical analysis (see also Section 3.3).  
The proposed closed testing procedure starts with testing the global intersection hypothesis. If 
this hypothesis can be rejected, testing of hypotheses of the next levels is possible while keeping 
the overall type-1 error rate. The elementary hypothesis (lowest level in the hierarchy of 
hypotheses) can be tested if all hypotheses of higher levels containing this hypothesis have been 
rejected at the corresponding error rate. In case of DRM, the testing stops after rejection of the 
primary hypothesis of interest, the elementary hypothesis to compare the original active 
treatment arms vs. placebo are not of interest (see Appendix 5).  
Key secondary endpoint inclusion into the testing procedure 
If the global null hypothesis for the primary endpoints is rejected (i.e. if either the pooled TTE 
test is significant at 4% or the pooled APCC test is significant at 1% in the default scenario), 
then the key-secondary endpoint CDR-SOB will be tested at alpha=5% using the same closed 
testing strategy outlined in Appendix 5.  
False rejection of the global null hypothesis for the primary efficacy (successfully rejecting the 
at least one of hypotheses for the primary endpoints) as well as for the global key secondary 
hypothesis is thus controlled at alpha=5%. 
Additional details 
Multiple safety interim analyses are foreseen to mitigate the risk to participants over the 
treatment duration in case the benefit/risk expectations of CNP520 are not likely to be met. 
An adjustment of the FWER α (5% two-sided) will be performed only for the IA based on 
primary endpoints, which allows for early stopping due to exceptional efficacy. A small portion 
of 1/1000 of the FWER of 5% will be spent for the IA on primary endpoints with the intent to 
pre-define a high hurdle for early stopping. Hence, the actual alpha level to be used in the final 
closed testing procedure analysis will be slightly smaller than 5% (thus 4.995%), but for 
simplicity’s sake this has been ignored in the above description of the testing procedure (see 
Section 17 Appendix 5). 
Since regular DMC related analyses target primarily the safety of the participants without the 
intent to stop the study due to efficacy or any other modifications of the subsequent study 
conduct related to efficacy, no alpha adjustment is required.  
Similarly, the biomarker based futility analysis is only assessing CNS activity, but not the 
primary endpoints. Therefore, this IA for CNS activity cannot lead to early stopping of the trial 
due to exceptional efficacy and an adjustment of the FWER is not required. 

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9.8 
Sample size calculation 
A total of 2000 participants will be randomized into the study, with a sample size of 800 for the 
initial target dose of CNP520 50 mg once daily and placebo, respectively, thereby achieving a 
1:1 ratio for this initial primary dose regimen of CNP520 50 mg once daily vs. placebo. Sample 
size calculations were mainly based on reaching a target power of 80% for the test of the 
elementary hypothesis on the TTE endpoint for the 50 mg once daily dose of CNP520 vs. 
placebo.  
Type I error rate alpha and power 
The FWER α will be 5% (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 on the two primary endpoints 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 (0.004% and 0.001%, respectively) of the error rates will be spent in a 
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. 
Sample size calculations were mainly driven by power considerations for the primary endpoint 
time to first diagnosis of MCI or dementia due to AD, based on the planned recruitment time of 
two years and variable observation period of five to seven years. The power, i.e. the probability 
to detect a true difference between treatment arms, was set to be at least 80% for this analysis.  
The power for the primary analysis does not account for the potential and non-negligible 
inflation of the type II error due to futility analyses using biomarkers and the primary efficacy 
endpoints. On the other hand, the potential inflation of the type II error due to the option for 
DRM is expected to be minimal and hence, has been ignored for the calculations of sample size.  
Simulations 
The sample size of the trial has been supported by simulations. Further details are described in 
the Sample Size documentation. 
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 estimates 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, Memory and 
Aging Project, or the Minority Aging Research Study); 
• Longitudinal data from the National Alzheimer’s Coordinating Center (NACC), 
Washington University which specifically included a sub-group of APOE4 HMs- or HTs 
in the age range of 60 to 75 years. 

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• Longitudinal data from ADNI which specifically included a sub-group of APOE4 HMs or 
HTs amyloid positive carriers participants who are cognitively normal at baseline and in 
the age range of 60 to 75 years. 
• Longitudinal data from AIBL which specifically included a sub-group of APOE4 HMs or 
HTs with elevated brain who are cognitively normal at baseline and in the age range of 
60-75 years. 
Brain amyloid status is determined by using measurements of Aβ in the CSF or brain amyloid 
PET scans. Since amyloid status information is available only from ADNI and AIBL cohort 
data, accordingly, the lower bound estimates for the expected event rates were taken from 
cohorts without amyloid status (Rush, NACC) and the upper bound estimates were taken from 
cohorts with amyloid status (ADNI, AIBL). 
The cohort data were the basis 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 trials have been simulated to investigate the power under 
different assumptions, as for instance on the age distribution. An age distribution of 1:4:3 for 
the age groups 60 to 64, 65 to 69, and 70 to 75 has been chosen which holds the quota of a 
maximum of 20% of participants in the lower age group. The observed event rate in five years 
in the simulated trials was about 30% which is in line with the assumption on the event rate in 
five years in the target population of 25 to 35%. 
Sample size calculation based on the primary endpoint time to MCI / dementia 
due to AD 
The sample size calculation for the TTE 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: 
• two years accrual period, 
• five to seven years observation period,  
• 30% of participants experiencing an event in the control group in 60 months observation 
period, 
• a hazard ratio of 0.75 in favor of the active treatment arm, 
• 30% drop-out rate over 60 months (corresponding to a yearly drop-out rate of about 
6.9%), 
• α = 4%, two-sided test. 

