A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Efficacy, Safety and Biomarker Effects of ALZ-801 in Subjects With Early Alzheimer's Disease and APOE4/4 Genotype
Phase: PHASE3
Conditions: Early Alzheimer's Disease
Sponsor: Alzheon Inc.

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CLINICAL STUDY PROTOCOL 
A 
PHASE 
3, 
MULTICENTER, 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF THE EFFICACY, SAFETY AND 
BIOMARKER EFFECTS OF ALZ-801 IN SUBJECTS WITH EARLY 
ALZHEIMER’S DISEASE AND APOE4/4 GENOTYPE 
 
Short Title: 
Phase 3 Study of ALZ-801 in APOE4/4 Early AD 
Subjects 
Study Abbreviation: 
APOLLOE4 
Sponsor: 
Alzheon, Inc. 
111 Speen Street, Suite 306 
Framingham, MA 01701 USA 
Sponsor Medical Officer: 
Susan Abushakra, MD 
ICON Global Lead Medical Monitor: 
Heber Varela, MD 
ICON Backup and Regional Medical 
Monitor (Europe): 
Dominika Brykajlo, MD 
Clinical Research Organization:  
ICON plc 
Sponsor Protocol No.: 
ALZ-801-AD301 
IND Number: 
125760 
EudraCT Number:  
2020-005755-20 
Study Drug Name 
ALZ-801 
Development Phase: 
Phase 3 
Date of Original Protocol: 
24 DEC 2020 
Amendment Number: 
2 
Date of Amendment 1: 
09 FEB 2021 
Date of Amendment 2: 
24 JAN 2022 
Version of Protocol: 
3.0 
The study will be conducted according to the protocol and in compliance with Good Clinical Practice 
(GCP), with the Declaration of Helsinki, and with other applicable regulatory requirements. 
Confidentiality Statement 
The contents of this document are confidential and proprietary to Alzheon, Inc. Neither this document, nor 
any portion thereof, shall be disclosed to any persons without prior written authorization from Alzheon, 
Inc. No disclosure of the contents of this document to other persons may be made without informing the 
recipient of its confidential and proprietary nature and that further disclosure is not allowed. Alzheon, Inc. 
shall be notified of any requirements to disclose the contents of this document under applicable laws and 
regulations prior to such disclosure, unless such notification is barred by law. 

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SPONSOR SIGNATURE PAGE 
 
Declaration of Sponsor:  
 
Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the 
Efficacy, Safety and Biomarker Effects of ALZ-801 in Subjects with Early Alzheimer’s Disease 
and APOE4/4 Genotype 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. The 
information it contains is consistent with the current risk/benefit evaluation of the investigational 
product as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki and the guidelines on Good Clinical Practice (GCP). 
 
 
_____________________________________ 
_____________________ 
Susan Abushakra, MD 
 
 
 
Date 
Chief Medical Officer 
Alzheon, Inc.   
 
 
 
 
 
111 Speen Street, Suite 306 
Framingham, MA 01701 USA 
Telephone: +1 (508) 861-7709 

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STATEMENT OF COMPLIANCE  
 
Declaration of Principal Investigator: 
 
Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the 
Efficacy, Safety and Biomarker Effects of AlZ-801 in Subjects with Early Alzheimer’s Disease 
and APOE4/4 Genotype 
 
I have read this study protocol, including all appendices. By signing this protocol, I agree to 
conduct the clinical study, following approval by an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), in accordance with the study protocol, the current 
International Council for Harmonisation (ICH) Guideline for GCP, and applicable regulatory 
requirements. I will ensure that all personnel involved in the study under my direction will be 
informed about the contents of this study protocol and will receive all necessary instructions for 
performing the study according to the study protocol. 
 
Principal Investigator 
 
 
_____________________________________ 
_____________________ 
Name: 
Date 
Title:  
Institution:  

Protocol ALZ-801-AD301 (APOLLOE4) Amendment 2 
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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ................................................................................................ 2 
STATEMENT OF COMPLIANCE ............................................................................................. 3 
TABLE OF CONTENTS ............................................................................................................ 4 
LIST OF TABLES .................................................................................................................... 10 
LIST OF FIGURES .................................................................................................................. 10 
LIST OF APPENDICES ........................................................................................................... 10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................................. 11 
1. 
PROTOCOL SYNOPSIS........................................................................................ 15 
2. 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE ......................................................................................................... 23 
2.1. 
Background Information ......................................................................................... 25 
2.1.1. 
Disease Background ............................................................................................... 25 
2.1.2. 
Current and Emerging Treatments for AD .............................................................. 27 
2.1.2.1. 
Challenges of Amyloid Immunotherapy .................................................................. 27 
2.2. 
Tramiprosate and ALZ-801 .................................................................................... 28 
2.2.1. 
Tramiprosate Background ....................................................................................... 28 
2.2.2. 
Tramiprosate Mechanism of Action ........................................................................ 28 
2.2.3. 
ALZ-801 ................................................................................................................ 29 
2.2.4. 
Nonclinical Experience ........................................................................................... 29 
2.3. 
Rationale for Current Study .................................................................................... 29 
2.3.1. 
Clinical Experience................................................................................................. 30 
2.3.1.1. 
Overview of Original Phase 3 Program with Tramiprosate ...................................... 30 
2.3.1.2. 
Overview of ALZ-801 Phase 1 and 2 Studies .......................................................... 32 
2.3.2. 
Rationale for Development in APOE4/4 Subjects ................................................... 33 
2.3.3. 
Rationale for Choice of Clinical Outcomes ............................................................. 34 
2.3.4. 
Rationale for Fluid Biomarker and MRI Assessments ............................................. 34 
2.4. 
Potential Risks and Benefits.................................................................................... 36 
3. 
OBJECTIVES AND PURPOSE ............................................................................. 37 
3.1. 
Objectives............................................................................................................... 37 
3.1.1. 
Primary Objectives ................................................................................................. 37 
3.1.2. 
Secondary Objectives ............................................................................................. 37 
4. 
STUDY DESIGN AND ENDPOINTS.................................................................... 38 

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4.1. 
Description of the Study Design ............................................................................. 38 
4.2. 
Study Endpoints ..................................................................................................... 40 
4.2.1. 
Primary Endpoints .................................................................................................. 40 
4.2.2. 
Secondary Endpoints .............................................................................................. 40 
4.2.3. 
Other Endpoints ...................................................................................................... 41 
5. 
STUDY ENROLLMENT AND WITHDRAWAL .................................................. 41 
5.1. 
Inclusion Criteria .................................................................................................... 41 
5.2. 
Exclusion Criteria ................................................................................................... 44 
5.3. 
Prohibited Medications and Exceptions .................................................................. 46 
5.4. 
Subject Identification and Allocation to Treatment ................................................. 50 
5.4.1. 
Subject Identification .............................................................................................. 50 
5.4.2. 
Treatment Allocation .............................................................................................. 50 
5.5. 
Subject Withdrawal, Termination, and Replacement ............................................... 51 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................... 52 
6.1. 
Investigational Medicinal Product and Control Description ..................................... 52 
6.1.1. 
Formulation, Appearance, Packaging, Labeling, and Shipping ................................ 53 
6.1.2. 
Product Storage and Stability .................................................................................. 54 
6.1.3. 
Replacement Procedures for Investigational Medicinal Product .............................. 54 
6.2. 
Dosing and Administration, and Adjustment ........................................................... 55 
6.2.1. 
Dosing Regimen ..................................................................................................... 55 
6.2.2. 
Dose Adjustments/Modifications/Delays ................................................................ 55 
6.3. 
Study Drug Accountability ..................................................................................... 55 
6.4. 
Study Drug Compliance .......................................................................................... 56 
7. 
STUDY PROCEDURES AND SCHEDULE .......................................................... 56 
7.1. 
Study Specific Procedures/Evaluations ................................................................... 56 
7.1.1. 
Remote Visits ......................................................................................................... 56 
7.1.2. 
Informed Consent ................................................................................................... 57 
7.1.3. 
Prohibited Medications ........................................................................................... 57 
7.1.4. 
Permitted Medications ............................................................................................ 57 
7.1.5. 
APOE Genotyping .................................................................................................. 57 
7.1.6. 
Future Potential Genomic Testing ........................................................................... 57 
7.1.7. 
Subject Demographics and Medical History............................................................ 57 
7.1.8. 
Prior and Concomitant Medications ........................................................................ 58 

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7.1.9. 
Subject Eligibility ................................................................................................... 58 
7.1.10. 
Safety Assessments................................................................................................. 58 
7.1.10.1. 
Assessment of Adverse Events ............................................................................... 58 
7.1.10.2. 
Physical Examination ............................................................................................. 58 
7.1.10.3. 
Neurological Examination ...................................................................................... 58 
7.1.10.4. 
Height and Weight Measurements .......................................................................... 58 
7.1.10.5. 
Vital Signs .............................................................................................................. 59 
7.1.10.6. 
Brain Imaging ......................................................................................................... 59 
7.1.10.7. 
Electrocardiogram .................................................................................................. 59 
7.1.10.8. 
Columbia-Suicide Severity Rating Scale ................................................................. 59 
7.1.10.9. 
Safety Laboratory Assessments............................................................................... 60 
7.1.10.10. Serum FSH or hCG Test ......................................................................................... 62 
7.1.10.11. Urine Pregnancy Test ............................................................................................. 62 
7.1.10.12. Urine Drug Screen .................................................................................................. 62 
7.1.10.13. Screens for HIV and Hepatitis B and C ................................................................... 62 
7.1.11. 
Clinical Efficacy Assessments ................................................................................ 62 
7.1.11.1. 
Alzheimer’s Disease Assessment Scale – Cognitive Subscale ................................. 63 
7.1.11.2. 
Amsterdam Instrumental Activities of Daily Living ................................................ 63 
7.1.11.3. 
Disability Assessment for Dementia ....................................................................... 63 
7.1.11.4. 
Clinical Dementia Rating – Global Score and Sum of Boxes .................................. 63 
7.1.11.5. 
Repeatable Battery for the Assessment of Neuropsychological Status 
(RBANS) – Delayed Memory Index Score ............................................................. 64 
7.1.11.6. 
Mini-Mental State Examination .............................................................................. 64 
7.1.11.7. 
Neuropsychiatric Inventory ..................................................................................... 64 
7.1.11.8. 
Quality of Life in Alzheimer’s Disease ................................................................... 65 
7.1.11.9. 
Resource Utilization in Dementia ........................................................................... 65 
7.1.12. 
Biomarker Assessments .......................................................................................... 65 
7.1.12.1. 
Cerebrospinal Fluid Biomarkers ............................................................................. 65 
7.1.12.2. 
Plasma Biomarkers ................................................................................................. 66 
7.1.12.3. 
Imaging Biomarkers ............................................................................................... 66 
7.1.13. 
Pharmacokinetic Assessments................................................................................. 66 
7.1.14. 
Total Volume of Blood Collection .......................................................................... 66 
7.1.15. 
COVID-19 Related Special Consideration .............................................................. 67 

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7.1.15.1. 
COVID-19 Infection ............................................................................................... 67 
7.1.15.2. 
COVID-19 Vaccination .......................................................................................... 67 
7.2. 
Procedures by Visit ................................................................................................. 68 
7.2.1. 
Screening- Part 1 Visit – (Up to 3 months prior to Baseline Visit)........................... 68 
7.2.2. 
Screening Part 2 Visit ............................................................................................. 68 
7.2.3. 
Visit 2 – Baseline Visit (Day 1) .............................................................................. 69 
7.2.4. 
Visit 3 (Phone) – Week 2 (Day 15 ± 2 days) ........................................................... 71 
7.2.5. 
Visit 4 – Week 6 (Day 43 ± 7 days) ........................................................................ 71 
7.2.6. 
Visit 5 – Week 13 (Day 92 ± 14 days) .................................................................... 71 
7.2.7. 
Visit 6 (Phone) – Week 20 (Day 141 ± 2 days) ....................................................... 72 
7.2.8. 
Visit 7 – Week 26 (Day 183 ± 14 days) .................................................................. 72 
7.2.9. 
Visit 8 – Week 39 (Day 274 ± 14 days) .................................................................. 73 
7.2.10. 
Visit 9 – Week 52 (Day 365 ± 14 days) .................................................................. 74 
7.2.11. 
Visit 10 – Week 65 (Day 456 ± 14 days)................................................................. 75 
7.2.12. 
Visit 11 – Week 78 (Day 547 ± 14 days) [End of Treatment] .................................. 76 
7.2.13. 
Safety Follow-up Visit – Week 82 (Day 574 ± 7 days) [End of Study] .................... 77 
7.2.14. 
Early Termination Visit .......................................................................................... 78 
7.2.15. 
Retrieved Dropout Visit .......................................................................................... 79 
7.2.16. 
Unscheduled Visit .................................................................................................. 79 
8. 
ADVERSE EVENTS.............................................................................................. 79 
8.1. 
Specification of Safety Parameters .......................................................................... 79 
8.1.1. 
Definition of Adverse Event (AE) ........................................................................... 80 
8.1.2. 
Definition of Serious Adverse Event (SAE) ............................................................ 81 
8.1.3. 
Definition of Unanticipated Problems ..................................................................... 82 
8.2. 
Classification of an Adverse Event ......................................................................... 83 
8.2.1. 
Severity of Event .................................................................................................... 83 
8.2.2. 
Causality ................................................................................................................ 83 
8.2.3. 
Expectedness .......................................................................................................... 84 
8.3. 
Time Period and Frequency for Event Assessment and Follow-up .......................... 84 
8.4. 
Collecting, Reporting, and Recording Procedures ................................................... 85 
8.4.1. 
Collecting, Reporting, and Recording Adverse Events ............................................ 85 
8.4.2. 
Collecting, Reporting, and Recording Serious Adverse Events................................ 85 
8.4.3. 
Collecting, Reporting, and Recording Pregnancy .................................................... 86 

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8.5. 
Safety Oversight ..................................................................................................... 87 
9. 
CLINICAL MONITORING AND COMPLIANCE ................................................ 88 
9.1. 
Study Monitoring.................................................................................................... 88 
9.2. 
Data Quality Assurance .......................................................................................... 88 
9.3. 
Audits and Inspections ............................................................................................ 89 
9.4. 
Archiving Study Documents ................................................................................... 89 
10. 
STATISTICAL METHODS AND DATA ANALYSIS .......................................... 89 
10.1. 
General Considerations ........................................................................................... 89 
10.2. 
Endpoints for Statistical Considerations .................................................................. 90 
10.3. 
Determination of Sample Size................................................................................. 90 
10.3.1. 
Primary Clinical Outcome ...................................................................................... 90 
10.3.2. 
Fluid Biomarker Outcome ...................................................................................... 90 
10.3.3. 
Imaging Biomarker Outcome .................................................................................. 91 
10.4. 
Subject Stratification .............................................................................................. 91 
10.5. 
Study Populations ................................................................................................... 91 
10.5.1. 
Safety Population.................................................................................................... 91 
10.5.2. 
Modified Intent-to-Treat Population (mITT) ........................................................... 91 
10.5.3. 
Per Protocol Population (PPP) ................................................................................ 92 
10.5.4. 
Completer Population (CP) ..................................................................................... 92 
10.5.5. 
Pharmacokinetic Population.................................................................................... 92 
10.5.6. 
Populations for Exploratory Analyses ..................................................................... 92 
10.6. 
Demographics, Baseline Characteristics, and Other Background Information ......... 92 
10.6.1. 
Demographics and Baseline Characteristics ............................................................ 92 
10.6.2. 
Prior and Concomitant Medications ........................................................................ 92 
10.6.3. 
Subject Disposition ................................................................................................. 92 
10.6.4. 
Study Drug Compliance .......................................................................................... 92 
10.7. 
Efficacy Analyses ................................................................................................... 93 
10.7.1. 
Hierarchical Hypothesis Testing ............................................................................. 93 
10.7.2. 
Primary Efficacy Analysis ...................................................................................... 94 
10.7.3. 
Secondary Endpoint Analyses ................................................................................. 95 
10.7.4. 
Subgroup Analyses ................................................................................................. 95 
10.8. 
Biomarker Analyses ............................................................................................... 95 
10.8.1. 
Cerebrospinal Fluid Biomarker Analyses ................................................................ 95 