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Power has been investigated for the comparison of the CNP520 50 mg once daily dose versus 
placebo using a log-rank test under Lakatos approximation. Based on the above-mentioned 
assumptions, a sample size of 1600 participants (800 participants in the 50 mg once daily 
CNP520 dose group and placebo, respectively) need to be randomized to achieve at least 80% 
power. The targeted number of events required to be observed in the active treatment arm is 
180 and that placebo group is 228 adding up to a total of 408 target events for the comparison 
of the primary active arm versus placebo in case of no DRM. Assuming the same underlying 
event rate of 22.5% in the two active treatment arms, the targeted number of events in the 
secondary active arm is calculated as 22.5% of the total number of participants in the arm (i.e. 
90 events). Supposing a total of 2000 participants randomized, the overall targeted number of 
events is 498 (= 228 + 180 + 90). This target total number of events also defines the target 
number of events for primary analysis in case of DRM. Due to blinding across all three 
treatment arms, the statistical analysis will only be performed after the total target number of 
events has been observed. This applies to both situations, with and without DRM. The power 
estimation using the log-rank test provides a conservative estimate and should thus be 
interpreted as the lower limit of power.  
In the simulation setting, the trial data were simulated using models which included certain 
prognostic factors. This enabled the investigation of different population assumptions and 
allowed each subject to have its own TTE distribution depending on baseline characteristics. 
The power estimates based on the adjusted Cox PH model hence were overly optimistic and 
should be interpreted as the upper limit of power which may only be reached in a best case 
scenario. Power for the TTE endpoints reached 89% and more in simulations depending on the 
underlying assumptions on the population. 
The above calculation was done using the commercial software PASS 2008. 
Power calculations based on the primary endpoint APCC 
Power considerations for the APCC have been based on the MMRM model generated from the 
simulated trials and on standard power calculation based on a t-test. The following assumptions 
for the power calculations based on the change from baseline to month 60 in APCC were used:  
• Statistical test used: t-test (standard) and MMRM (simulations), 
• 30% drop-out rate over five years,  
• Target power of 80%,  
• α = 1%, two-sided test. 
The sample size of n = 800 participants in the selected CNP520 dose arm and placebo, 
respectively, is sufficient to detect an effect size of 0.20 with 80% power. Results from 
simulations indicate that using a longitudinal model and adjusting for prognostic factors will 
increase power to detect an effect size of 0.20. 
Power calculations for APCC using the two-sided t-test have been performed with nQuery 
Advisor 7.0. 

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Power in case of DRM and overall power 
In case of DRM, the primary analysis will compare pooled active treatment arms vs. placebo. 
Treatment effect will be assumed to be similar across different treatment regimen of CNP520 
as described in Section 3.3. Hence, the target number of events is the same as for the situation 
without DRM. Due to the higher number of participants included in the primary analyses, power 
will be higher in case of DRM compared to without DRM. 
The overall power to detect a true treatment effect in at least one of the two endpoints is higher 
as compared to the power for the single endpoints. The difference in power between the dual 
and single endpoints is largest when the endpoints are independent and will be small when the 
endpoints are strongly positively correlated. 
10 
Ethical considerations 
10.1 
Regulatory and ethical compliance  
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guidelines for Good Clinical 
Practice, with applicable local regulations (including European Directive 2001/20/EC, US Code 
of Federal Regulations (CFR) 21, and Japanese Ministry of Health, Labor, and Welfare), and 
with the ethical principles laid down in the Declaration of Helsinki. 
10.2 
Informed consent procedures  
Eligible participants may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. The participant must 
indicate assent by personally signing and dating the written informed consent document or a 
separate assent form. Informed consent must be obtained before conducting any study-specific 
procedures (e.g. all of the procedures described in the protocol). The process of obtaining 
informed consent must be documented in the participant source documents.  
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form that complies with the ICH GCP guideline and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC approval. 
A preliminary consent for collection of the buccal swab for genotyping of APOE is provided 
for sites who need to select from the general population and need to establish their local database. 
The study includes optional assessments for biomarkers (amyloid PET scans and/or CSF post-
baseline) that will be captured in the main informed consent, requiring separate agreements if 
the participant agrees to them. It is required as part of this protocol that the investigator presents 
all options to participants. Declining to participate in these voluntary assessments will in no 
way affect the participant’s ability to participate in the main research study. 

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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 5.6.2 in case of progression to late-moderate or severe dementia.  
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 must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (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 Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
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 immediately that this 
request has been made. 
10.4 
Publication of study protocol and results 
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. 
10.5 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management (QM) system that includes all activities 
involved in quality assurance and quality control, including the assignment of roles and 
responsibilities, the reporting of results, and the documentation of actions and escalation of 
issues identified during the review of quality metrics, incidents, audits and inspections. 

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Audits of investigator sites, vendors, and Novartis systems are performed by Novartis Pharma 
Auditing and Compliance Quality Assurance, a group independent from those involved in 
conducting, monitoring or performing quality control of the clinical trial. The clinical audit 
process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
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 is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol. 
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.  
11.1 
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 participant 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 must be followed. 

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Maurer W, Glimm E, Bretz F (2011) Multiple and repeated testing of primary, coprimary and 
secondary hypotheses. Statistics in Biopharmaceutical Research p. 336-52. 
Mawuenyega KG, Sigurdson W, Ovod V, et al. (2010) Decreased clearance of CNS beta-
amyloid in Alzheimer's disease. Science: 330(6012):1774.  
McKhann GM, Knopman DS, Chertkow H, et al (2011) The diagnosis of dementia due to 
Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 
p. 263-9. 
Meiser B, Butow PN, Barratt AL, et al (2001) Long-term outcomes of genetic counseling in 
women at increased risk of developing hereditary breast cancer. Patient Educ Couns p. 215-
25. 
Mukai Y, Mo Y, Sur C, et al (2015) Predictors of Amyloid Positivity in a Study Sample With 
Amnestic Mild Cognitive Impairment. Presented at CTAD. 
Petersen RC, Thomas RG, Grundman M, et al (2005) Vitamin E and donepezil for the 
treatment of mild cognitive impairment. N. Engl. J. Med. p. 2379-88. 
Qian J, Wolters FJ, Beiser A, et al (2017) APOE-related risk of mild cognitive impairment 
and dementia for prevention trials: An analysis of four cohorts. PLoS Med. p. e1002254. 
Randolph C, Tierney MC, Mohr E, et al (1998) The Repeatable Battery for the Assessment of 
Neuropsychological Status (RBANS): preliminary clinical validity. J Clin Exp Neuropsychol 
p. 310-9. 
Raven JC, Court JH, Raven J (1992) Standard progressive matrices-1992 edition; Raven 
manual: Section 3. Oxford Psychologists Press; Oxford. 
Raven JC (2000) Standard Progressive Matrices-1998 Edition, updated 2000. Manual for 
Standard Progressive Matrices (Section 3): NCS Person, Inc.; San Antonio. 
Reiman EM, Chen K, Liu X, et al (2009) Fibrillar amyloid-beta burden in cognitively normal 
people at 3 levels of genetic risk for Alzheimer's disease. Proc. Natl. Acad. Sci. U.S.A. p. 
6820-5. 
Reiman EM, Langbaum JB, Fleisher AS, et al (2011) Alzheimer's Prevention Initiative: a plan 
to accelerate the evaluation of presymptomatic treatments. J. Alzheimers Dis. p. 321-9. 
Rhodes J, Clay C, Phillips M (2013) The surface area of the hand and the palm for estimating 
percentage of total body surface area: results of a meta-analysis. Br. J. Dermatol. p. 76-84. 
Roberts JS, Christensen KD, Green RC (2011) Using Alzheimer's disease as a model for 
genetic risk disclosure: implications for personal genomics. Clin. Genet. p. 407-14. 
Rodriguez F, Harrison RW, Wojdyla D, et al (2015) Lost to Follow-up and Withdrawal of 
Consent in Contemporary Global Cardiovascular Randomized Clinical Trials. Crit Pathw 
Cardiol p. 150-3. 
Romano G, Raghavan N, Tymofyeyev Y, et al.  (2018) Preliminary Analyses of Data from an 
Ongoing Trial of Atabecestat in Preclinical Alzheimer’s.  J Prev Alz Dis 5(S1): S44-S45. 
Ropacki MT, Hannesdottir K, Hendrix S, et al (2014) Consortia driven approach to addressing 
clinical meaningfulness in early AD. Clinical Trial I: Trial Design and Outcome Measures; 
01-05-03. 

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13 
Appendix 1: Clinically notable criteria 
13.1 
Clinically notable test values and vital signs 
13.1.1 
Vital signs 
Table 13-1 
Clinically notable vital signs 
Variable 
 
 
Change relative to baseline 
Heart Rate 
> 120 bpm 
< 50 bpm 
and an 
and a 
increase of ≥ 15 bpm 
decrease of ≥ 15 bpm 
Systolic BP 
> 180 mm Hg 
< 90 mm Hg 
and an 
and a 
increase of ≥ 20 mm Hg 
decrease of ≥ 20 mm Hg 
Diastolic BP 
> 105 mm Hg 
< 50 mm Hg 
and an 
and a 
increase of ≥ 15 mm Hg 
decrease of ≥ 15 mm Hg 
Weight 
 
 
change of ≥ +/- 7% 
13.1.2 
Clinically notable ECG and laboratory values 
Abnormal ECG values will be specified in the manual from the centralized ECG vendor, with 
specific telephone alert values and panic alert values. 
Figure 13-1 
Abnormal ECG measurements leading to exclusion alerts 
Category 
Values leading to exclusion alerts 
HR_MN 
< 40 or > 120 
Mean QRS interval 
> 140 ms 
Mean QTcF interval 
> 500 ms 
Abnormal laboratory values will be specified in the manual from the central laboratory with 
specific telephone alert values and panic alert values. 
The Novartis Medical Monitor will be notified by email and fax at the same time as the 
investigator for all types of alerts. 
Discontinuation of study medication, for individual participant, is required in case of clinically 
significant ECG or laboratory findings considered to be suspected to be related to study 
medication, as judged by Investigator or the DMC, respectively. 
Table 13-2 
Abnormal laboratory values leading to participant exclusion 
Organ 
Laboratory value 
Limits 
Liver 
ALT or AST 
> 5 × ULN 
 