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10.8.2. 
Plasma Biomarker Analyses ................................................................................... 96 
10.8.3. 
Imaging Biomarker Analyses .................................................................................. 96 
10.9. 
Tests of Cognition and Function ............................................................................. 96 
10.10. 
Safety Analyses ...................................................................................................... 96 
10.10.1. 
Adverse Events ....................................................................................................... 97 
10.10.2. 
Clinical Laboratory Evaluations .............................................................................. 97 
10.10.3. 
MRI Safety Evaluations .......................................................................................... 97 
10.10.4. 
Vital Signs .............................................................................................................. 97 
10.10.5. 
Electrocardiograms ................................................................................................. 98 
10.10.6. 
Physical Examination ............................................................................................. 98 
10.10.7. 
Neurological Examination ...................................................................................... 98 
10.10.8. 
Deaths .................................................................................................................... 98 
10.11. 
Pharmacokinetic Analyses ...................................................................................... 99 
10.11.1. 
Descriptive Pharmacokinetic Analysis .................................................................... 99 
10.12. 
Interim Analyses ..................................................................................................... 99 
10.13. 
Measures to Minimize Bias ..................................................................................... 99 
10.13.1. 
Enrollment/ Randomization/ Blinding Procedures ................................................... 99 
10.13.2. 
Blinding at the Study Site and Sponsor Personnel ................................................... 99 
10.13.3. 
Breaking the Study Blind/Participant Code ............................................................. 99 
11. 
DATA HANDLING AND RECORD KEEPING .................................................. 100 
11.1. 
Data Collection and Management ......................................................................... 100 
11.2. 
Access to Source Data/Case Report Forms............................................................ 100 
11.3. 
Subject Confidentiality and Data Protection .......................................................... 101 
12. 
QUALITY MANAGEMENT ............................................................................... 101 
13. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ................................ 101 
13.1. 
Ethical Conduct of the Study ................................................................................ 101 
13.2. 
Informed Consent ................................................................................................. 101 
13.3. 
Regulatory Approval ............................................................................................ 102 
13.4. 
Ethics Committee Approval .................................................................................. 102 
13.5. 
Data and Safety Monitoring Board Review and Approval ..................................... 103 
13.6. 
Protocol Amendments and Study Termination ...................................................... 103 
13.7. 
Ethical Considerations .......................................................................................... 104 
13.8. 
Finance, Insurance, and Indemnity ........................................................................ 104 

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14. 
PUBLICATION PLAN ........................................................................................ 104 
15. 
CONFLICT OF INTEREST POLICY .................................................................. 104 
16. 
REFERENCE LIST .............................................................................................. 105 
17. 
APPENDIX .......................................................................................................... 111 
LIST OF TABLES 
Table 1 
Prohibited Medications and Specified Washout Period ........................................... 46 
Table 2 
Clinical Laboratory Tests ........................................................................................ 61 
Table 3 
Approximate Blood Volume to be Drawn at Each Study Visit ................................ 67 
Table 4 
Criteria for Clinically Notable Vital Sign Abnormalities ......................................... 98 
Table 5 
Criteria for Clinically Notable Electrocardiogram Interval Abnormalities ............... 98 
LIST OF FIGURES 
Figure 1 
Study Schema of Study ALZ-801-AD301: Overview of Study Structure and 
Visits (Detailed Schedule of Assessments in Appendix 2) ....................................... 22 
Figure 2  
ALZ-801: A pro-drug of tramiprosate. After absorption into the systemic 
circulation, ALZ-801 is rapidly and fully converted into tramiprosate and 
valine. ..................................................................................................................... 24 
Figure 3 
Large Combined Safety Database of Tramiprosate & ALZ-801 .............................. 24 
Figure 4  
Tramiprosate Effects in APOE4/4 Subjects with Mild AD (MMSE 22-26) 
over 78 Weeks ........................................................................................................ 31 
Figure 5 
Imaging Effects of Tramiprosate: Dose-Dependent Decrease in 
Hippocampal Atrophy............................................................................................. 32 
Figure 6 
The Evolution of CSF Biomarker Changes in AD [Mattsson-Carlgren et al. 
2020] ...................................................................................................................... 35 
Figure 7  
Appearance of ALZ-801 and Matching Placebo Tablets ......................................... 53 
Figure 8  
Representative Label of Drug Product .................................................................... 54 
Figure 9  
Hierarchical Testing Process in Study ALZ-801-AD301 ......................................... 94 
 
LIST OF APPENDICES 
Appendix 1 Key Personnel ...................................................................................................... 111 
Appendix 2 Schedule of Assessments ...................................................................................... 112 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
Aβ 
Amyloid-β or beta amyloid peptide 
AChEI 
Acetyl cholinesterase inhibitors 
AD 
Alzheimer’s disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale – cognitive subscale 
ADAS-Cog 11 
ADAS-Cog 11 items 
ADAS-Cog 13 
ADAS-Cog 13 items 
AE 
Adverse event 
A-IADL 
Amsterdam Instrumental Activities of Daily Living 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ALZ-801 
Pro-drug of tramiprosate; tramiprosate conjugated to valine 
ANCOVA 
Analysis of covariance 
APOE 
Apolipoprotein E 
APOE4 
ε4 allele of apolipoprotein E gene 
APOE4/4 
Homozygosity for ε4 allele of apolipoprotein E gene 
APOE4 carrier 
Subject who is either heterozygous or homozygous for the ε4 allele of 
apolipoprotein E gene 
aPTT 
activated partial thromboplastin time 
ARIA-E 
Amyloid related imaging abnormalities with vasogenic edema 
ARIA-H 
Amyloid-related imaging abnormalities due to haemosiderin deposition 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
β 
Beta 
BACE 
β-secretase or β-site amyloid precursor protein cleaving enzyme  
BID 
Twice per day 
BMI 
Body mass index 
BP 
Blood pressure 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CAA 
Cerebral amyloid angiopathy 
CBD 
Cannabidiol 
CBL 
Change from baseline  
CDR 
Clinical Dementia Rating  
CDR-SB 
Clinical Dementia Rating– Sum of Boxes 
cGMP 
current Good Manufacturing Practices 
COVID-19 
Coronavirus disease 2019 
CP 
Completer population 
CRA 
Clinical research associate 
CSF 
Cerebrospinal fluid 
CT 
Computed tomography 
CTA 
Clinical Trial Agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
d 
Day 

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Abbreviation 
Definition 
DAD 
Disability Assessment for Dementia 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
eCRF 
electronic case report form 
EDC 
Electronic data capture 
ECG 
Electrocardiogram 
eGFR 
estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 
ET 
Early termination 
EU 
European Union 
FDG  
Fluorodeoxyglucose  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GFAP 
Glial fibrillary acidic protein 
GI 
Gastrointestinal 
GGT 
γ-Glutamyl transferase 
HbA1c 
Glycosylated hemoglobin 
hCG 
human chorionic gonadotropin 
HCV RNA 
Hepatitis C virus RNA 
Hep B S Ag 
Hepatitis B surface antigen 
Hep C Ab 
Hepatitis C antibody 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
LP 
Lumbar puncture 
LFT 
Liver function test 
MAD 
Multiple ascending dose 
MAO 
Monoamine oxidase 
MCI 
Mild cognitive impairment 
MCV 
Mean corpuscular volume 
MDD 
Major depressive disorder 
MDMA 
3,4-Methylenedioxymethamphetamine 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
Minute(s) 

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Abbreviation 
Definition 
mITT 
modified intent-to-treat 
MMRM 
Mixed effects model repeated measures 
MMSE 
Mini-Mental State Examination 
MRI 
Magnetic resonance imaging 
NfL 
Neurofilament light 
NFT 
Neurofibrillary tangles 
NIA 
National Institute on Aging 
NIA-AA 
National Institute on Aging-Alzheimer’s Association 
NPI 
Neuropsychiatric Inventory 
OC 
Observed case 
OHRP 
Office of Human Research Protection 
p-tau, P-tau 
Phosphorylated tau 
p-tau181 
Tau phosphorylated at threonine 181 
p-tau217 
Tau phosphorylated at threonine 217 
PET 
Positron emission tomography 
PK 
Pharmacokinetic(s) 
PPP 
Per protocol population 
PR interval 
Time from the onset of the P wave to the start of the QRS complex 
PT 
Prothrombin time 
QA 
Quality assurance 
QC 
Quality control 
QoL 
Quality of life 
QoL-AD 
Quality of Life in Alzheimer’s Disease 
QRS duration 
Interval from the beginning of the Q wave to the termination of the S wave, 
representing the time for ventricular depolarization 
QT interval 
Interval representing the time for both ventricular depolarization and 
repolarization to occur 
QTc 
corrected QT (interval) 
QTcF 
corrected QT interval using Fridericia’s correction 
RBANS 
Repeatable Battery for the Assessment of Neuropsychological Status 
RBC 
Red blood cell 
RDO 
Retrieved dropout 
RUD Lite 
Resource Utilization in Dementia, Lite version 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDV 
Source data verification 
SMC 
Safety Management Committee 
SNRI 
Serotonin and norepinephrine (noradrenaline) re-uptake inhibitors 
SOP 
Standard operating procedure 
3-SPA 
3-Sulfopropanioc acid 
SSRI 
Selective serotonin reuptake inhibitors 
SUSAR 
Suspected unexpected serious adverse reaction  

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Abbreviation 
Definition 
TBD 
To be determined 
TBL 
Total bilirubin 
TEAE 
Treatment-emergent adverse event 
TRT 
Treatment group 
TSH 
Thyroid-stimulating hormone 
t-tau, T-tau 
Total tau 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
V 
Visit  
vMRI 
volumetric magnetic resonance imaging 
w 
Week 

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1. 
PROTOCOL SYNOPSIS 
Abbreviated Title 
A 
Phase 
3, 
Multicenter, 
Randomized, 
Double-blind, 
Placebo-controlled Study of the Efficacy, Safety and Biomarker 
Effects of ALZ-801 in Subjects with Early Alzheimer’s Disease and 
APOE4/4 Genotype 
Short Title 
Phase 3 Study of ALZ-801 in APOE4/4 Early AD Subjects 
Sponsor 
Alzheon Inc. 
Clinical Indication 
Early Alzheimer’s Disease (AD) 
Study Phase  
3 
Number of Arms 
2 
Treatment Groups  
ALZ-801 265mg or placebo twice per day (BID) 
Active Ingredient 
The 
active 
ingredient 
is 
tramiprosate: 
(S)-3-(2-amino-3-
methylbutanamido) propane-1-sulfonic acid  
ALZ-801, a prodrug of tramiprosate, is tramiprosate conjugated to the 
amino acid valine. 
Assignment 
Randomized, double-blinded 
Treatment Duration 
18 months 
Estimated Date First 
Subject Enrolls 
May 2021 
Estimated Date Last 
Subject Completes 
Study 
August 2024 
Primary Objectives 
Primary Clinical 
• To evaluate the efficacy of oral ALZ-801 on cognition in subjects 
with Early AD who are homozygous for the ε4 variant of the 
Apolipoprotein E gene (APOE4 homozygous or APOE4/4) using 
the 13-item Alzheimer’s Disease Assessment Scale – cognitive 
subscale (ADAS-Cog 13) 
• To evaluate the safety and tolerability of ALZ-801 over 78 weeks 
in Early AD subjects with the APOE4/4 genotype  

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Primary Fluid Biomarkers 
• To evaluate the effects of ALZ-801 on fluid biomarkers of core 
AD pathology (phosphorylated tau [p-tau]): 
o Cerebrospinal fluid (CSF) biomarker: tau phosphorylated at 
threonine 181 (p-tau181) in CSF sub-study 
o Plasma p-tau181 in all subjects 
Primary Imaging Biomarker  
• To evaluate the effects of ALZ-801 on hippocampal volume 
using volumetric magnetic resonance imaging (vMRI) 
Secondary Objectives 
Key Secondary Clinical 
• To evaluate the effects of ALZ-801 on functional, disability, and 
composite cognitive/functional outcomes: 
o Amsterdam Instrumental Activities of Daily Living (A-IADL) 
o Clinical Dementia Rating – Sum of Boxes (CDR-SB) 
o Disability Assessment for Dementia (DAD)  
Additional Secondary Clinical 
• To evaluate the effects of ALZ-801 on neuropsychiatric symptoms 
of AD: 
o Neuropsychiatric Inventory (NPI, 12-item form) 
• To evaluate the effects of ALZ-801 on additional measures of 
cognition: 
o 11-item Alzheimer’s Disease Assessment Scale – cognitive 
subscale (ADAS-Cog 11) 
o Mini-Mental State Examination (MMSE)  
• To evaluate the effects of ALZ-801 on quality of life (QoL):  
o Quality of Life in Alzheimer’s Disease (QoL-AD) 
• To assess levels of healthcare and caregiver resource usage: 
o Resource Utilization in Dementia, Lite version (RUD Lite) 
Secondary Fluid Biomarkers 
• To evaluate the effects of ALZ-801 on other CSF biomarkers of 
core AD pathology, neurodegeneration, and neuroinflammation in 
the CSF sub-study: 
o Core AD pathology: tau phosphorylated at threonine 217 
(p-tau217), beta amyloid (Aβ40, Aβ42) 
o Neurodegeneration in AD: Neurofilament Light (NfL) and 
total tau (t-tau) 
o Synaptic toxicity: neurogranin 
o Neuroinflammation: sTREM2 (microglia), and astrocytic 
markers YKL-40 and glial fibrillary acidic protein (GFAP) 

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• To evaluate the effects of ALZ-801 on other plasma biomarkers of 
AD pathology, neurodegeneration and neuroinflammation in all 
subjects: 
o Core AD pathology: p-tau217, Aβ40, Aβ42 
o Neurodegeneration: NfL 
o Neuroinflammation: GFAP 
• To evaluate other potential biomarkers of interest in plasma or CSF 
(to be specified and included in the final statistical analysis plan 
[SAP]) 
Secondary Imaging Biomarkers 
• To evaluate the effect of ALZ-801 on cortical thickness using 
vMRI 
• To evaluate the effect of ALZ-801 on whole brain volume using 
vMRI 
Other Objectives 
Pharmacokinetics 
• To analyze plasma and CSF levels of ALZ-801 and its metabolites 
and to build a population pharmacokinetic (PK) model of ALZ-801 
in this AD population 
• To evaluate the correlation of PK measures to clinical efficacy, 
biomarker, and safety outcomes 
Number of Subjects 
and Sites 
Approximately 300 subjects will be recruited; approximately 
120 subjects will participate in a CSF sub-study 
Approximately 85 sites in North America and Europe 
Methodology 
This is a Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group, two-arm study, with a treatment 
duration of 78 weeks (18 months) [Figure 1; Appendix 2]. 
Study Population 
The study will enroll male and female subjects, aged 50 to 80 years 
(inclusive), with a clinical diagnosis of AD, who carry the APOE4/4 
genotype, and who are at the early stage of disease (Early AD), which 
includes Mild Cognitive Impairment (MCI) and Mild Dementia due 
to AD (Mild AD).  
• MMSE 22 to 30 (inclusive), 
• Clinical Dementia Rating (CDR) – Global score of 0.5 or 1 and 
CDR Memory Box Score ≥ 0.5, 
• Repeatable Battery for the Assessment of Neuropsychological 
Status (RBANS) delayed memory index score ≤ 85, and 
• Evidence of progressive memory loss over the last 12 months per 
investigator assessment 

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Study Sample Size 
Approximately 300 subjects will be enrolled with a goal of having 
approximately 250 completers. Based on APOE4/4 prevalence of 
10% to 15% among AD patients, approximately 3000 AD subjects 
may need to be pre-screened to identify 300 eligible APOE4/4 
subjects. In order to minimize the number of non-APOE4/4 subjects 
who would otherwise undergo extensive screening tests, screening 
will be conducted in two parts. Screening – Part 1 (Visit 1a) will 
include APOE4 genotyping and MMSE testing. Eligible APOE4/4 
subjects will enter Screening – Part 2 (Visit 1b) which includes the 
full screening procedures. It is estimated that out of 3000 AD subjects 
who undergo Screening – Part 1, approximately 400 subjects will be 
eligible for Screening – Part 2.  
Eligible subjects will be randomized 1:1 to receive treatment with oral 
ALZ-801 or matching placebo (N = 150 each). Approximately 
120 subjects (60 per group) will be recruited to participate in a CSF 
biomarker sub-study. All subjects (150 per group) will provide plasma 
samples for biomarker and PK assessments. All subjects will 
participate in the vMRI component of the study. 
Study Drug 
All subjects will receive study drug, one tablet BID, taken with a 
morning and evening meal (or within 30 minutes after each meal) with 
approximately 10 to 12 hours between doses. Subjects in the placebo 
treatment arm will receive placebo tablets BID throughout the study. 
Subjects in the active treatment arm will receive placebo in the 
morning and a 265mg tablet of ALZ-801 in the evening during the 
first two weeks of the study; thereafter, they will receive a 265mg 
tablet BID. This dose provides plasma exposures equivalent to 
tramiprosate (the active moiety) 150mg BID, which showed 
promising efficacy in APOE4/4 subjects in a Phase 3 program. This 
level of tramiprosate exposure showed full inhibition of amyloid 
oligomer formation in an in vitro assay. ALZ-801 will be provided as 
immediate release tablets (cGMP grade) for oral administration.  
On clinic visit days, only one dose of study drug will be taken from 
one of the newly dispensed blister cards and administered at the study 
site. 
Duration of Treatment  
Treatment duration with study drug will be 78 weeks. Subjects will 
participate in the study for up to 95 weeks: up to approximately 
13 weeks for Screening, 78 weeks of treatment, and 4 weeks until the 
Safety Follow-up Visit.  