ALP 
> 2 × ULN (in the absence of known bone 
pathology) 
 
TBL 
> 2 × ULN (in the absence of known Gilbert 
syndrome) 
 
ALT or AST 
and 
INR 
> 3 × ULN 
and 
> 1.5 

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Organ 
Laboratory value 
Limits 
Renal 
Estimated glomerular 
filtration rate (GFR) 
<30mL/min (calculated using the Cockcroft-
Gault formula) 
Blood (chemistry) 
Calcium (mg/dL) 
<7.0; >12.5 
 
Phosphorus (mg/dL) 
<2.0 
 
Sodium (mmol/L) 
<125; >155 
 
Potassium  (mmol/L) 
<3.0; >6.0 
 
Magnesium (mg/dL) 
>3.0 
Blood (Hematology) 
HGB (g/dL) 
<8.0; ≥19.0 
 
WBC (GI/L) 
<2.0; ≥13.0 
 
Platelets (GI/L) 
<50; ≥700 
13.2 
Neurological symptoms or signs  
New neurological findings are defined as clinical signs or symptoms that raise concern in 
respect to neurological conditions. 
They include but are not limited to: 
• significant new or worsening neurological symptoms or signs, as reported spontaneously 
by the participants/caregivers at any time, or detected during the scheduled 
physical/neurological examinations or on MRI scans. These might be events such as new 
or worsening peripheral neuropathies, visual disturbances, or seizures; 
• worsening of cognition not consistent with the previous clinical course, as reported 
spontaneously by the participants/caregivers at any time or observed at the clinical 
assessments (e.g. APCC, CDR-SOB, RBANS, NPI-Q). 
Investigators will be asked to review the finding in consultation with an appointed neurologist 
(when applicable) and initiate any additional tests as needed. Summary of the findings will be 
provided for the attention of the Safety Monitor who will assess the need to consult the DMC, 
regardless of the suspected relationship to investigational treatment. 
Further tests will be scheduled to monitor the time-course of the findings until resolution if 
possible, and detailed information on the results will be communicated to the DMC. 
Discontinuation of study medication will be considered in case of clinically significant findings 
considered to be suspected to be related to study medication, as judged by investigator and 
DMC. 
These findings will be reported additionally as AEs only if they are symptomatic (i.e. reported 
spontaneously and not only observed at scheduled assessments), require symptomatic treatment, 
or impact study medication (suspension or discontinuation). 
In case MRI findings indicating CNS inflammation, additional clinical investigations including 
physical and neurological examinations and laboratory evaluations will be performed. Final 
interpretation of the safety MRI scans, including assessment of ARIA, white matter, stroke or 
other findings will be provided to the site by the Imaging vendor.  

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13.3 
Liver and renal event and laboratory trigger definitions and 
follow-up requirements 
Note: Tests below are recommended to be performed at a local lab for a faster result availability. 
However, if required exception testing by central lab can also be organized even if they are not 
part of the regular laboratory testing. 
Table 13-3 
Liver Event and Laboratory Trigger Definitions 
 
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
3 x ULN < ALT / AST ≤ 5 x ULN 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
ALT or AST > 5 × ULN 
 
ALP > 2 × ULN (in the absence of known bone pathology) 
 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
ALT or AST > 3 × ULN and INR > 1.5  
 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN 
and TBL > 2 × ULN [mainly conjugated fraction] without 
notable increase in ALP to > 2 × ULN) 
 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash with 
eosinophilia 
 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms 
TBL: total bilirubin; ULN: upper limit of normal  
Table 13-4 
Follow-up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s 
Law casea 
Discontinue the study treatment 
immediately 
Hospitalize, if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
ALT or AST 
> 8 × ULN 
Discontinue the study treatment 
immediately 
Hospitalize if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN and 
INR > 1.5 
Discontinue the study treatment 
immediately 
Hospitalize, if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 

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Criteria 
Actions required 
Follow-up monitoring 
> 5 to ≤ 8 × ULN 
Repeat LFT within 48 hours 
If elevation persists, continue follow-up 
monitoring 
If elevation persists for more than 2 
weeks, discontinue the study drug 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 × ULN 
accompanied by 
symptomsb 
Discontinue the study treatment 
immediately 
Hospitalize if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
> 3 to ≤ 5 × ULN 
(participant is 
asymptomatic) 
Repeat LFT within the next week 
If elevation is confirmed, initiate close 
observation of the participant 
Investigator discretion 
Monitor LFT within 1 to 4 weeks  
ALP (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
bone pathology) 
Repeat LFT within 48 hours 
If elevation persists, establish causality 
Complete liver CRF 
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
TBL (isolated) 
 
 
> 2 × ULN (in the 
absence of known 
Gilbert syndrome) 
Repeat LFT within 48 hours 
If elevation persists, discontinue the 
study drug immediately 
Hospitalize if clinically appropriate 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 1.5 to ≤ 2 × ULN 
(participant is 
asymptomatic) 
Repeat LFT within the next week 
If elevation is confirmed, initiate close 
observation of the participant  
Investigator discretion 
Monitor LFT within 1 to 4 weeks or 
at next visit 
Jaundice 
Discontinue the study treatment 
immediately 
Hospitalize the participant 
Establish causality 
Complete liver CRF 
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc 
(frequency at investigator 
discretion) 
Any AE potentially 
indicative of a 
liver toxicity* 
Consider study treatment interruption or 
discontinuation  
Hospitalization if clinically appropriate 
Establish causality 
Complete liver CRF 
Investigator discretion 
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia  
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death. 
 

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Table 13-5 
Specific Renal Alert Criteria and Actions 
Serum Event 
Serum creatinine increase 
25 – 49% compared to baseline 
Confirm 25% increase after 24-48h  
Follow up within 2-5 days 
Acute Kidney Injury: Serum creatinine increase 
≥ 50% compared to baseline 
Follow up within 24-48h if possible 
Consider study treatment interruption  
Consider participant hospitalization /specialized 
treatment 
Urine Event 
New dipstick proteinuria ≥1+ 
Albumin- or Protein-creatinine ratio increase 
≥2-fold 
Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 
mg/mmol; 
Protein-creatinine ratio (PCR )≥150 mg/g 
or >15 mg/mmol 
Confirm value after 24-48h 
Perform urine microscopy 
Consider study treatment interruption / or 
discontinuation  
New dipstick glycosuria ≥1+ not due to 
diabetes 
Blood glucose (fasting) 
Perform serum creatinine, ACR  
New dipstick hematuria ≥1+ not due to trauma 
Urine sediment microscopy 
Perform serum creatinine, ACR  
For all renal events: 
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and 
additional diagnostic procedures performed  
Monitor participant regularly (frequency at investigator’s discretion) until either:  
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months. 

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Appendix 2: Role of study partner and key site personnel  
Study partner 
The study partner is expected to spend sufficient time with the participant to be familiar with 
his/her overall function and behavior, and be able to provide adequate information about the 
participant including: (a) knowledge of domestic activities, hobbies, routines, social skills and 
basic activities of daily life; (b) work and educational history; (c) cognitive performance, 
including memory abilities, language abilities, temporal and spatial orientation, judgment, and 
problem solving; (d) emotional and psychological state; and (e) general health status.  
Although the study partner is expected to accompany the participant to all relevant visits, if 
unavailable to attend a given site visit (e.g. if traveling or sick), his/her input to clinical scales 
can be organized via a telephone interview 
. Yet for CDR and ECog, a 
site visit is preferable 
The study partner and/or the participant will be requested to call the site to inform about any 
study partner unavailability or transition to a new one. Of note: a study partner needs to be 
identified and documented before the next study treatment dispensing visit, otherwise the study 
treatment would be suspended until a new partner is identified.  
The study partner is excluded from participating in any study in the Generation Program 
(CCAPI015A2201J and CCNP520A2202J).  The study partner may only be a participant if 
another study partner can be identified. A participant cannot act as study partner for another 
participant. 
 
Key study personnel 
Key site personnel include (but are not limited to) the following individuals: 
Investigator 
The investigator will be responsible for: 
• Overall conduct of the study at the study site including assigning per protocol required 
study site personnel 
• Organization of the referral and recruitment strategies at the site level (see also Appendix 
4)  
• Organizing for the genetic disclosure as per local regulations if not done by genetic 
counselor (see below genetic counselor description) 
• Organizing for the disclosure of the Amyloid status test results to the participants after 
receiving the results on elevated or non-elevated status from the centralized assessment 
performed by the central reader at the Imaging vendor.  
Of note: the local read should never be communicated to the participant. 
• Management of the routine clinical care of the study participants 
• Confirmation of participant’s eligibility for randomization 
• Supervision of study drug dispensing. The investigator may delegate this responsibility 
to the Study Nurse/Study Coordinator as appropriate and permissible by local regulation 

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• The genetic counselor as well as the rater who assesses the psychological readiness with 
GDS and STAI-AD before disclosure are expected to be blind to the actual APOE4 
genotype for the participant until disclosure occurs. 
• Once readiness of the participant to receive their individual information is confirmed, the 
counselor will obtain the genotype result and disclose it to the participant.  
• Confirming to the SC that disclosure occurred and/or follow-up steps required. 
Raters 
Raters will be certified by the cognition vendor based on their qualifications and previous 
experience in rating the APCC scales. Training may be required in addition at study start, and 
regular re-training will also occur during the course of the study. 
The initial MMSE at first Screening visit to verify a score >24 for inclusion can be performed 
by a non-certified rater (eg. Study Nurse or Study Coordinator) and be performed on paper not 
transcribed to the Virgil tablet in such case. Other scales which are not contributing to the APCC 
can also be administered by a non-certified rater or by the CDR rater. 
Requirement for separate raters: 
At least three different raters are needed for any given cognitive assessment: a CDR rater, a 
rater for other APCC scales, a physician to complete the diagnostic evaluation. The certified 
raters at the site will administer the clinical scales using the tablet provided by the Cognition 
vendor. 
A separate rater for CDR scale is required, so that CDR rating is blinded to the other APCC 
scales’ results. 
The physician who completes the diagnostic evaluation form should not have administered the 
CDR at that given visit. 
MRI technician 
The MRI technician will be responsible for: 
• Familiarization with the MRI manual procedures and the study specific MRI protocol 
• Proceeding with the calibration and qualification steps required by Imaging vendor 
• Performance of high-quality MRI scans using the study specific parameters stored in 
the designated MRI scanner for the duration of the study 
• Submission of the MRIs in the appropriate format to the Imaging vendor for assessment 
by the central MRI reader  
Nuclear Medicine Specialists 
The NM technician will be responsible for: 
• Familiarization with the PET manual procedures and the study specific PET protocol for 
amyloid radiotracer(s) available for the site 
• Proceeding with the calibration and qualification steps required by Imaging vendor 

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• Performance of high-quality PET scans using the study specific parameters stored in 
the designated PET scanner for the duration of the study 
• Submission of the PET scans in the appropriate format to the Imaging vendor for 
centralized assessment.  
Of note: local evaluation SHOULD never be communicated to the participant. 
Lumbar Puncture specialist 
Lumbar punctures should be performed by a qualified and experienced specialist (e.g. 
anesthesiologist or physician) with regular practice of lumbar punctures. 
The procedure and details on possible side-effects and minimization methods will be described 
to the participant upfront. 