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Subjects who discontinue the study drug during the trial will be 
encouraged to remain in the study (off study drug) for continued 
follow-up by attending Week 52 and Week 78 visits with select 
study-related procedures performed [retrieved dropouts (RDO)]. For 
those subjects who choose to completely withdraw from the study at 
any point, they will be encouraged to return at Week 78 to finish the 
aforementioned procedures. 
Key Inclusion & 
Exclusion Criteria 
Key Inclusion Criteria 
1. Male or female between the ages of 50 and 80 years (inclusive) at 
the Screening – Part 1 Visit. 
2. Clinical diagnosis of MCI or Mild Dementia due to AD consistent 
with the National Institute on Aging-Alzheimer’s Association 
(NIA-AA) Working Group Criteria. 
3. Homozygous for the ε4 allele of the apolipoprotein E gene 
(APOE4/4).  
4. MMSE score of 22 to 30 (inclusive) at the Screening – Part 1 
Visit. 
5. CDR – Global score of 0.5 or 1 and CDR Memory Box Score 
≥ 0.5. 
6. RBANS delayed memory index score ≤ 85. 
7. Evidence of progressive memory loss over the last 12 months 
per investigator assessment. 
Key Exclusion Criteria 
1. Brain magnetic resonance imaging (MRI) indicative of significant 
abnormality per central reader, other than AD related atrophy. 
Computed tomography (CT) scan acceptable for subjects who can 
not undergo MRI (CT is not allowed for subjects at sites in 
Germany). 
2. Diagnosis of a neurodegenerative disorder other than AD. 
3. Diagnosis of major depressive disorder (MDD) within one year 
prior to the Baseline Visit (Visit 2).  
4. Currently taking memantine or has taken memantine within 
12 weeks prior to the Baseline Visit. 
5. History of suicidal behavior within one year prior to the Baseline 
Visit or has ongoing suicidal ideation. 
6. History of seizures, excluding febrile seizures of childhood or a 
single distant seizure (≥ 5 years prior to the Baseline Visit).  
7. Medically confirmed history of recent cerebral infarct or transient 
ischemic attack within one year prior to the Baseline Visit. 

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Estimated Duration of 
Study 
Sponsor estimates the study will be approximately 42 months from 
the time the first subject signs the informed consent form (ICF) to the 
last subject participation (last subject, last visit). 
Statistical 
Considerations 
Primary Efficacy Endpoint 
• Cognitive Endpoint: Change from baseline (CBL) to Week 78 in 
ADAS-Cog 13 scores 
Primary Fluid Biomarker Endpoints 
• CBL to Week 78 in CSF p-tau181 (in CSF sub-study) 
• CBL to Week 78 in plasma p-tau181 in all subjects 
Primary Imaging Biomarker Endpoint 
• CBL to Week 78 in total hippocampal volume as assessed by 
vMRI 
Safety and Tolerability 
• Incidence and nature of treatment-emergent adverse events 
(TEAEs), serious TEAEs, and TEAEs leading to withdrawal. 
• CBL in vital signs and physical exam, including body weight 
• CBL in laboratory parameters (clinical chemistry, hematology, 
coagulation tests) 
• CBL in 12-lead electrocardiogram (ECG) parameters. 
• CBL in MRI central readings for amyloid-related imaging 
abnormalities with vasogenic edema (ARIA-E) or due to 
haemosiderin deposition (ARIA-H) 
• CBL in the Columbia-Suicide Severity Rating Scale (C-SSRS) 
Analysis Population 
The primary efficacy population will be the Modified Intent-To-Treat 
(mITT) Population, which is defined as all randomized subjects who 
have received at least one dose of study drug, have one baseline 
assessment, and have also completed at least one scheduled 
post-baseline visit with at least one valid post baseline assessment.  
Analysis of Primary Efficacy Endpoints 
Analyses of the primary efficacy endpoint (CBL in ADAS-Cog 13 
scores) will be performed on the mITT Population using on-treatment 
observed case (OC) data. Effects between treatment groups will be 
assessed using a mixed effects model with repeated measures 
(MMRM) that includes treatment and stratification factors: use of 
concomitant AD medications [acetyl cholinesterase inhibitors or 
none], age group (50 through 65 years or > 65 years at the Screening 

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– Part 1 Visit), gender, disease severity based on MMSE at the 
Baseline Visit, baseline ADAS-Cog 13 values, visit (VISIT), and 
treatment by visit interaction. 
Justification of the Sample Size 
For the primary efficacy outcome of ADAS-Cog 13, this study is 
powered to detect a 3.0 point difference between ALZ-801 and 
placebo in the CBL to Week 78. This assumes a within-treatment SD 
of approximately 8.1 in the drug arm and 5.6 in the placebo arm. 
A sample size of 125 subjects per arm will provide approximately 
90% power to show a 3-point difference between the two treatment 
groups at a significance level of α = 0.05 (2-sided). The drop-out rate 
is estimated to be approximately 17% at 78 weeks, thus a total of 
300 subjects enrolled would provide approximately 250 completers or 
approximately 125 per arm. 

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Figure 1 
Study Schema of Study ALZ-801-AD301: Overview of Study Structure and Visits (Detailed Schedule of 
Assessments in Appendix 2) 
 
AD: Alzheimer’s Disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale – cognitive subscale; AE: adverse event; A-IADL: Amsterdam Instrumental 
Activities of Daily Living; APOE: apolipoprotein E; BID: twice per day; CDR: Clinical Dementia Rating; CSF: cerebrospinal fluid; C-SSRS: Columbia-
Suicide Severity Rating Scale; CT: computed tomography (not allowed for subjects at sites in Germany); DAD: Disability Assessment for Dementia; ECG: 
electrocardiogram; FU: follow-up; MMSE: Mini-Mental State Exam; MRI: magnetic resonance imaging; NPI: Neuropsychiatric Inventory; PK: 
pharmacokinetics; QoL-AD: Quality of Life in Alzheimer’s Disease; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status; RUD 
Lite: Resource Utilization in Dementia, Lite version; Tel: telephone; V: visit; W: week 
 

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2. 
INTRODUCTION: BACKGROUND INFORMATION AND 
SCIENTIFIC RATIONALE 
ALZ-801 is an oral agent that is being developed as a potential disease modifying treatment for 
AD. This 78-week Phase 3 study will focus on Early AD subjects who carry the APOE4/4 
genotype, and is designed according to current regulatory guidance for trials in symptomatic 
patients with Early AD.  
The active agent in ALZ-801 is tramiprosate, a small molecule that inhibits the formation of 
soluble beta amyloid (Aβ42) oligomers [Kocis et al. 2017; Liang et al. 2019]. Tramiprosate had 
been evaluated in 5 clinical trials in AD patients, across all apolipoprotein E (APOE) genotypes. 
In a Phase 3 trial in Mild to Moderate AD, efficacy was not achieved in the overall study 
population, but a meaningful signal was observed in subjects who are either heterozygous or 
homozygous for the ε4 allele of apolipoprotein E gene (APOE4 carriers), which was further 
analyzed to identify the optimal study population. Tramiprosate showed promising clinical 
efficacy in APOE4 homozygotes and heterozygtoes subgroups [Abushakra et al. 2016]. These 
positive clinical effects were especially significant in APOE4/4 homozygotes [Abushakra et al. 
2017] and were observed at a tramiprosate dose (150mg BID) that showed favorable long term 
safety.  
In the Phase 3 studies which included 2025 AD patients, oral tramiprosate showed favorable 
long-term safety over 2.5 years, with nausea and vomiting being the main TEAEs. There were no 
events of vasogenic edema in these studies. PK analyses from these studies also showed high 
variability in plasma levels of tramiprosate. ALZ-801 was therefore developed as a pro-drug of 
tramiprosate to improve its oral bioavailability and gastrointestinal (GI) tolerability. ALZ-801 is 
composed of tramiprosate conjugated to the essential amino acid valine [Figure 2]. Upon 
absorption into systemic circulation, ALZ-801 is rapidly converted into free tramiprosate and 
valine. 
The development of ALZ-801 was based on a bridging strategy to tramiprosate data. The bridging 
approach was discussed with the US FDA, which requested nonclinical safety and clinical PK and 
safety studies to compare ALZ-801 and tramiprosate. Nonclinical safety studies showed enhanced 
safety margins with ALZ-801 [Data on file]. ALZ-801 was evaluated in four bridging studies in 
134 subjects, including elderly and AD subjects. These studies allowed the selection of an 
ALZ-801 dose (265mg BID) that provides plasma levels bioequivalent to tramiprosate 150mg BID 
that showed efficacy in APOE4/4 homozygotes. In these Phase 1b studies, ALZ-801 showed 
improved GI tolerability with reports of mild and transient nausea. 

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Figure 2  
ALZ-801: A pro-drug of tramiprosate. After absorption into the systemic 
circulation, ALZ-801 is rapidly and fully converted into tramiprosate and 
valine. 
 
 
Based on the bridging of ALZ-801 to tramiprosate clinical data, the dose of ALZ-801 (265mg 
BID) used in this Phase 3 study is linked to and supported by the large safety data of tramiprosate, 
which includes a substantial number of long-term exposures in AD patients [Figure 3].  
Figure 3 
Large Combined Safety Database of Tramiprosate & ALZ-801 
 
AD: Alzheimer’s disease; CAA: cerebral amyloid angiopathy 

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In addition to the systematic analysis of clinical efficacy data from the tramiprosate Phase 3 study, 
volumetric MRI data was previously published [Gauthier et al. 2009]. The vMRI analyses of the 
North American Phase 3 study showed a dose-dependent, and significant, decrease in hippocampal 
atrophy, supporting the clinical data. Fluid biomarkers of AD pathology have advanced greatly 
and will be evaluated in this study to understand the effect of ALZ-801 on disease pathogenesis. 
A disease-modifying treatment for AD that provides meaningful efficacy with a favorable safety 
profile remains a major unmet need. In this Phase 3 trial, ALZ-801 is being evaluated in the 
APOE4/4 population with Early AD, as the initial AD indication. A future study in APOE4 
heterozygotes is also being planned.  
The efficacy objectives of this Phase 3 study are to prospectively evaluate clinical outcomes, 
volumetric imaging endpoints, and fluid biomarker effects of oral ALZ-801. The safety objective 
is to evaluate the long term safety and tolerability of ALZ-801 over 78 weeks.  
2.1. 
Background Information 
2.1.1. 
Disease Background 
Clinical and Pathological Features of AD 
AD is an irreversible, progressive neurodegenerative disorder, characterized by gradual cognitive 
and functional decline and personality changes. The early symptoms of AD usually begin with 
mild memory difficulties and gradually progress to severe cognitive and functional impairment at 
later stages. AD symptoms typically include changes in memory, verbal fluency, executive 
function, and judgment, as well as neuropsychiatric or behavioral symptoms. As these symptoms 
progress, they lead to functional loss of complex activities, and later to loss of the basic activities 
of daily living, requiring dependence on caregivers.  
The core neuropathological features of AD are the presence of amyloid plaques and neurofibrillary 
tangles (NFT), and neuronal loss [DeTure & Dickson, 2019]. Amyloid plaques consist of 
misfolded aggregates of Aβ40 and Aβ42 peptides, and NFT consist of misfolded 
hyperphosphorylated tau protein. Brain MRI studies in AD patients show progressive cortical 
atrophy and ventriculomegaly, reflecting progressive neurodegeneration. 
Biological Definition of AD 
The diagnosis of AD for enrollment in clinical trials has evolved from that of a clinical syndrome 
to a biological diagnosis based on evidence of the core underlying pathologies. Longitudinal 
biomarker studies using sensitive CSF biomarkers and positron emission tomography (PET) 
imaging of amyloid and tau pathologies have elucidated the sequence of events from the 
presymptomatic stage, to MCI, and to symptomatic AD, leading to a new biomarker based 
definition of AD [Jack et al. 2018]. These biomarker studies reveal that amyloid pathology starts at 
least a decade prior to symptom onset, followed by tau pathology, neuronal network dysfunction, 
microglial activation, neuronal loss, and brain atrophy. With advancing age in individuals at risk 
of AD, soluble Aβ levels in CSF show the earliest changes with progressive decline in the 
Aβ42/Aβ40 ratio as amyloid monomers aggregate into soluble oligomers, and insoluble fibrillary 
forms in the cortex. The insoluble aggregated fibrils and plaques can be detected by amyloid PET 
imaging. Once amyloid plaque burden reaches a certain threshold, there is a progressive increase 
of hyperphosphorylated tau reflected as elevation of CSF soluble p-tau, followed by intra-neuronal 

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tau aggregation and positive tau PET imaging. The tau PET signal is first detected in the medial 
temporal lobe, and then progressively spreads to other cortical areas. This sequence, of amyloid 
pathology being upstream of, and driving, tau pathology followed by cognitive decline, was 
demonstrated in a longitudinal imaging study [Hanseeuw et al. 2019].  
CSF biomarkers in AD reflect this cascade of events with early and progressive decrease in 
Aβ42/Aβ40, followed by progressive elevation of CSF p-tau levels [Blennow et al. 2019]. Though 
early studies focused on p-tau181 in AD, recent studies suggest that p-tau217 may also be of value 
as a core AD biomarker [Janelidze et al. 2020a]. The other CSF biomarkers reflect synaptic 
dysfunction, microglial activation and progressive neuronal injury. Biomarkers of microglial 
activation and neuroinflammation, such as sTREM2 and YKL-40 respectively, become elevated 
in AD [Craig-Schapiro et al. 2010; Gispert et al. 2017; Nordengen et al. 2019]. YKL-40 levels are 
also reported to be higher in APOE4 carriers [Gispert et al. 2017; Wang et al. 2020]. Recent studies 
have shown elevation of the astrocytic marker GFAP in CSF [Abu-Rumeileh et al. 2020]. Other 
CSF biomarkers that show progressive elevation are those that reflect synaptic toxicity such as 
neurogranin [Kvartsberg et al. 2019], and neuronal injury including NfL and t-tau [Mattsson et al. 
2016]. Both CSF p-tau181 and NfL have shown potential as biomarkers of drug effects in large 
clinical studies [Budd-Haeberlein et al. 2019; Swanson et al. 2018]. 
Plasma biomarkers including Aβ42, Aβ40, p-tau181, NfL, and t-tau are also being actively studied 
in AD [Molinuevo et al. 2018]. In particular, recent assays of plasma p-tau and NfL seem 
promising [Ashton et al. 2019; Mattsson et al. 2019; Mielke et al. 2018]. While plasma NfL may 
be elevated in other neurodegenerative diseases, p-tau181 seems to be specific to AD and has good 
diagnostic and prognostic value [Janelidze et al. 2020b; Karikari et al. 2020]. Recent studies in 
AD patients have also shown elevation of the astrocytic marker GFAP in plasma [Verberk et al. 
2020]. Plasma p-tau181, NfL and GFAP therefore have potential to become valuable non-invasive 
biomarkers of drug effects in clinical studies.  
These advances in fluid biomarkers and PET imaging in AD have led to new AD diagnostic 
framework for clinical research [Jack et al. 2018]. This diagnostic framework is based on the 
presence of amyloid and tau pathology, with or without evidence of neuronal injury (A/T/N 
framework). This framework may be expanded to also include glial activation (A/T/N/G). 
APOE4 carriers with cognitive symptoms have high prevalence of positive amyloid PET scans. In 
longitudinal studies, > 90% of all APOE4 carriers were positive across all ages, and in those aged 
50 through 80 years, ≥ 95% had positive amyloid scans [Ossenkoppele et al. 2015]. In APOE4/4 
homozygotes evaluated in a drug trial, 98% had positive amyloid scans [Degenhardt et al. 2016]. 
Eligible subjects will have a clinical diagnosis of AD, carry the APOE4/4 genotype, be at the early 
stage of disease (Early AD) (i.e., MCI or Mild Dementia due to Alzheimer’s disease), and have 
MMSE score at Screening of 22 to 30 (inclusive), a CDR – Global score of 0.5 or 1 and CDR 
Memory Box Score ≥ 0.5, an RBANS delayed memory index score ≤ 85, and evidence of 
progressive memory loss over the last 12 months per investigator assessment. 
Since this Phase 3 study is enrolling APOE4/4 homozygotes between the ages of 50 and 80 years 
with at least a 1 year history of progressive memory deficits, it is expected that ≥ 95% of these 
patients will have positive amyloid scans. 
Since cognitive deficits correlate best with synaptic dysfunction and elevated levels of CSF p-tau, 
it is expected that enrolled subjects will also have increased CSF p-tau levels at baseline. 

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Approximately 40% of enrolled subjects will have baseline CSF testing, which will confirm the 
elevated p-tau181 and p-tau217 levels. 
2.1.2. 
Current and Emerging Treatments for AD 
There is an urgent need for treatments that can meaningfully slow or arrest the progressive 
cognitive and functional decline of patients with AD (i.e., disease modification). The two classes 
of approved symptomatic drugs, AChEI and memantine, have not shown efficacy beyond 6 months 
of treatment. These two classes of drugs, which constitute the current standard of care, target the 
secondary neurotransmitter deficiencies seen in AD, but do not address the underlying disease 
pathology. The most advanced drugs in development target the hallmark amyloid pathology. One 
approach is to promote amyloid clearance using passive amyloid immunotherapy. There are 
several antibodies in development that target various forms of amyloid: monomers, soluble 
oligomers, insoluble fibrils, aggregated plaques, or a combination of these forms. Amyloid 
antibodies, which primarily target monomers, or a combination of monomers and other insoluble 
amyloid forms, have failed to show efficacy in clinical studies. To date, four amyloid antibodies 
have shown promising clinical efficacy or biomarker effects in Early AD. These antibodies share 
one feature: they target soluble amyloid oligomers at least partially, supporting the importance of 
soluble Aβ oligomers as therapeutic targets [Tolar et al. 2020a, Tolar et al. 2020b]. Aducanumab 
and lecanemab (BAN2401) have shown promising clinical efficacy and supportive CSF biomarker 
effects on p-tau181 [Budd-Haeberlein et al. 2019; Swanson et al. 2018; Swanson et al. 2020]. A 
third antibody, donanemab, showed significant but modest effects on composite clinical outcomes, 
supported by significant effects on plasma p-tau217 [Mintun et al. 2021, Sims et al. 2021]. A fourth 
antibody, gantenerumab, showed significant but small effects on CSF p-tau [Ostrowitzki et al. 
2017], and is being evaluated at a higher dose in new Phase 3 trials. In June 2021, aducanumab 
received “Accelerated Approval” by the US FDA, on the basis of amyloid plaque reduction in 
Early AD patients [FDA News Release, 2021]. In two identical Phase 3 trials of aducanumab, only 
one trial showed significant efficacy on the primary clinical outcome.  
2.1.2.1. 
Challenges of Amyloid Immunotherapy 
One of the risks of amyloid immunotherapy is the occurrence of vasogenic edema, and 
microhemorrahges, also called ARIA-E and ARIA-H [Sperling et al. 2011; Salloway et al. 2014]. 
The risk of ARIA-E is especially elevated in APOE4 carriers, likely related to their higher burden 
of vascular amyloid. The incidence of ARIA-H (microhemorrhages or haemosiderin deposits) is 
also increased in subjects who developed ARIA-E. This presents a major development challenge, 
since the highest doses that showed clinical benefit were associated with high rates of ARIA-E, 
while lower doses did not provide meaningful efficacy. In clinical trials, ARIA-E was reported in 
approximately 40% of APOE4 carriers with aducanumab, in 35% of APOE4 carriers with 
donanemab, and in approximately 15% of APOE4 carriers with BAN-2401 [Budd-Haeberlein et 
al. 2019, Mintun et al. 2021, Sevigny et al. 2016; Swanson et al. 2018]. Although ARIA-E maybe 
asymptomatic or mildly symptomatic, some patients developed serious events such as seizures and 
descreased levels of consciousness. The risk of ARIA requires MRI monitoring in clinical studies, 
which is burdensome and could limit the utility of these drugs in clinical practice. The delivery of 
these antibodies as monthly or twice monthly intravenous infusions may be associated with 
infusion reactions, and is inconvenient to patients and their caregivers.  

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A convenient oral drug like ALZ-801 that can selectively inhibit the formation of amyloid 
oligomers at a target efficacious dose that shows favorable safety and tolerability profile would 
provide a preferable option to immunotherapies. A particular advantage is the low risk of ARIA-E 
and ARIA-H. This would provide an optimal drug for AD patients who are APOE4 carriers and 
who constitute 65% to 70% of all AD patients in clinical studies. 
2.2. 
Tramiprosate and ALZ-801 
2.2.1. 
Tramiprosate Background 
Tramiprosate, the active agent of oral ALZ-801, is a small molecule that was originally developed 
as an amyloid anti-aggregation agent, and had shown positive effects in preclinical, in vitro and in 
vivo, models of AD [Gervais et al. 2007; Martineau et al. 2010]. In a Phase 2 study in AD patients, 
tramiprosate showed a dose dependent reduction of Aβ42 levels in CSF, with 50% to 70% 
reduction at the highest dose of 150mg BID [Aisen et al. 2006]. This dose, 150mg BID, as well as 
100mg BID, were evaluated in two Phase 3 studies in Mild to Moderate AD. In the completed 
North American Phase 3 study, the 150mg BID dose showed cognitive benefits in APOE4 carriers. 
In APOE4/4 homozygotes, tramiprosate showed dose-dependent efficacy, with significant and 
meaningful benefits at 150mg BID. 
In recent studies further evaluating its mechanism of action, tramiprosate inhibited the formation 
of soluble Aβ42 oligomers in a dose-dependent fashion, with the highest concentrations fully 
blocking oligomer formation in vitro [Kocis et al. 2017]. This concentration corresponded to the 
central nervous system concentrations observed with 150mg BID in AD patients [Hey et al. 
2018b]. The anti-oligomer effects of tramiprosate were recently replicated by an independent 
academic group [Liang et al. 2019].  
Soluble Aβ oligomers are now thought to play an important role in AD pathogenesis [Selkoe & 
Hardy 2016; Tolar et al. 2020a; Viola & Klein 2015]. Aβ oligomers appear early in the disease 
and induce synaptic neurotoxicity and impaired memory [Shankar et al. 2008]. Some forms of Aβ 
oligomers also trigger tau hyperphosphorylation and other signaling cascades leading to neuronal 
loss [Jin et al. 2011]. AD patients who are APOE4/4 homozygotes have brain levels of Aβ 
oligomers that are approximately three times higher than APOE4 non-carriers [Hashimoto et al. 
2012], and therefore could potentially benefit from a drug that targets Aβ oligomer formation.  
2.2.2. 
Tramiprosate Mechanism of Action 
The mechanism of action of tramiprosate was studied both in vivo and in vitro [Gervais et al. 2007; 
Martineau et al. 2010]. Tramiprosate was originally found to maintain Aβ in a non-fibrillary, 
soluble form resulting in inhibition of neuronal toxicity. In vivo, chronic oral tramiprosate 
treatment of TgCRND8 mice resulted in a significant reduction (~ 30%) in brain amyloid plaque 
load (quantified via histopathology), and significantly reduced levels of soluble and insoluble 
Aβ40 and Aβ42 amyloid species. In recent studies, tramiprosate and its active metabolite 
3-sulfopropanioc acid (3-SPA) were shown to interact with soluble Aβ monomers to prevent 
amyloid aggregation by blocking monomeric assembly, thus preventing the formation of soluble 
toxic oligomer intermediates, from dimers to decamers [Kocis et al. 2017].  
New in vitro mechanistic studies have been conducted to elucidate the anti-amyloid action of 
tramiprosate, and its primary metabolite 3-SPA, which has been recently discovered to be an 

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endogenous molecule in human brain. These studies included computational modeling (i.e., 
molecular dynamics), NMR and ion-mobility spectrometry-mass spectrometry studies [Hey et al. 
2018a; Kocis et al. 2017]. These studies showed that both tramiprosate and 3-SPA inhibit the 
formation of Aβ42 oligomers by interacting directly with Aβ42 monomers via a molecular “Aβ 
enveloping action.” In addition, these effects occur at tramiprosate concentrations that were 
achieved at the Phase 3 clinical dose in AD patients [Hey et al. 2018b]. 
In summary, these studies show that increasing concentrations of tramiprosate and its metabolite, 
3-SPA, interact directly with Aβ42 monomers via a molecular “Aβ enveloping action,” which in 
turn, inhibits the formation of toxic Aβ42 oligomers [Hey et al. 2018a; Kocis et al. 2017; Liang et 
al. 2019]. It is hypothesized that steady state tramiprosate treatment exerts anti-Aβ oligomer effects 
that are neuroprotective and, over time, will reduce amyloid neurotoxicity, synaptic dysfunction, 
and neuronal loss, and ameliorate the progressive course of AD. 
2.2.3. 
ALZ-801 
ALZ-801 is a pro-drug of tramiprosate, formed by the conjugation of the amino acid valine to 
tramiprosate (the active agent in ALZ-801). In the original Phase 3 studies with tramiprosate, 
nausea and vomiting were the most common dose-dependent adverse events (AEs). At the high 
dose of 150mg BID, drug-related nausea was reported in 14% to 18% of subjects and led to 
withdrawal in approximately 5% of subjects in the North American study. The plasma levels of 
tramiprosate showed high intersubject variability. The pro-drug, ALZ-801, was developed to 
provide enhanced oral absorption, a more consistent PK profile, and improved GI tolerability. The 
data from several Phase 1b studies with ALZ-801 support this enhanced profile, as described in 
[Section 2.3.1], and was recently published [Hey et al. 2018b]. Since the pharmacologically active 
agent in ALZ-801 is tramiprosate, the safety and efficacy of ALZ-801 can be bridged to 
tramiprosate data when using a bioequivalent dose. 
2.2.4. 
Nonclinical Experience 
Nonclinical studies have been conducted with both tramiprosate and ALZ-801 to elucidate the 
mechanism of action of the compound. Additionally, nonclinical pharmacology, safety 
pharmacology, PK, metabolism, toxicology, and mutagenicity studies have been conducted in 
several in vitro and in vivo models with both tramiprosate and ALZ-801. Results of these studies 
can be found in the current version of the Investigator’s Brochure. 
2.3. 
Rationale for Current Study 
The aim for this study is to replicate and confirm the previously described clinical efficacy in 
APOE4/4 homozygotes with Early AD. The prior tramiprosate data included Mild AD patients 
with MMSE 22 to 26. Since amyloid oligomer toxicity is thought to be an early event in AD 
pathogenesis, anti-amyloid agents are likely to show efficacy at earlier stages of AD. Recent AD 
studies with amyloid antibodies (Aducanumab and BAN2401) have included MCI subjects with 
MMSE > 26, who have indeed shown promising efficacy. Therefore, ALZ-801 is expected to show 
positive efficacy when including MCI subjects. The population of Mild AD and MCI subjects is 
now collectively called Early AD. In addition to cognitive and functional clinical outcomes, 
ALZ-801 effects on fluid AD biomarkers and downstream effects on hippocampal volume and 
cortical thickness will also be evaluated. 

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2.3.1. 
Clinical Experience 
2.3.1.1. 
Overview of Original Phase 3 Program with Tramiprosate 
The tramiprosate Phase 3 program in AD included two Phase 3 placebo-controlled studies of 
78 weeks duration: one in North America and the other in Europe. The diagnosis of Mild to 
Moderate AD in these studies was based only on clinical criteria without biomarker evidence of 
amyloid pathology. The design of these two studies was almost identical, except that the North 
American study allowed for use of memantine and anticholinesterase medications as background 
medication while the European study did not allow use of memantine. These studies included brain 
MRI imaging in a subset of subjects. the North American study had an open-label safety extension 
study. The North American study was initiated on 05 August 2004, and the last subject completed 
the study on 09 February 2007. The co-primary outcomes in the overall population did not achieve 
statistical significance. When the results of the North American study became available, the 
European study was still ongoing. The Sponsor of that study, Bellus Health Inc., decided for 
business reasons to discontinue tramiprosate development and the European study was terminated 
prior to its completion. The clinical efficacy and safety results of the North American study have 
been published [Aisen et al. 2011]. 
The co-primary outcomes in both studies included a cognitive and a composite/functional scale. 
The cognitive scale was the ADAS-Cog 11 [Rosen et al. 1984], and the composite scale was the 
CDR-SB [Hughes et al. 1982; Morris 1993], which combines cognitive and functional measures. 
The secondary outcomes included the functional DAD [Gélinas et al. 1999], the MMSE [Folstein 
et al. 1975] a cognitive, staging instrument, and the NPI [Cummings 1997], which evaluates the 
presence and severity of 12 neuropsychiatric symptoms (items) that are common in dementia 
subjects. 
The protocol of the North American study specified analysis by APOE4 genotype, and this analysis 
was recently undertaken. Phase 3 data were analyzed based on the number of APOE4 alleles (0, 1 
or 2). These results were published for the overall, Mild, and Moderate population [Abushakra et 
al. 2016], and for the Mild subgroup of APOE4/4 patients [Abushakra et al. 2017]. 
In these efficacy analyses, tramiprosate 150mg BID showed the greatest cognitive efficacy in 
APOE4/4 homozygotes, intermediate efficacy in heterozygotes, and no efficacy in non-carriers. 
This difference in efficacy may be explained by the accuracy of AD diagnosis in the study 
population. These studies predated the current biomarker based diagnosis of AD [Jack et al. 2018]; 
they did not use amyloid PET imaging or CSF biomarkers as inclusion criteria. Therefore, it is 
likely that many APOE4 noncarrier patients did not have amyloid pathology underlying their 
dementia [Ossenkoppele et al. 2015]. Data from solanezumab Phase 3 studies that enrolled a 
similar population and included an amyloid-PET sub-study, revealed that 98% of APOE4/4 
homozygotes and 80% of APOE4 heterozygotes, but only 63% of non-carriers, were amyloid 
positive [Degenhardt. 2016]. Therefore, tramiprosate showed positive efficacy signals in the 
subgroups that had the highest diagnostic accuracy and highest rates of amyloid pathology.  
Efficacy Data 
In APOE4/4 subjects with Mild to Moderate AD, tramiprosate showed significant efficacy on 
ADAS-Cog, with a numerical benefit on the CDR-SB at 78 weeks. In APOE4/4 subjects with Mild 
AD, the effects on ADAS-Cog and CDR-SB were larger (ADAS-Cog approximately 5 points; 
CDR-SB 1.25 points), statistically significant, and sustained at 78 weeks [Figure 4]. These effects 

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represent cognitive and functional benefits of 125% and 81%, respectively, compared to placebo 
and are clinically meaningful [Abushakra et al. 2017]. Tramiprosate effects on the DAD also 
showed significant benefits of 71% compared to placebo [Figure 4].  
Figure 4  
Tramiprosate Effects in APOE4/4 Subjects with Mild AD (MMSE 22-26) 
over 78 Weeks 
 
 
ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale; BID: twice per day; CDR-SB: Clinical 
Dementia Rating – Sum of Boxes; DAD: Disability scale for dementia; MMSE: Mini-Mental State Examination. 
Subjects who completed the North American study were enrolled in an extension study where 
subjects from the 3 dose groups received high dose tramiprosate (150mg BID) for an additional 
52 weeks. In the APOE4/4 Mild group, subjects who received high dose tramiprosate over 
2.5 years consistently performed better on the ADAS-Cog compared to the placebo-tramiprosate 
group [Data on file]. 
Volumetric Imaging Data 
In the North American study, there were 265 MRI suitable for volumetric analyses including 
assessment of hippocampal volumes. These vMRI analyses showed a dose dependent decrease in 
hippocampal atrophy, as shown in [Figure 5], supporting the clinical data [Gauthier et al. 2009]. 