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Appendix 4: Recruitment methods 
It is anticipated that there will be different methods of recruitment, with site and/or country 
specificity. Some potential participants will already be part of a local/regional/national registry. 
Some potential participants will be known to investigators as the relatives of affected 
participants. Some may be self-referred from an initial assessment/memory check (e.g. 
subjective complains or concern due to familial history) or because they are already aware of 
their APOE4 genotype (e.g. from private genetic testing companies). 
Additionally, country specific programs may potentially be offered. For example, in the US, 
potential participants may be referred to a trial-independent APOE genotyping program. This 
program will apply an algorithm to invite APOE4 carriers (HMs and HTs) and non-carriers that 
meet basic eligibility criteria to participate in this study.  
Table 16-1 
Referral source of participants  
Referral method 
Participants referred for screening part I and genetic 
disclosure 
1) Potential participants with 
previous genotype information and 
genetic disclosure performed in the 
API015A2201J study  
HTs will still have to undergo amyloid testing and disclosure 
in screening part II. See Section 6.1.2  
2) Pre-existing registries/local 
databases with available and 
previously disclosed genotype 
information, as per local clinical 
practice; informed consent allows 
for re-contact for potential clinical 
trial participation based on the 
genotype. 
HTs and HMs will be invited to the screening part I including 
the genetic counseling and disclosure despite their genotype 
knowledge to ensure the same process and counseling 
steps are followed. The buccal swab will need to be 
repeated at the study central laboratory even with 
appropriate confirmed documentation of genotype. See 
more information in Section 6.1.2 
3) Pre-existing registries/local 
databases with available but not 
disclosed genotype information; 
informed consent allows for re-
contact. 
HTs, HMs and a sufficient proportion of non-carriers will be 
invited to attend the screening visit part I. The exact ratio of 
each genotype will not be disclosed to the participants in 
order to prevent implicit disclosure by invitation. During the 
initial contact with participants inviting them to the screening 
part I, it must be highlighted that those with and without the 
genotype of interest are invited at this stage. See more 
information in Section 6.1.2 
4) De novo genotyping: Newly 
identified potential participants, 
without prior genotype information. 
The investigator will assess the most efficient way* to 
identify HMs and HTs to build a local database according to 
the local regulations and in collaboration with the Sponsor. A 
buccal swab will be performed to obtain the APOE genotype 
under the preliminary informed consent ICF#A. The 
genotyping will be performed at the central laboratory. The 
site will identify a dedicated recipient of the genotype results 
as described above for scenario 3. Not all participants that 
perform the genetic testing will be disclosed*. 
*The process will be documented in the local study file. Such a process will be site/country-specific. 
The person delivering the genetic counseling and disclosure should be qualified according to local 
regulations 
APOE4 = Apolipoprotein E4; HM = homozygote; HT= heterozygote. 

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17 
Appendix 5: A testing strategy with option for dose regimen 
modification and two endpoints 
17.1 
Design and definitions 
At randomization, participants are randomized to two active doses, CNP520 50 mg once daily 
(H) and CNP520 15 mg once daily (L) and a placebo control (C) in a 2:1:2 ratio into the 3 
respective treatment arms. In case of no DRM, the CNP520 50 mg once daily dose arm is 
considered as the primary active arm, that is, the active arm to be used for comparison with 
placebo in the final primary analyses. In case of DRM, the primary active arm will be defined 
by pooling of the two active treatment arms (pooled P: H and L). The primary efficacy analysis 
furthermore consists of two endpoints (e), Time-To-Event (TTE) and API Preclinical 
Composite Cognitive Battery (APCC), designated as 𝑒𝑒= 𝑇𝑇, 𝐴𝐴.  
A DRM may be triggered upon DMC recommendation and/or Sponsor’s decision. The DRM 
will be a modification to lower either dose strength or dosing frequency. This lower dose 
regimen is referred to as the LDR. 
In case that no DRM occurs, the 3 treatment arms remain the same as planned originally. The 
primary treatment arms are CNP520 50 mg once daily or matching placebo in a respective ratio 
of 1:1.  
In case the DRM is implemented, the same randomization ratio is maintained. The primary 
active arm (pooled across all active arms) consists of the following participants: 
• those who received CNP520 50 mg once daily dose followed by CNP520 LDR (those who 
were originally randomized to Arm #1, and subsequently switch to the lower dose 
regimen) and  
• those who received CNP520 15 mg once daily dose followed by CNP520 LDR (those who 
were originally randomized to Arm #2, and subsequently switch to the lower dose 
regimen) and  
• those who received CNP520 LDR dose only (those who were randomized to active 
treatment arm after the DRM). 
The trial then proceeds to the final analysis and only at the final analysis, a statistical test of the 
treatments 𝐿𝐿, 𝐻𝐻 or P vs 𝐶𝐶 is performed. The preplanned testing strategy follows the closed test 
principle (Marcus et al 1976).  
Definitions and abbreviations:  
• Comparisons of treatment vs. control: 𝑖𝑖= 𝐿𝐿, 𝐻𝐻, 𝑃𝑃, where L denotes the comparison of the 
low dose vs. placebo control C, H the comparison of the high dose vs. placebo control and 
P the comparison of the pooled high and low dose vs. placebo control.  
• Endpoints: 𝑒𝑒= 𝑇𝑇, 𝐴𝐴 where T is the time to diagnosis and A the composite endpoint APCC.  
 