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Figure 5 
Imaging Effects of Tramiprosate: Dose-Dependent Decrease in Hippocampal 
Atrophy  
 
BID: twice per day 
 
APOE4/4 homozygotes with Mild AD seem to be an ideal population for tramiprosate studies. 
This finding is consistent with the fact that APOE4/4 homozygotes have high levels of Aβ 
oligomers [Hashimoto et al. 2012], compared to non-carriers, and that tramiprosate inhibits 
oligomers at concentrations achieved with the dose used in the North American Phase 3 trial [Kocis 
et al. 2017].  
Based on the above clinical benefits in APOE4/4 subjects, in this study, ALZ-801 at a dose of 
265mg BID is expected to provide significant clinical benefit over 78 weeks. This dose has been 
selected to provide bioequivalent tramiprosate levels (i.e., bridging dose) to the tramiprosate 
150mg BID dose used in used in the North American Phase 3 trial. 
Safety Data 
The combined safety data of both tramiprosate Phase 3 studies includes 2025 subjects treated for 
up to 78 weeks, and approximately 400 treated up to 130 weeks, and suggests a favorable long 
term safety profile. In the overall safety population, the most common AEs with incidence > 2 × 
placebo rates were nausea, vomiting, and weight loss [Abushakra et al. 2016]. The safety profile 
was similar in the APOE4/4 subjects [Abushakra et al. 2017]. There was a low incidence of serious 
adverse events (SAEs) leading to withdrawal. Most TEAEs were mild to moderate in severity.  
An important safety advantage of tramiprosate was that no cases of ARIA-E (vasogenic edema) 
were detected by central MRI assessments of 426 AD subjects, including APOE4 carriers 
[Abushakra et al. 2016].  
2.3.1.2. 
Overview of ALZ-801 Phase 1 and 2 Studies  
ALZ-801 was evaluated in a total of 4 Phase 1 studies that included 3 studies in healthy volunteers 
including elderly subjects, and 1 study in AD patients. The Phase 1 studies in volunteers included: 

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(1) a single ascending dose (SAD) study; (2) a 14-day multiple ascending dose (MAD) study; and 
(3) a single-dose tablet food effect study. The detailed PK, safety and tolerability results of these 
studies were published [Hey et al. 2018b], and described in the Investigator’s Brochure.  
In summary, ALZ-801, when administered in capsule and tablet forms, showed excellent oral 
safety and tolerability in healthy adults and elderly volunteers, with decreased incidence of nausea. 
These studies showed significantly improved PK characteristics over oral tramiprosate, with 
markedly decreased inter-subject variability in tramiprosate plasma levels. A clinical dose of 
ALZ-801 (265mg BID) was established that achieves the target area under the concentration-time 
curve (AUC) exposure of 150mg BID of tramiprosate in plasma, which had shown positive clinical 
effects in APOE4/4 AD subjects in the North American Phase 3 study. 
ALZ-801 safety and PK was also evaluated in AD subjects, in an open-label Phase 1b study of 
2 weeks duration. This study enrolled 7 AD subjects who had either the APOE4/4 or APOE3/4 
genotype. PK analyses from this study confirmed the favorable steady-state characteristics of 
ALZ-801 with improved elimination half-life and reduced plasma variability of tramiprosate. All 
subjects completed the study and no SAEs were reported [Data on file] ALZ-801 also 
demonstrated improved GI tolerability, with only mild and transient AEs of nausea.  
The biomarker effects of ALZ-801 are currently being evaluated in a Phase 2 study (Study AD201) 
in approximately 40 Early AD subjects with either APOE4/4 or APOE3/4 genotype. Subjects will 
receive ALZ--01 at 265mg BID over 2 years, and provide serial CSF and plasma for AD 
biomarkers, vMRI assessments, and exploratory cognitive outcomes. 
2.3.2. 
Rationale for Development in APOE4/4 Subjects 
High Burden of Extracellular Aggregated β-Amyloid 
The APOE4 allele is the strongest genetic risk factor for the development of sporadic AD. It 
confers a 4- to12-fold higher risk of developing AD with an earlier age of onset, with APOE4/4 
subjects being at highest risk [Farrer et al. 1997; Roses 1996]. APOE4 carriers accumulate more 
amyloid pathology and at a faster rate than non-carriers [Jansen et al. 2015; Kim et al. 2009; 
Ossenkoppele et al. 2015]. In amyloid imaging studies, the prevalence of amyloid pathology was 
highest in APOE4/4 subjects, followed by heterozygotes, and lowest in APOE4 non-carriers 
[Jansen et al. 2015]. In the clinical study population, positive amyloid scans were found in 98% of 
homozygotes, 80% of heterozygotes, and only 63% of non-carriers [Degenhardt et al. 2016]. In 
AD and MCI, CSF Aβ42 showed an APOE4 gene-dose effect, with the lowest (most abnormal) 
levels in APOE4/4 homozygotes followed by APOE4 heterozygotes [Lautner et al. 2014; Prince 
et al. 2004]. APOE4 carriers also show faster rates of cognitive decline at the MCI and AD stages 
[Caselli et al. 2009; Martins et al. 2005; Petersen et al. 2005]. 
Consistent with the higher amyloid burden, APOE4/4 subjects exhibit an earlier and faster rate of 
cognitive decline compared to APOE4 non-carriers [Breitner et al. 1999; Cosentino et al. 2008; 
Rogers et al. 2012], becoming symptomatic approximately a decade earlier. 
High Burden of Aggregated β-Amyloid in Vasculature  
APOE4 carriers also develop more vascular amyloid pathology [Chalmers et al. 2003; Schmechel 
et al. 1993], which may underlie their increased risk of ARIA-E with amyloid immunotherapies. 
From a safety perspective, APOE4 carrier AD patients, especially APOE4/4 homozygotes, have a 
clear need for an agent that delivers efficacy without the increased risk of ARIA-E. 

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High Burden of Soluble β-Amyloid Oligomers  
The APOE4/4 genotype is associated with higher levels of soluble Aβ oligomers [Hashimoto et al. 
2012; Tai et al. 2013], which are known to be highly synaptotoxic [Viola & Klein 2015]. Since 
ALZ-801 inhibits the formation of Aβ oligomers [Kocis et al. 2017], APOE4/4 homozygotes 
would be an ideal population to evaluate its efficacy [Tolar et al. 2020a]. Indeed, in the Phase 3 
NA study, tramiprosate showed meaningful clinical efficacy in APOE4 carriers, especially 
APOE4/4 [Abushakra et al. 2016; Abushakra et al. 2017]. Clinical efficacy in APOE4/4 subjects 
will be confirmed in this ALZ-801 Phase 3 trial (Study AD301). 
To date, no other program has specifically targeted symptomatic APOE4/4 subjects with cognitive 
and early functional deficits. Therefore, APOE4/4 subjects with Early AD who are already 
receiving symptomatic medications represent a population with urgent treatment needs. This Phase 
3 study will be in APOE4/4 homozygotes, and a study in APOE4 heterozygotes is being planned. 
2.3.3. 
Rationale for Choice of Clinical Outcomes 
The clinical data in APOE4/4 Mild AD subjects from the North American study [Abushakra et al. 
2017], had shown statistically (nominally) significant and clinically meaningful effects on the 
co-primary outcomes ADAS-Cog 11 and CDR-SB, and on the DAD. The magnitude of benefit 
was highest with ADAS-Cog 11, followed by the functional outcomes. A similar pattern of 
efficacy has been shown with BAN-2401 and aducanumab, where ADAS-Cog effects were more 
robust that the CDR-SB [Budd-Haeberlein et al. 2019; Swanson et al. 2018]. 
At earlier stages of the disease, cognition is expected to decline before function, making cognitive 
outcomes a good choice in earlier stage AD studies. This is consistent with the findings in 
BAN-2401 and aducanumab studies, where ADAS-Cog 13 effects were more robust than CDR-SB 
effects in Early AD patients [Budd-Haeberlein et al. 2019; Swanson et al. 2018]. Since this Phase 
3 study will enroll Early AD subjects, ADAS-Cog 13 will be designated the primary efficacy 
outcome. The ADAS-Cog 13 includes the original 11 items, plus 2 items assess executive tasks.  
The cognitive outcome will be supported by a functional scale, namely the A-IADL, which is 
designated a key secondary outcome with appropriate step-down analysis.  
The other functional outcomes, DAD and CDR-SB will be additional secondary outcomes. The 
ADAS-Cog 11 will also be included as a secondary outcome, since it has been used in other AD 
studies. The 12-item NPI will be used to assess behavioral effects of ALZ-801.  
2.3.4. 
Rationale for Fluid Biomarker and MRI Assessments  
Longitudinal studies in AD subjects have shown that amyloid levels, as they increase in brain, 
induce abnormal phosphorylation of neuronal tau, and a progressive elevation of p-tau in CSF. 
This progressive increase in CSF p-tau precedes the appearance of intraneuronal NFTs, the tau 
pathology that can be detected by tau PET-imaging [Mattsson-Carlgren et al. 2020]. Increases in 
toxic amyloid oligomers and p-tau induce downstream synaptic dysfunction, microglial activation, 
and neuronal injury [Figure 6]. 
Since ALZ-801 inhibits the formation of toxic soluble Aβ42 oligomers, it is expected to inhibit the 
downstream effects of toxic Aβ42 oligomers, namely formation of p-tau181 and other p-tau 
isoforms. Two other late stage anti-amyloid antibodies (BAN2401 and aducanumab) that target 
Aβ oligomers at least partially, have shown clinical efficacy in Early AD patients, and have shown 

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significant lowering effects on CSF p-tau181 after 78 weeks of treatment [Tolar et al. 2020b]. In 
Early AD patients, CSF p-tau181 levels in the placebo arm remain stable over 78 weeks, while the 
drug arms induced a dose-dependent and significant (13% to 17%) reduction relative to baseline 
[Budd-Haeberlein et al. 2019; Swanson et al. 2018].  
Figure 6 
The Evolution of CSF Biomarker Changes in AD [Mattsson-Carlgren et al. 
2020] 
 
Aß: beta amyloid peptide; AD: Alzheimer’s disease; CSF: cerebrospinal fluid; FDG PET: fluorodeoxyglucose 
positron emission tomography; MRI: magnetic resonance imaging: PET: positron emission tomography P-tau: 
phosphorylated tau; T-tau: total tau. 
In another study in Early (Prodromal) AD with the anti-amyloid antibody, gantenerumab, CSF 
p-tau181 in the placebo arm was also stable over 104 weeks, while the highest antibody dose 
reduced p-tau181 by < 8%, and there was no evidence of clinical efficacy at that dose. [Ostrowitzki 
et al. 2017]. Therefore, a consistent reduction in CSF p-tau181 is observed with two antibodies that 
share the anti-oligomer mechanism of action and show promising cognitive benefits. Since 
ALZ-801/tramiprosate is an anti-oligomer agent with promising clinical efficacy in APOE4 
carriers (similar to BAN2401 and aducanumab), it is expected that ALZ-801 will decrease CSF 
p-tau181 by at least 15% compared to placebo. To date, no studies have reported drug effects on 
CSF p-tau217, but this will be evaluated in this trial.  
The two anti-amyloid agents (aducanumab and BAN2401) have also shown effects on downstream 
CSF biomarkers, namely biomarkers of synaptic injury (neurogranin) and NfL, or on tau-PET 
imaging [Tolar et al. 2020b]. Therefore the key secondary objectives of this study are to evaluate, 
in the CSF sub-study, the effects of ALZ-801 on CSF levels of NfL, t-tau (another biomarker of 
neuronal injury) and neurogranin, and on neuroinflammatory biomarkers known to be involved in 
AD pathology (sTREM2, YKL-40, GFAP).  
For plasma biomarkers of AD, well performing plasma assays for p-tau181, NfL and GFAP were 
recently reported [Karikari et al. 2020; Mattsson et al. 2019; Verberk et al. 2020]. Plasma levels 

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of p-tau181 and NfL are designated as key secondary fluid biomarker outcomes, and plasma GFAP 
will be evaluated as an additional secondary outcome. CSF and plasma levels of soluble Aβ42/ 
Aβ40 will also be evaluated. 
Hippocampal volume and cortical thickness are commonly included as volumetric imaging 
biomarkers in AD, and are especially relevant in APOE4 carriers [Hostage et al, 2013]. Both 
measures show accelerated atrophy in APOE4/4 homozygotes with Early AD compared to 
APOE3/3 subjects [Abushakra et al. 2020]. Tramiprosate, the active agent in ALZ-801, had shown 
protective effects on hippocampal volume in the Phase 3 North American study [Gauthier et al. 
2009]. Therefore, ALZ-801 is expected to decrease hippocampal atrophy and loss of cortical 
thickness at 78 weeks. Hippocampal volume is designated as primary imaging outcome, and 
cortical thickness as an additional outcome. 
The study will also allow PK-pharmacodynamic correlations between exposures of tramiprosate 
(and its metabolite) in plasma/CSF, clinical outcomes, and biomarker effects.  
This study will also further support the long term safety and tolerability of ALZ-801 in AD patients 
with the APOE4/4 genotype. 
2.4. 
Potential Risks and Benefits 
Tramiprosate, the active agent of ALZ-801, has been studied in 3295 adults across 16 clinical 
studies, including 2800 AD subjects. The Phase 3 studies included 2025 subjects treated for up to 
78 weeks, of whom 714 subjects were treated for up to 52 additional weeks in an extension study. 
Therefore, a total of 371 AD subjects received tramiprosate for up to 2.5 years. In the controlled 
Phase 3 studies, the most common AEs showing dose-dependence were GI in nature and included 
nausea, vomiting, and weight loss. Nausea and vomiting were mostly mild to moderate, led to low 
number of withdrawals, and likely represent local effects of tramiprosate on the GI mucosa.  
In the safety extension study, the most common AEs were falls, nausea, urinary tract infection, 
and diarrhea; typically seen in AD studies. There was no organ toxicity with long-term treatment.  
The other AEs were representative of the comorbidities seen in this population and, therefore, no 
specific risks were identified. The AE profile seemed similar among the APOE4 non-carriers and 
the APOE4 heterozygous and APOE4/4 homozygous subgroups. 
Central brain MRI assessments from 426 subjects in the tramiprosate Phase 3 studies, of whom 
254 were APO4 carriers, showed no occurrence of vasogenic edema (ARIA-E) on active drug. 
The benefits seen in APOE4/4 subjects with Mild AD include lesser decline in cognition and 
function over 78 weeks, and lower disability scores. These effects were demonstrated in subjects 
already receiving maximum standard of care; therefore, representing additional benefits of 
tramiprosate treatment.  
Safety data from the ALZ-801 Phase 1 program which included AD patients and healthy 
volunteers supports improved GI tolerability especially when taken with food. This protocol 
requires that ALZ-801 be taken with or within 30 minutes after food. 
Based on the promising efficacy in APOE4/4 subjects and the favorable safety profile in all 
subjects including APOE4 carriers, tramiprosate seems to provide a favorable benefit risk profile 
in subjects with Mild or Early AD. ALZ-801 at a dose of 265mg BID will provide equivalent 

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exposures to tramiprosate 150mg BID, and is expected to provide a favorable benefit-risk profile 
in APOE4/4 homozygotes with AD. 
3. 
OBJECTIVES AND PURPOSE 
3.1. 
Objectives 
3.1.1. 
Primary Objectives 
Primary Clinical 
• To evaluate the efficacy of oral ALZ-801 on cognition in subjects with Early AD who are 
homozygous for the ε4 variant of the APOE gene (APOE4 homozygous or APOE4/4) using 
ADAS-Cog 13 
• To evaluate the safety and tolerability of ALZ-801 over 78 weeks in Early AD subjects 
with the APOE4/4 genotype 
Primary Fluid Biomarkers 
• To evaluate the effects of ALZ- 
• 801 on fluid biomarkers of core AD pathology (p-tau): 
o CSF biomarker: p-tau181 (in CSF sub-study) 
o Plasma p-tau181 in all subjects 
Primary Imaging Biomarker 
• To evaluate the effects of ALZ-801 on hippocampal volume using vMRI 
3.1.2. 
Secondary Objectives 
Key Secondary Clinical 
• To evaluate the effects of ALZ-801 on cognitive and/or functional outcomes: 
o A-IADL 
o CDR-SB 
o DAD 
Additional Secondary Clinical 
• To evaluate the effects of ALZ-801 on neuropsychiatric symptoms of AD: 
o NPI (12-item form) 
• To evaluate the effects of ALZ-801 on additional measures of cognition: 
o ADAS-Cog 11 
o MMSE 

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• To evaluate the effects of ALZ-801 on QoL: 
o QoL-AD 
• To assess levels of healthcare and caregiver resource usage: 
o RUD Lite 
Secondary Fluid Biomarkers 
• To evaluate the effects of ALZ-801 on other CSF biomarkers of core AD pathology, 
neurodegeneration, and neuroinflammation in the CSF sub-study: 
o Core AD pathology: p-tau217, beta amyloid (Aβ40, Aβ42) 
o Neurodegeneration in AD: NfL and t-tau 
o Synaptic toxicity: neurogranin 
o Neuroinflammation: sTREM2 (microglia), and astrocytic markers YKL-40 and GFAP 
• To evaluate the effects of ALZ-801 on other plasma biomarkers of AD pathology, 
neurodegeneration and neuroinflammation in all subjects: 
o Core AD pathology: p-tau217, Aβ40, Aβ42 
o Neurodegeneration: NfL 
o Neuroinflammation: GFAP 
• To evaluate other potential biomarkers of interest in plasma or CSF (to be specified and 
included in the final SAP)  
Secondary Imaging Biomarkers 
• To evaluate the effect of ALZ-801 on cortical thickness using vMRI 
• To evaluate the effect of ALZ-801 on whole brain volume using vMRI 
Pharmacokinetics 
• To analyze plasma and CSF levels of ALZ-801 and its metabolites and to build a population 
PK model of ALZ-801 in this AD population 
• To evaluate the correlation of PK measures to efficacy, biomarker and safety outcomes 
4. 
STUDY DESIGN AND ENDPOINTS 
4.1. 
Description of the Study Design 
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group, 
two-arm study, with a treatment duration of 78 weeks (18 months).  
Study Population 
The study will enroll male and female subjects, aged 50 to 80 years (inclusive), with a clinical 
diagnosis of AD, who carry the APOE4/4 genotype, and who are at the early stage of disease 
(Early AD), which includes MCI and Mild AD. 

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• MMSE 22 to 30 (inclusive), 
• CDR – Global score of 0.5 or 1 and CDR Memory Box Score ≥ 0.5, 
• RBANS delayed memory index score ≤ 85, and 
• Evidence of progressive memory loss over the last 12 months per investigator assessment 
as captured on the diagnostic verification form 
Study Drug 
All subjects will receive study drug, one tablet BID, taken with a morning and evening meal (or 
within 30 minutes after each meal) with approximately 10 to 12 hours between doses. Subjects in 
the placebo treatment arm will receive placebo tablets BID throughout the study. Subjects in the 
active treatment arm will receive placebo in the morning and a 265mg tablet of ALZ-801 in the 
evening during the first two weeks of the study; thereafter, they will receive a 265mg tablet BID. 
This dose provides plasma exposures equivalent to tramiprosate (the active moiety) 150mg BID, 
which showed promising efficacy in APOE4/4 subjects in a Phase 3 program. This level of 
tramiprosate exposure showed full inhibition of amyloid oligomer formation in an in vitro assay. 
ALZ-801 will be provided as immediate release tablets (cGMP grade) for oral administration.  
On clinic visit days, only one dose of study drug will be taken from one of the newly dispensed 
blister cards and administered at the study site.  
Study Sample Size 
Approximately 300 subjects will be enrolled across approximately 85 study sites in the U.S., 
Canada, and Europe with a goal of having approximately 250 completers. Based on APOE4/4 
prevalence of 10% to 15% among AD patients, approximately 3000 AD subjects may need to be 
pre-screened to identify 300 eligible APOE4/4 subjects. In order to minimize the number of 
non-APOE4/4 subjects who would otherwise undergo extensive screening tests, screening will be 
conducted in two parts. Screening – Part 1 will include APOE4 genotyping, MMSE testing, 
prohibited medications screening, demographics, and medical history. Eligible subjects will enter 
Screening Part 2 which includes rest of the screening procedures. It is estimated that, of the 
approximately 3000 AD subjects who undergo Screening – Part 1, approximately 400 subjects will 
be eligible for Screening – Part 2.  
Eligible subjects will be randomized 1:1 to receive treatment with oral ALZ-801 or matching 
placebo (N = 150 each). Approximately 120 subjects (60 per group) will be recruited to participate 
in a CSF biomarker sub-study. All subjects (150 per group) will provide plasma samples for 
biomarker and PK assessments. All subjects will participate in the vMRI component of the study. 
Duration of Treatment 
Treatment duration with study drug will be 78 weeks. Subjects will participate in the study for up 
to 93 weeks: up to 11 weeks for Screening, 78 weeks of treatment, and 4 weeks until the Safety 
Follow-up Visit.  
Study Conduct Duration 
It is estimated that it will take approximately 18 months to recruit subjects into the study. The total 
duration of the study including recruitment, screening, main treatment and safety follow-up will 
be approximately 42 months.  

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4.2. 
Study Endpoints 
4.2.1. 
Primary Endpoints 
Primary Efficacy Endpoint 
• Cognitive Endpoint: Difference between study drug and placebo in the mean CBL to Week 
78 in ADAS-Cog 13 scores 
Primary Fluid Biomarker Endpoints 
• CBL to Week 78 in CSF p-tau181 (in CSF sub-study) 
• CBL to Week 78 in plasma p-tau181 in all subjects 
Primary Imaging Biomarker Endpoint 
• CBL to Week 78 in total hippocampal volume as assessed by vMRI 
Safety and Tolerability 
• Incidence and nature of TEAEs, serious TEAEs, and TEAEs leading to withdrawal 
• CBL in vital signs and physical exam, including body weight 
• CBL in laboratory parameters (clinical chemistry, hematology, coagulation tests) 
• CBL in 12-lead ECG parameters 
• CBL in MRI central readings for ARIA-E or ARIA-H 
• CBL in the C-SSRS 
4.2.2. 
Secondary Endpoints  
Key Secondary Efficacy Endpoint 
• CBL to Week 78 in the following scales: 
o A-IADL 
o CDR-SB 
o DAD 
Additional Secondary Efficacy Endpoints 
• CBL to Week 78 in the following scales: 
o NPI  
o ADAS-Cog 11 
o MMSE 
o QoL-AD 
o RUD Lite 
• CBL for the following scales and time points: 

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o ADAS-Cog 13 and ADAS-Cog 11 scores to Weeks 13, 26, and 52 
o A-IADL, CDR-SB, DAD, and NPI scores to Weeks 26 and 52  
o MMSE scores to Weeks 13, 26, 39, 52, and 65 
o QoL-AD and RUD Lite scores to Week 52 
Secondary Fluid Biomarker Endpoints 
• CBL to Week 78 in CSF p-tau217, Aβ40, Aβ42, NfL, t-tau, neurogranin, sTREM2, YKL-40, 
and GFAP (in CSF sub-study) 
• CBL to Week 78 in plasma p-tau217, Aβ40, Aβ42, NfL, and GFAP in all subjects 
• CBL to 52 weeks in all CSF biomarkers  
• CBL to Weeks 13, 26, 39, 52, and 65 in all plasma biomarkers 
• CBL to Weeks 13, 26, 39, 52, 65, and/or 78 for other potential biomarkers of interest in 
plasma or CSF, including assay of CSF Aβ oligomers (to be specified and included in the 
final SAP) 
Secondary Imaging Biomarker Endpoints 
• CBL for the following MRI measures: 
o Total hippocampal volume to Weeks 26 and 52 
o Cortical thickness and whole brain volume to Weeks 26, 52, and 78 
4.2.3. 
Other Endpoints 
Pharmacokinetic Endpoints 
• Plasma and CSF levels of ALZ-801, tramiprosate, and metabolite 3-SPA at each visit in 
the study, and update of the population PK model 
• Correlation of PK levels to efficacy and biomarker outcomes 
• Correlation of PK levels to safety parameters 
5. 
STUDY ENROLLMENT AND WITHDRAWAL 
The study population will include subjects, aged 50 to 80 years (inclusive), who have a clinical 
diagnosis of Early AD and who carry the APOE4/4 genotype.  
All Screening assessments must be completed and reviewed to confirm the potential subject meets 
all eligibility criteria. 
5.1. 
Inclusion Criteria 
To be considered eligible to participate in the study, the subject must meet all of the following 
requirements: 
1. Be male or female between the ages of 50 and 80 years (inclusive) at the Screening – Part 1 
Visit. 

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2. Has a clinical diagnosis of MCI or Mild Dementia due to AD consistent with the NIA-AA 
Working Group Criteria [Albert et al. 2011; Jack et al. 2018; McKhann et al. 2011]. 
3. Is homozygous for the ε4 allele of the APOE gene (APOE4/4).  
4. Has an MMSE score of 22 to 30 (inclusive) at the Screening – Part 1 Visit. 
5. Has a CDR Global score at Screening of 0.5 or 1, and a CDR Memory Box score ≥ 0.5. 
6. Has an RBANS delayed memory index score ≤ 85. 
7. Has evidence of progressive memory loss over the last 12 months per investigator 
assessment as captured on the diagnostic verification form. 
8. Can complete the cognitive testing and all other required study procedures.  
9. Has completed at least 6 years of formal education after age of 5 years, and is able to read 
at minimum of 6th grade level or equivalent per investigator assessment. 
10. Lives at home independently, in a senior living facility, or in an assisted living facility. 
11. Has a body mass index (BMI) between 17-40 (inclusive). 
12. Except for a diagnosis of AD and the presence of stable medical conditions, is, in the 
opinion of the Investigator, in good general medical health based upon the results of 
medical history, physical examination, laboratory tests, vital signs, and ECG.  
13. Has a reliable caregiver or study partner who is willing and able to sign an ICF, to 
accompany the subject to study visits, and adhere to study requirements (The caregiver or 
study partner, in the Investigator's opinion, has adequate contact with the subject to be able 
to provide accurate information about the participant's cognitive and functional abilities). 
14. Is willing to sign an IRB/IEC approved informed consent document indicating that he/she 
understands the purpose of the study and the procedures that are required for the study, and 
that he/she is willing to participate in the study. If a subject is unable or deemed not 
competent to sign the consent form, the subject’s legally authorized representative may 
sign the consent form with the subject’s assent, except where local regulations and 
IRB/IEC approval do not allow subjects who are unable or deemed not competent to sign 
the consent form, to participate in the study. 
Note: The subject who participates in the CSF sub-study will sign an additional ICF 
specific for the sub-study.  
15. Both subject and caregiver/study partner are fluent in, and able to read, the local language 
in which study assessments are administered at the study site. 
16. Subject and caregiver/study partner agree to be compliant with study procedures and 
adhere to study protocol. 
17. Subject and caregiver/study partner agree not to receive or administer any prohibited 
concomitant medications during the study. 
18. If female, must be non-breastfeeding, and 
EITHER be of non-childbearing potential, described as either:  

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• Postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal status 
(FSH analysis will be done at the Screening – Part 2 Visit and FSH levels should be in 
the postmenopausal range as determined by the laboratory), or 
• Documented sterilization procedure (hysteroscopic sterilization, bilateral tubal ligation 
or bilateral salpingectomy, hysterectomy, or bilateral oophorectomy) at least 6 months 
prior to the first dose. 
OR 
• If of childbearing potential, defined as a premenopausal female capable of becoming 
pregnant, must also have negative serum and urine pregnancy results prior to dosing, 
and either sexually inactive (sexually abstinent for 14 days prior to the first dose 
continuing through 28 days after the last dose) or use a highly effective method of 
contraception (with a failure rate of less than 1% per year when used consistently and 
correctly) 14 days prior to the first dose continuing through 28 days after the last dose. 
Note: Highly effective methods include the following: 
• 
intrauterine device (IUD),  
• 
surgical sterilization of the partner (vasectomy for 6 months minimum),  
• 
combined (estrogen or progestogen containing) hormonal contraception associated 
with the inhibition of ovulation (either oral, intravaginal, or transdermal),  
• 
progestogen only hormonal contraception associated with the inhibition of ovulation 
(either oral, injectable, or implantable),  
• 
intrauterine hormone-releasing system (IUS), or 
• 
bilateral tubal occlusion.  
19. If male,  
EITHER be non-vasectomized and agrees to use a condom with spermicide or abstain from 
sexual intercourse during the study until 90 days after the last dose of study medication and 
the female partner agrees to inclusion criterion 18,  
OR 
be vasectomized at least 6 months prior to first dose and agrees to use a condom during 
sexual intercourse, or less than 6 months prior to first dose and must follow the same 
restrictions as a non-vasectomized male. 
20. If treated with an AChEI, must be on a stable treatment for at least 12 weeks prior to the 
Baseline Visit and must be able to continue on the same drug for the duration of the study. 
21. If treated with permitted antidepressants, mood stabilizers, or other psychotropic 
medications, must be on a stable dose according to [Table 1]. Only two anticonvulsants are 
permitted (for any use) as indicated in Table 1. 
22. If taking permitted, non-psychotropic medications for the treatment of non-excluded 
medical conditions, must be on a stable dose according to [Table 1].  

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5.2. 
Exclusion Criteria 
To be considered eligible to participate in the study, the subject must not meet any of the following 
exclusion criteria: 
1. Has a screening brain MRI indicative of significant abnormality per central reader, other 
than AD related atrophy, including, but not limited to,  
• prior large vascular territorial infarct,  
• > 2 lacunar infarcts (size > 1.5 cm) outside the brain stem, 
• severe white matter changes (deep white matter changes Fazekas grade = 3), 
• ventriculomegaly related to normal pressure hydrocephalus  (after clinical correlation), 
or 
• aneurysm, subdural hematoma, abscess, or brain tumor (other than meningiomas or 
benign pituitary adenoma). 
Note 1: A subject with any of the following conditions may be included in the study but 
requires prior approval from the Sponsor Medical Monitor:  
(a) > 10 microhemorrhages,  
(b) a focal area of superficial hemosiderosis > 1 cm,  
(c) prior hemorrhage > 1 cm3 
(d) small vascular malformation, or  
(e) meningiomas ≥ 1 cm, or benign pituitary adenoma 
Note 2: For a subject who cannot undergo MRI, brain CT is acceptable but requires prior 
approval from Medical Monitor. CT showing significant pathology per the central reader, 
other than AD related findings, will be excluded. 
Note 3: CT is not allowed for subjects at sites in Germany. 
2. Has a diagnosis of a neurodegenerative disorder other than AD. 
3. Has been diagnosed with MDD according to the criteria of the Diagnostic and Statistical 
Manual of Mental Disorders – Fifth Edition (DSM-5), within one year prior to the Baseline 
Visit. A subject who does not meet criteria for MDD and who is on stable doses of 
antidepressants or mood stabilizers may be included in the study at the discretion of the 
Investigator. 
4. Is currently taking memantine or has taken memantine within 12 weeks prior to the 
Baseline Visit. 
5. Has a history of suicidal behavior within one year prior to the Baseline Visit; or has ongoing 
suicidal ideation with intent, with or without a specific plan or method (e.g., positive 
response to C-SSRS items 4 or 5 during the past 6 months). 
6. Has a history of seizures, excluding febrile seizures of childhood or a single distant seizure 
(≥ 5 years rior to the Baseline Visit). 
7. Has a medically confirmed history of recent cerebral infarct or transient ischemic attack 
within one year prior to the Baseline Visit.  
8. Has a medically confirmed history of recent myocardial infarction or unstable, untreated 
coronary artery disease, or angina pectoris within 1 year prior to the Baseline Visit. 
9. Has a lifetime history of schizophrenia, schizoaffective disorder, or bipolar disorder. 