• A single null hypothesis of no effect of treatment comparison 𝑖𝑖 on endpoint 𝑒𝑒 is denoted 
by 𝐻𝐻𝑒𝑒
𝑖𝑖.  
Intersection hypotheses are denoted by concatenating the index pairs𝑖𝑖
𝑒𝑒 of each hypothesis, 

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for example, 𝐻𝐻𝑇𝑇𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿𝐿𝐿= 𝐻𝐻𝑇𝑇
𝐿𝐿∩𝐻𝐻𝑇𝑇
𝐻𝐻∩𝐻𝐻𝐴𝐴
𝐻𝐻.  
An intersection hypothesis that reference both treatment arms for an endpoint 𝑒𝑒 are 
abbreviated as 𝐻𝐻𝑒𝑒
𝑃𝑃= 𝐻𝐻𝑒𝑒
𝐿𝐿∩𝐻𝐻𝑒𝑒
𝐻𝐻. Whenever such a pair occurs it will be collapsed to one 
hypothesis since the data will be pooled and a single test conducted, for example, 
𝐻𝐻𝑇𝑇,𝑇𝑇,𝐴𝐴
𝐿𝐿,𝐻𝐻,𝐻𝐻= 𝐻𝐻𝑇𝑇,𝐴𝐴
𝑃𝑃,𝐻𝐻.  
Thus, the 15 intersection hypotheses resulting from the 4 original elementary hypotheses 
on 2 doses and 2 endpoints can be rewritten with either one or two index pairs.  
• P-values resulting from the 4 univariate tests across both stages are denoted as 𝑝𝑝𝑒𝑒
𝑖𝑖 for, 𝑒𝑒=
𝑇𝑇, 𝐴𝐴; 𝑖𝑖= 𝐿𝐿, 𝐻𝐻, while p-values for the 2 possible pooled tests on the 2 endpoints are 
denoted as 𝑝𝑝𝑒𝑒
𝑃𝑃, 𝑒𝑒= 𝑇𝑇, 𝐴𝐴.  
P-values resulting from tests on first and second stage data are accordingly denoted by 
𝑝𝑝𝑒𝑒,𝑗𝑗
𝑖𝑖, 𝑒𝑒= 𝑇𝑇, 𝐴𝐴; 𝑖𝑖= 𝐿𝐿, 𝐻𝐻; 𝑗𝑗= 1,2 and 𝑝𝑝𝑒𝑒,𝑗𝑗
𝑃𝑃, 𝑒𝑒= 𝑇𝑇, 𝐴𝐴; 𝑗𝑗= 1,2.  
• Pooling of doses refers to pooling of all participant data initially randomized to both the 50 
mg and 15 mg once daily dose arms, irrespective of dose regimen changes during the course 
of the trial. 
17.2 
The closed multiple testing procedure  
To test the four elementary hypotheses 𝐻𝐻𝑒𝑒
𝑖𝑖 with familywise error rate control, a Bonferroni 
based closed test procedure will be used on the 24 −1 = 15 intersection hypotheses. This 
section describes the closed testing procedure. The Bonferroni test is only needed to control the 
type I error for the multiplicity incurred by the two endpoints (with unknown correlation). The 
multiplicity due to the two doses in an intersection of two hypotheses on the same endpoint is 
taken care of by pooling the data from the two dose levels.  
The following general rules apply: 
• Any intersection hypothesis involving both endpoints, 𝑇𝑇 and 𝐴𝐴 is rejected if either the test 
for 𝑇𝑇 is significant at level 𝛼𝛼𝑇𝑇= 4/5𝛼𝛼 or if the test for 𝐴𝐴 is significant at level 𝛼𝛼𝐴𝐴=
1/5𝛼𝛼.  
• An intersection hypothesis involving only one endpoint can be tested at full level 𝛼𝛼.  
• An elementary hypothesis can be rejected if and only if all intersection hypotheses 
containing it can be rejected at full level 𝛼𝛼.  
Table 17-1 
Closed test for the standard design option 
Hypothesis 
index no. 
Hypothesis 
Reject if  
1  
𝐻𝐻𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿= 𝐻𝐻𝑇𝑇𝑇𝑇
𝑃𝑃𝑃𝑃  
𝑝𝑝𝑇𝑇
𝑃𝑃< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝑃𝑃< 𝛼𝛼𝐴𝐴  
2  
𝐻𝐻𝑇𝑇𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿𝐿𝐿= 𝐻𝐻𝑇𝑇𝑇𝑇
𝑃𝑃𝑃𝑃  
𝑝𝑝𝑇𝑇
𝑃𝑃< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝐿𝐿< 𝛼𝛼𝐴𝐴  
3  
𝐻𝐻𝑇𝑇𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿𝐿𝐿= 𝐻𝐻𝑇𝑇𝑇𝑇
𝑃𝑃𝑃𝑃  
𝑝𝑝𝑇𝑇
𝑃𝑃< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝐻𝐻< 𝛼𝛼𝐴𝐴  
4  
𝐻𝐻𝑇𝑇𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿𝐿𝐿= 𝐻𝐻𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿  
𝑝𝑝𝑇𝑇
𝐿𝐿< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝑃𝑃< 𝛼𝛼𝐴𝐴  
5  
𝐻𝐻𝑇𝑇𝑇𝑇𝑇𝑇
𝐻𝐻𝐻𝐻𝐻𝐻= 𝐻𝐻𝑇𝑇𝑇𝑇
𝐻𝐻𝐻𝐻  
𝑝𝑝𝑇𝑇
𝐻𝐻< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝑃𝑃< 𝛼𝛼𝐴𝐴  
6  
𝐻𝐻𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿= 𝐻𝐻𝑇𝑇
𝑃𝑃  
𝑝𝑝𝑇𝑇
𝑃𝑃< 𝛼𝛼  
7  
𝐻𝐻𝐴𝐴𝐴𝐴
𝐿𝐿𝐿𝐿= 𝐻𝐻𝐴𝐴
𝑃𝑃  
𝑝𝑝𝐴𝐴
𝑃𝑃< 𝛼𝛼  