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10. Has a history of, or currently has, any clinically significant ECG finding, or a QT interval 
corrected by Fridericia’s method (QTcF) of > 450 msec for males and > 470 msec for 
females. 
11. Has a history of cancer, diagnosed and treated within the last 3 years prior to the Baseline 
Visit, with the exception of the following: (a) treated basal cell carcinoma of the skin, 
(b) treated cutaneous squamous cell carcinoma in situ, (c) treated in situ or Stage 1 prostate 
cancer, (d) treated in situ cervical cancer, and (e) resected and cured early stage cutaneous 
melanoma (all require approval by the Sponsor’s Medical Officer). 
12. Has donated blood > 250 mL within 6 weeks prior to the Baseline Visit. 
13. Has a history of alcohol or drug dependence or abuse according to the criteria of the DSM-5 
within 2 years prior to the Baseline Visit. 
Note: A positive urine drug screen does not automatically exclude the subject, but requires 
review by Sponsor Medical Officer.   
14. Has any significant medical condition or infection (e.g., uncontrolled cardiovascular, GI, 
endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, 
neurologic, dermatologic, renal, or other major disease or malignancy) that is unstable and 
that would either: (a) place the subject at undue risk from administration of study drug or 
from undergoing study procedures, or (b) interfere with the interpretation of safety or 
efficacy evaluations obtained in the course of the study. 
15. Is unable to swallow ALZ-801 tablets or has a known intolerance or hypersensitivity to 
tramiprosate or any of the excipients contained in the ALZ-801 tablets.  
16. Except when otherwise specified, has clinical laboratory tests outside normal limits per the 
laboratory’s specification and considered clinically significant by the investigator at the 
Screening – Part 2 Visit. 
17. Has clinically relevant abnormalities in serum thyroid-stimulating hormone (TSH) or 
calcium. If the subject is taking thyroid hormone replacement therapy, corresponding 
Screening test values must be considered not clinically significant by the investigator.  
18. Has serum vitamin B12 below the lower limit of normal at the Screening – Part 2 Visit. A 
subject can be rescreened if he/she receives vitamin B12 treatment, and has a normal 
vitamin B12 level at least four weeks post-treatment. 
19. Has any clinical chemistry laboratory value greater than or equal to Common Terminology 
Criteria for Adverse Events (CTCAE; version 5.0; National Cancer Institute 2018) 
Grade 2, unless considered not clinically relevant by the Investigator. 
20. Has one or more of the following at the Screening – Part 2 Visit: 
• Alanine aminotransferase (ALT) > 3 × upper limit of normal (ULN),  
• Aspartate aminotransferase (AST) > 3 × ULN, or 
• Total bilirubin (TBL) > 1.5 × ULN (except for subjects with diagnosed Gilbert 
syndrome with isolated hyperbilirubinemia).  

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21. Has an estimated glomerular filtration rate (eGFR) < 40 mL/min per 1.73 m2 according to 
the Modification of Diet in Renal Disease (MDRD) formula [see National Institute of 
Diabetes and Digestive and Kidney Diseases website for formula MDRD formula for 
eGFR (SI units)]. 
22. Has a glycosylated hemoglobin (HbA1c) > 8% (National Glycohemoglobin 
Standardization Program) or 64 mmol/mol (International Federation of Clinical Chemistry) 
at the Screening – Part 2 Visit. 
23. Only for subjects participating in the CSF sub-study: has impaired coagulation as 
determined by a prothrombin time (PT) according to the international normalized ratio 
(INR) > 1.5 or a platelet count < 50 × 109/L prior to CSF sampling. 
24. Has a history of human immunodeficiency virus (HIV), or hepatitis B or C, or positive 
serology at the Screening – Part 2 Visit  
Note: Subjects with a history of hepatitis C who have been treated and cured (no detectable 
HCV RNA) are allowed. 
25. Has participated in a clinical trial of any investigational drug, device, or experimental 
medication or intervention within 24 weeks prior to the Baseline Visit [Table 1]. 
26. Has participated in a clinical study and received active treatment with an anti-amyloid 
vaccine or an anti-tau vaccine [Table 1].  
27. Has received any of the treatments listed in [Table 1] more recently than the indicated 
period prior to the Baseline Visit or plans to receive any of those during the study. 
28. Anticipates receiving any of the treatment listed in [Table 1] during the current clinical 
study, or is currently participating in an ongoing clinical trial or plans to participate in a 
future clinical trial during the conduct of this study.  
 
5.3. 
Prohibited Medications and Exceptions 
Table 1 
Prohibited Medications and Specified Washout Period 
Prohibited Medications and Exceptions 
Washout Period 
Before Baseline 
Visit (Visit 2) 
Anti-amyloid or Anti-tau vaccine: Subjects who received active drug 
in a vaccine study are not eligible (subjects who received placebo are 
eligible) 
Any use 

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Prohibited Medications and Exceptions 
Washout Period 
Before Baseline 
Visit (Visit 2) 
Potential disease modifying AD treatment: Subjects who received 
aducanumab treatment (US subjects) or who participated in a clinical 
study and received active drug: 
• Anti-amyloid or anti-tau antibodies (passive immunotherapy) 
• β-secretase or β-site amyloid precursor protein cleaving enzyme 
(BACE) inhibitors 
• Amyloid anti-aggregation agents 
• Anti-complement, anti-inflammatory, kinase inhibitors or other 
mechanisms 
24 weeks 
AChEI: Subject should remain on the same drug at the same dose 
during the study. 
Exception: During the study, down titration to a lower dose is allowed 
if necessary because of tolerability issues. This dose adjustment requires 
discussion with the Sponsor Medical Monitor. 
Not applicable 
Memantine: Memantine is not approved for subjects with MCI or Mild 
AD, and is not allowed in the study. Subjects requiring memantine after 
randomization must be withdrawn from the study. 
12 weeks 
Anti-parkinsonian medications: For example, L-dopa, amantadine, 
bromocriptine, pergolide, selegiline, I-deprenyl/selegiline, rasagiline).  
[Subjects with Parkinson’s disease are excluded from the study.] 
Exception: carbidopa/levodopa and dopamine agonists are allowed for 
treating restless leg syndrome, but dose should be stable for at least 4 
weeks prior to the Baselne Visit. 
12 weeks 
Oral Anticholinergic medications: Regularly used (> 3 doses/week) 
anticholinergic medications of ≥ moderate potency (e.g., benztropine, 
cyclobenzaprine, cyproheptadine, dicyclomine, diphenhydramine, 
promethazine, diphenoxylate with atropine, hydroxyzine, hyoscyamine, 
prochlorperazine, trihexyphenidyl, trimethobenzamide).  
[These drugs may interfere with cognitive assessments.] 
4 weeks 
Overactive Bladder medications: Oxybutynin.  
[The anticholinergic effect of this drug may interfere with cognitive 
assessments.] 
Exception: Daily use of the following medications are allowed: 
mirabegron, tolterodine, darifenacin, solifenacin, trospium, fesoterodine. 
Extended release formulations, where available, are preferred. 
Botulinum neurotoxin injection is allowed. 
4 weeks 

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Prohibited Medications and Exceptions 
Washout Period 
Before Baseline 
Visit (Visit 2) 
Antidepressants: MAO inhibitors or antidepressants with ≥ moderate 
anticholinergic potency, including tricyclic antidepressants.  
Examples of prohibited antidepressants are: amitryptyline, amoxapine, 
clomipramine, desipramine, imipramine, isocarboxazide, maprotiline, 
nortriptyline, phenelzine, protriptyline, tranylcypromine, trimipramine. 
Exception: Use of antidepressants with < moderate anticholinergic 
potency such as SSRIs or SNRIs are acceptable if stable for at least 4 
weeks before the Screening – Part 2 Visit 
Examples of allowed antidepressants are: citalopram, escitalopram, 
fluoxetine, paroxetine, sertraline, serotonin, duloxetine, venlafaxine, 
desvenlafaxine, trazodone, and mirtazapine.  
4 weeks 
Neuroleptics: Neuroleptics with ≥ moderate anticholinergic potency 
such as chlorpromazine, fluphenazine, loxapine, perphenazine, 
thioridazine, thiothixene, trifluoperazine, clozapine.  
Exception: Low doses of oral atypical antipsychotics are allowed, this 
includes 
• First generation drugs (olanzapine, quetiapine, risperidone, 
ziprasidone) 
• Second generation drugs (aripiprazole, asenapine, brexipiprazole, 
cariprazine, iloperidone, lurasidone and paliperidone) 
4 weeks 
Mood stabilizers and anticonvulsants: Lithium, valproic acid, 
phenytoin, levetiracetam, and carbamazepine. 
[These drugs may affect cognitive outcomes.] 
Exception: Use of pregabalin and gabapentin for neuropathic pain, and 
a stable low doses of zonisamide (≤ 100 mg/day) for pain, migraine, or 
sleep is acceptable. 
4 weeks 

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Prohibited Medications and Exceptions 
Washout Period 
Before Baseline 
Visit (Visit 2) 
Sedatives/benzodiazepines: Regularly used (> 3 doses/week) 
sedatives/benzodiazepines (e.g., chlordiazepoxide, clonazepam, 
diazepam, meprobamate).  
[These drugs may interfere with cognitive assessments of clinical 
status.] 
Exception: Daily use of the following medications is acceptable if 
stable for at least 4 weeks before the Baseline Visit:  
• Hypnotic drugs used for insomnia, for example, zaleplon ≤ 5 mg, 
zopiclone ≤ 7.5mg, eszopiclone ≤ 3mg, ramelteon ≤ 8 mg, 
suvorexant ≤ 15 mg, and zolpidem ≤ 5 mg (or equivalent doses of 
same class) 
• Any as needed (prn) use ≤ 3 days per week  
• Short term use with > 3 doses/week is acceptable, even if tested 
positive for sedatives/benzodiazepines, may enter the study. Short 
term use is defined as ≤ 1 month.   
• Regular (> 3 days/week) use of low dose of 
sedatives/benzodiazepines, for example, lorazepam, temazepam, 
flurazepam, triazolam, estazolam, and quazepam (or equivalent 
doses of same class) allowed if stable for at least 4 weeks before 
the Baseline Visit after review by Sponsor Medical Officer 
• Regardless of sedatives/benzodiazepines usage, it is strongly 
recommended that subjects do not take these medications for at 
least 24 hours prior to cognitive assessments taken during clinic 
visits.  
4 weeks 
Analgesics/Narcotics: Regularly used (> 3 doses/week) narcotic 
analgesics (e.g., codeine, morphine, hydromorphone, oxycodone, 
propoxyphene and its variations, & combination products that contain a 
narcotic).  
[These drugs may interfere with cognitive assessments of clinical 
status.] 
Exception: Short term use (< 1 month) more than 3 doses/week is 
acceptable for temporary conditions. Narcotics are not to be used within 
48 hours of cognitive testing at study visits. 
4 weeks 
Stimulant medications: For example, amphetamine, methylphenidate, 
atomoxetine, modafinil 
[These drugs may affect cognitive outcomes.] 
4 weeks 

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Prohibited Medications and Exceptions 
Washout Period 
Before Baseline 
Visit (Visit 2) 
Anticoagulants: For example, warfarin, dabigatran, apixaban or other 
blood factor or thrombin inhibitor.  
[Increased risk of cerebrovascular events in APOE4/4 homozygotes 
carriers with potential cerebral amyloid angiopathy; anticoagulants also 
increase potential risks associated with LP.] 
Exception: Use of single anti-platelet therapy (e.g., aspirin or 
dipyridamole or clopidogrel) is permitted. Use of dual anti-platelet 
therapy (low-dose aspirin with dipyridamole or clopidogrel) is 
permitted. Subjects on dual anti-platelet therapy may be allowed to 
participate in the CSF sub-study after discussion with Sponsor Medical 
Monitor. 
4 weeks 
Corticosteroids: Systemic use: oral, intravenous, or intramuscular 
[These drugs may affect assessment of the neuroinflammatory 
biomarkers.] 
Exceptions: The following are acceptable:  
• Low dose oral treatment with the equivalent of ≤ 10mg prednisone 
• Short-term oral treatment with the equivalent of ≤ 60mg 
prednisone for < 4 weeks 
• Local injections into joints or bursae; topical, inhaled, or nasal use 
4 weeks 
BACE: β-secretase or β-site amyloid precursor protein cleaving enzyme; LP: lumbar puncture; MAO: monoamine 
oxidase; SNRI: serotonin and norepinephrine (noradrenaline) re-uptake inhibitors; SSRI: selective serotonin reuptake 
inhibitors. 
Note: This is not a complete list of prohibited medications. Contact the Medical Monitor if there is a question about 
a specific medication. 
5.4. 
Subject Identification and Allocation to Treatment 
5.4.1. 
Subject Identification 
Initials, year of birth, and age of subjects who have signed the ICF to begin Screening procedures 
will be collected in the source data for verification purpose. At Screening – Part 1 Visit, a unique 
identification number will be assigned by the interactive response technology (IRT). Any subject 
records or dataset that are transferred to the Sponsor will contain the identifier only; subject names, 
initials, date of birth, or any information which would make the subject identifiable will not be 
transferred. 
In the rare circumstance where a subject is entered into the treatment part of the study, but does 
not receive the first dose of study drug, the Study Coordinator/Research Nurse must immediately 
inform the Clinical Research Associate (CRA) that the study drug was not administered. 
5.4.2. 
Treatment Allocation 
All subjects will be randomized to receive double-blind treatment consisting of either ALZ-801 
265mg or placebo in a 1:1 ratio. Randomization will be stratified by use of concomitant AD 
medications (AChEI or none), age (50 through 65 years or > 65 years at the Screening – Part 1 
Visit, gender, and disease stage (MMSE ≤ 26 or > 26 at the Baseline Visit). It is expected that 

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approximately 60% will be AD subjects with MMSE 22-26 (inclusive), and approximately 40% 
will be AD subjects with MMSE 27–30 (inclusive). Double-blind treatment will be dispensed in 
blister cards.  
5.5. 
Subject Withdrawal, Termination, and Replacement 
Study subjects may discontinue from the study or be withdrawn from the study for any of the 
following reasons: 
• At the subject’s or the subject’s legally authorized representative with the subject’s assent 
request for any reason (withdrawal of consent) 
• Subject whose cognitive function declines and is deemed by the Investigator to be unable 
to provide assent/consent for continuation in the study 
• At the discretion of the Investigator, if deemed appropriate, for any reason 
• At the discretion of the Sponsor, if deemed appropriate, for any reason 
• Subject for whom investigator deems initiation of memantine medically necessary must be 
withdrawn 
• Subject noncompliance: If a subject takes less than 70% of study drug tablets, this may be 
considered reason for withdrawal, by Investigator or Sponsor request  
• Protocol violation that compromises subject safety  
• For safety concerns; medically significant AE(s) or SAE(s) with CTCAE > Grade 3 may 
be considered reason for withdrawal, if appropriate in the judgment of the Investigator 
• Subject who becomes pregnant must be withdrawn from the study 
• The subject’s caregiver/study partner is no longer willing or able to participate in the study 
and a suitable replacement caregiver/study partner cannot be found 
• Brain MRI findings: subject who has any of the following findings on central reading: 
o Macrohemorrhage: defined as hemorrhage with size > 1 cm3  
o ARIA-E (vasogenic edema) associated with neurologic symptoms: dosing will be 
halted for 1 month and MRI repeated. Resumption of dosing may be considered after 
discussion between Investigator and Sponsor’s medical officer.  
• Subject who experiences an event of syncope without a clear triggering event (e.g., blood 
draw or pain inducing a vasovagal episode) will be withdrawn from the study 
• Subject with clinically notable ECG abnormalities based on the average of triplicate ECG 
readings. The criteria for clinically notable or significant ECG results that require subject 
withdrawal are as follows: 
o QTcF (Fridericia’s correction) interval > 500 msec, and  
o An increase in QTcF interval of > 60 msec from baseline. 