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Hypothesis 
index no. 
Hypothesis 
Reject if  
8  
𝐻𝐻𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿  
𝑝𝑝𝑇𝑇
𝐿𝐿< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝐿𝐿< 𝛼𝛼𝐴𝐴  
9  
𝐻𝐻𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿  
𝑝𝑝𝑇𝑇
𝐿𝐿< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝐻𝐻< 𝛼𝛼𝐴𝐴  
10  
𝐻𝐻𝑇𝑇𝑇𝑇
𝐻𝐻𝐻𝐻  
𝑝𝑝𝑇𝑇
𝐻𝐻< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝐿𝐿< 𝛼𝛼𝐴𝐴  
11  
𝐻𝐻𝑇𝑇𝑇𝑇
𝐻𝐻𝐻𝐻  
𝑝𝑝𝑇𝑇
𝐻𝐻< 𝛼𝛼𝑇𝑇∨𝑝𝑝𝐴𝐴
𝐻𝐻< 𝛼𝛼𝐴𝐴  
12-13  
𝐻𝐻𝑒𝑒
𝐿𝐿, 𝑒𝑒= 𝑇𝑇, 𝐴𝐴  
𝑝𝑝𝑒𝑒
𝐿𝐿< 𝛼𝛼  
14-15  
𝐻𝐻𝑒𝑒
𝐻𝐻, 𝑒𝑒= 𝑇𝑇, 𝐴𝐴  
𝑝𝑝𝑒𝑒
𝐻𝐻< 𝛼𝛼  
The above test procedure has the following property: If a hypothesis related to one of the 
endpoints can be rejected for both the high and the low dose arm, the hypotheses related to the 
other endpoint can be tested at full level alpha. This is illustrated with an example: 
Assume that 𝐻𝐻𝑇𝑇
𝐻𝐻 is rejected at 𝛼𝛼𝑇𝑇, then it implies that each of the intersection hypotheses with 
𝐻𝐻𝑇𝑇
𝐻𝐻are also rejected at 𝛼𝛼𝑇𝑇 (that is, hypothesis indexes 1, 2, 3, 5, 6, 10, 11 . This is the case if 
𝑝𝑝𝑇𝑇
𝑃𝑃< 𝛼𝛼𝑇𝑇 and 𝑝𝑝𝑇𝑇
𝐻𝐻< 𝛼𝛼𝑇𝑇. In order to reject 𝐻𝐻𝐴𝐴
𝐻𝐻, the intersection hypotheses 1, 3, 4, 5, 7, 9, 11, 
must be rejected.  
If hypothesis 9,  𝐻𝐻𝑇𝑇𝑇𝑇
𝐿𝐿𝐿𝐿, is not rejected because 𝑝𝑝𝑇𝑇
𝐿𝐿> 𝛼𝛼𝑇𝑇 then in order to reject this intersection 
hypothesis we must have 𝑝𝑝𝐴𝐴
𝐻𝐻< 𝛼𝛼𝐴𝐴 to declare 𝐻𝐻𝐴𝐴
𝐻𝐻 rejected at FWER 𝛼𝛼. If, however both 
hypothesis related to the T endpoints can be rejected for both the high and the low dose arm, 
then in order to reject, for example, 𝐻𝐻𝐴𝐴
𝐻𝐻, it is sufficient that the tests of the intersection 
hypotheses 7, 𝐻𝐻𝐴𝐴
𝑃𝑃, and of the hypothesis 𝐻𝐻𝐴𝐴
𝐻𝐻 are significant at level 𝛼𝛼.  
In case of no DRM, the primary analysis comprises testing of hypotheses  𝐻𝐻𝑇𝑇
𝐻𝐻 and 𝐻𝐻𝐴𝐴
𝐻𝐻. In case 
of DRM, the testing strategy stops earlier: the primary analysis comprises testing of hypotheses 
reject 𝐻𝐻𝑇𝑇
𝑃𝑃 and 𝐻𝐻𝐴𝐴
𝑃𝑃.