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Note: The criteria for QTcF are based on the upper threshold in elderly subjects who are 
known to have higher ULN [Reardon & Malik, 1996], and is the threshold commonly used 
in AD studies. 
• Subject with confirmed clinically notable changes in liver function tests (LFT) may be 
withdrawn from the study. The criteria for abnormal LFTs are as follows: 
o ALT or AST > 8 × ULN, 
o ALT or AST > 5 × ULN for more than 2 weeks, or 
o ALT or AST > 3 × ULN, and TBL > 2 × ULN or PT > 1.5 × ULN 
• Weight loss: Subjects who are not intentionally dieting who show the following degree of 
weight loss on study drug: 
o Weight loss > 6% of body weight compared to baseline, and 
o Reaching BMI < 22 if ≥ 65 years of age; or  
o Reaching BMI < 16 if < 65 years of age 
Note: The ideal body weight and BMI cut-off criteria for those < 65 years of age or ≥ 65 
years of age are based on a meta-analysis by Winter et al. (2017). 
The reason for discontinuation must be recorded on the appropriate page of the electronic case 
report form (eCRF).  
Early Termination 
Should a study subject request or decide to withdraw or is withdrawn by Investigator or Sponsor, 
an Early Termination (ET) Visit will be conducted at the time of discontinuation. All efforts should 
be made to conduct assessments and to complete and report observations as thoroughly as possible 
up to the date of withdrawal, including all the evaluations shown in the Schedule of Assessments 
[Appendix 2]. All information will be reported on the applicable pages of the eCRF. 
If the subject withdraws from the study due to an AE, every reasonable attempt should be made to 
follow the subject until the AE resolves or until the Investigator, after discussion with the Sponsor, 
deems the AE to be chronic or stable. All SAEs will continue to be followed for 4 weeks after the 
ET visit or until the AE is deemed to be either chronic or stable. 
Subject Replacement 
If drop-out rate is more than projected (approximately 18%), subjects including those in the CSF 
sub-study who drop out may be replaced after discussion with the Safety Management Committee 
(SMC). 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT 
6.1. 
Investigational Medicinal Product and Control Description 
The investigational medicinal product (IMP) will be 265mg ALZ-801 (provided as 1 × 265mg 
tablets) or matching placebo (1 × placebo tablets [size- and color-matched to ALZ-801]).  

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All subjects will receive study drug, one tablet BID, taken with a morning and evening meal (or 
within 30 minutes after each meal) with approximately 10 to 12 hours between doses. Subjects in 
the placebo treatment arm will receive placebo tablets BID throughout the study. Subjects in the 
active treatment arm will receive placebo in the morning and a 265mg tablet of ALZ-801 in the 
evening during the first two weeks of the study; thereafter, they will receive a 265mg tablet BID.  
On clinic visit days, only one dose of study drug will be taken from one of the newly dispensed 
blister cards and administered at the study site.  
6.1.1. 
Formulation, Appearance, Packaging, Labeling, and Shipping  
Formulation 
The ALZ-801 tablet consists of ALZ-801 drug substance, microcrystalline cellulose, silica 
colloidal anhydrous (Aerosil 200), PVP VA 64 (copovidone) and magnesium stearate. ALZ-801 
tablets are coated with Opadry II White. Each tablet contains 265mg of ALZ-801 drug substance. 
Placebo tablets contain all of the same excipients as ALZ-801 tablets, but do not contain any 
ALZ-801. ALZ-801 and placebo used for the tablets are manufactured under cGMP and meet 
specifications for clinical use.  
Appearance 
ALZ-801 is provided as white, oval-shaped, immediate release tablets [Figure 7].  
Figure 7  
Appearance of ALZ-801 and Matching Placebo Tablets 
 
 
Packaging 
ALZ-801 immediate-release tablets will be packaged as kits containing blister cards. Each blister 
card contains a 1-week supply with two blister strips, one for AM and one for PM dosing (8 tablets 
in each strip). The total number of tablets for a 1-week blister card is 16 tablets, for 7 days of 
dosing plus 1 day overage. The materials used for the blister strips are of standard commercial 
grade. The product contact side of this material conforms to FDA 21CFR175.300 and the Council 
of Europe Resolution AP (2004) and (EU) No. 10/2011. 
 

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Labeling 
Representative label is shown below in [Figure 8]. 
Figure 8  
Representative Label of Drug Product 
ALZ-801 265 MG                          Protocol code: ALZ-801-AD301 
FOR CLINICAL TRIAL USE ONLY 
Each blister card contains a 1-week supply with two blister strips (8 tablets in each strip) 
for AM and PM dosage of ALZ-801 immediate release tablets or placebo. The total 
number of tablets for a 1-week blister card is 16 tablets.  
 
Kit Number: 
Site Number:                                                            Batch Number:       
Patient Number:                                                      Investigator:       
Date of dispensation:                                               Expiry date: MMM/YYYY 
                                       
Dosing schedule:  
Orally, twice per day, approximately 10-12 hours apart. Tablets shall be taken with a full 
meal or within 30 minutes after a full meal.  
On clinic visit days, only one dose of study drug will be taken from one of the newly 
dispensed blister cards and administered at the study site. 
Use only according to study physician’s instructions. 
 
Store at room temperature (15-25 oC).  
Caution: NEW DRUG- Limited by Federal (U.S.A.) law to investigational use only. 
 
KEEP OUT OF REACH OF CHILDREN.  
Sponsor: Alzheon, Inc., 111 Speen Street, Suite 306, Framingham, MA 01701, USA; Tel.: 
+1-508-861-7709. 
 
Shipping 
Study drug will be shipped directly to the pharmacist or study coordinator/research nurse at the 
study site after all required regulatory and legal documents have been received by the Sponsor or 
its designee. Upon receipt of the study drug shipment, the pharmacist or study coordinator/research 
nurse will verify the condition of the study supplies, register the study drug, and document per 
instructions provided. 
Instructions for resupply shipments or replacement of study drug are provided in the IRT Manual. 
6.1.2. 
Product Storage and Stability 
IMP must be stored in a limited access area at room temperature (15°C to 25°C or 59°F to 77°F). 
Only authorized study personnel may access the study drug according to local and national 
regulations. 
6.1.3. 
Replacement Procedures for Investigational Medicinal Product  
Instructions to resupply shipments or replacement of study drug are provided in the IRT Manual. 

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6.2. 
Dosing and Administration, and Adjustment 
6.2.1. 
Dosing Regimen  
Study drug will be administered as an oral tablet beginning at the Baseline Visit (Day 1). The first 
dose of study drug will be administered in the clinic and must be administered to the study subject 
only after all pre-dose assessments (including the blood draw) are performed.  
The dosing regimen is one tablet orally BID except on clinic days when one tablet only will be 
administered at the study site. In the initial 2-week titration period, the active treatment group will 
receive placebo in the morning and ALZ-801 in the evening. Thereafter, ALZ-801 will be 
administered in the morning and evening. In the placebo group, subjects will always receive 
placebo in the morning and evening throughout the study. The last dose of study drug will be 
administered at the clinic on the morning of the Week 78 visit.  
The study drug should be taken with a full meal or within 30 minutes after a full meal (breakfast 
or dinner) with approximately 10 to 12 hours between doses. On days of clinic visits, dosing of 
study drug for the day will occur once and will be administered by the site staff at the site. The 
times of study drug administration the night prior to clinic visit and when taken at the study site 
will be recorded.  
6.2.2. 
Dose Adjustments/Modifications/Delays 
Dosage adjustments or down titration will not be allowed for ALZ-801 throughout the study except 
for the dose change on Day 15 after the titration period.  
No gradual reduction in medication is required for withdrawal from the study. If for any reason, a 
subject misses one or more doses of study drug, he/she should resume the regular dosing regimen, 
unless informed otherwise. The interruption in study drug dosing should be reported and recorded. 
6.3. 
Study Drug Accountability 
It is the responsibility of the Investigator to supervise accurate monitoring of the receipt, storage, 
dispensing, and accounting of all study drug according to accepted medical and pharmaceutical 
practice. Copies of all shipment records of study drug shipments must be retained. Accurate, 
original site records of study drug inventory and dispensing must be maintained using the forms 
provided or using the form the site pharmacy maintains, if they are approved for use by the Sponsor 
or designee. 
All study drug documentation must be maintained by the Pharmacist or dispenser. All disposition 
records must be made available for inspection by the Sponsor or their designee, upon request. 
Drug accountability forms will be provided for the accounting of study drug at the subject level 
and for the overall study inventory. A reason(s) must be provided for any tablets that are not 
accounted for. 
Only subjects enrolled in the study may receive study drug and only authorized study site personnel 
may supply or administer the drug. Only study drug with appropriate expiry dates may be 
dispensed. 
Study subjects will be instructed to return all dispensed study drug blister cards to the study site at 
each visit. Blister cards dispensed at the previous visit will be collected, and the Pharmacist or 

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designee at the site will inspect all returned blister cards, as well as record the number of used and 
unused tablets on the drug accountability log. Each site must keep all used and unused blister cards 
until the CRA either arranges return to the distribution center or gives instruction for their disposal. 
If unused tablets remain at the end of the study, they will be accounted for at the site close-out visit 
in the presence of the CRA, who will provide instructions for study drug disposal. 
6.4. 
Study Drug Compliance 
All subjects in this study will commence therapy onsite on Day 1 (Baseline); oral study drug will 
be administered under clinic staff supervision. After subjects are discharged to continue therapy at 
home, subjects and their caregivers/study partners should be counseled on the need to meet 100% 
compliance with study drug. The Investigator or designee should ensure that subjects meet this 
goal throughout the study period. Compliance will be assessed on subsequent visits by returned 
tablet count. Administration of investigational product and any deviation(s) from the prescribed 
dosage regimen should be recorded. 
7. 
STUDY PROCEDURES AND SCHEDULE 
7.1. 
Study Specific Procedures/Evaluations 
All study procedures and evaluations will be completed according to the Schedule of Assessments 
as shown in [Appendix 2]. Every effort should be made to complete the required procedures and 
evaluations at the designated visits and times. 
7.1.1. 
Remote Visits 
Coronavirus disease 2019 (COVID-19) has significantly impacted study subjects’ ability to attend 
study visits due to government-ordered lockdowns or the closure of state (domestic) and/or 
national borders and may continue to do so. 
Protocol deviations, urgent safety measures, and modifications to this protocol might be necessary 
to prioritize and ensure the safety of trial participants, their families, and study site teams, and 
maintain the integrity of the study. All measures and actions that may be implemented due to 
COVID-19 will be reviewed by the Data and Safety Monitoring Board (DSMB), Medical Monitor, 
and applicable Principal Investigators.  
For any skipped in-person visits based on the availability of the patient/ the study team, within 
approximately ± 3 days of the originally scheduled visit, the study team should contact the subject 
(and as applicable, their caregiver/study partner/legal representative) via phone/telemedicine to 
collect information in order to monitor AEs or SAEs, and provide study oversight (hereafter 
referred to as “remote visits”).  
Protocol deviations related to COVID-19 will be documented. These deviations in 
protocol-specific procedures due to COVID-19 (changes in study visit schedules, remote and/or 
missed visits, or patient discontinuations) may lead to missing information.  
For each patient, the eCRF will capture specific information that (as much as possible) explains 
the basis of the missing data, including the relationship to COVID-19 for missing 

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protocol-specified information (e.g., from missed study visits or study discontinuations due to 
COVID-19). 
7.1.2. 
Informed Consent  
At Screening – Part 1 Visit, prior to stated procedures (APOE genotyping, MMSE, demographics, 
medical history and prohibited medications) are performed, the site staff will obtain the signed ICF 
from each subject or the subject’s legally authorized representative with the subject’s assent. 
Complete signed ICF from subject and caregiver/study partner will be obtained prior to any other 
procedures at the Screening – Part 2 Visit or at the Screening – Part 1 Visit if APOE4/4 status is 
known or confirmed using a rapid genotype test. 
7.1.3. 
Prohibited Medications 
The list of prohibited medications starting at the Screening – Part 1 Visit and at all times during 
the study is provided in [Table 1]. 
7.1.4. 
Permitted Medications 
During the study, any concomitant medications deemed appropriate by the Investigator to treat the 
subject’s medical condition may be prescribed, excluding those that are prohibited. Refer to [Table 
1], which also lists the exceptions to prohibited medications. 
Change in dose of any permitted medications during the study period is discouraged. 
All concomitant medication usage will be recorded during each study visit. 
7.1.5. 
APOE Genotyping  
A blood sample for APOE genotyping will be required at the Screening – Part 1 Visit as shown in 
the Schedule of Assessments [Appendix 2]. Previous evidence of APOE4/4 status may be used as 
a reference and allow subjects to combine Screening – Part 1 Visit and Screening – Part 2 Visit 
together at the same day if the site and subject prefer. 
Result from the central laboratory blood test of APOE4/4 status must be available prior to 
randomization. 
The blood sample may be stored, with subject consent, for possible future analysis with core 
AD-related biomarkers, such as p-tau217, Aβ40, and Aβ42 as well as NfL and GFAP. Consent for 
use of this sample for possible future analysis with core AD-related biomarkers is optional. 
7.1.6. 
Future Potential Genomic Testing  
A blood sample for future potential genomic testing will be requested at the Screening – Part 2 
Visit as shown in the Schedule of Assessments [Appendix 2]. Consent for the collection and use 
of this sample is not required for study participation. 
7.1.7. 
Subject Demographics and Medical History 
At the Screening – Part 1 Visit, the subject’s demographics and medical history will be obtained. 
The demographics should include, but not be limited to, age, race, ethnicity, and gender. The 
medical history should include, but will not be limited to, the subject’s clinically significant and 
relevant medical history of the following body systems: head, eyes, ears, nose, and throat; 

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neurological; endocrine; dermatological; cardiovascular; respiratory; GI; genitourinary; 
musculoskeletal; hematological; hepatic; renal; and immunological systems. 
7.1.8. 
Prior and Concomitant Medications 
Prior medications and past treatment(s) taken within the last 24 weeks prior to the Baseline Visit, 
as well as ongoing medications taken before the administration of the first dose of study drug, will 
be recorded. 
A concomitant medication is defined as any medication that is taken after administration of the 
first dose of study drug (i.e., after receiving study drug at the Baseline Visit). Any use of 
concomitant medications will be recorded. During the study, initiation of or change in concomitant 
medications to treat an AE will also be recorded. 
7.1.9. 
Subject Eligibility 
At both the Screening – Part 2 and Baseline Visits (prior to dosing), the site staff will be responsible 
for reviewing the inclusion and exclusion criteria to determine the subject’s eligibility for the 
study. 
7.1.10. 
Safety Assessments 
7.1.10.1. Assessment of Adverse Events 
AEs will be recorded beginning after signing the ICF at the Screening – Part 1 Visit until 
completion of the study or the final Follow-up Visit, whichever is later. AEs will be evaluated by 
the Investigator for severity (using CTCAE version 5.0; National Cancer Institute 2018), 
seriousness, and attributability to study medication. Further details on AEs, including definitions, 
elicitation, and reporting are provided in [Section 8]. 
AEs that occur before receiving study drug at the Baseline Visit will be captured as non-treatment 
emergent AEs. Treatment-Emergent AEs are those that occur anytime after subject has received 
first dose of study drug at the Baseline Visit and until the end of the Safety follow up visit or the 
Early Termination Visit. 
7.1.10.2. Physical Examination 
Complete physical examination will be conducted at the scheduled visits prior to dosing shown in 
the Schedule of Assessments [Appendix 2].  
7.1.10.3. Neurological Examination 
Neurological examination will be conducted at the scheduled visits prior to dosing shown in the 
Schedule of Assessments [Appendix 2]. The neurological examination should include level of 
consciousness, speech, cranial nerves [including pupil equality and reactivity], motor assessment, 
sensory assessment, coordination, gait, reflexes, and Romberg test. 
7.1.10.4. Height and Weight Measurements 
Height will be collected at the Screening – Part 2 Visit only. Weight measurement will be taken at 
the Screening – Part 2 Visit and at all post treatment clinic visits as shown in the Schedule of 
Assessments [Appendix 2].  

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7.1.10.5. Vital Signs 
Vital sign measurements (blood pressure [BP], pulse, respiratory rate, and body temperature) will 
occur prior to dosing, lumbar puncture (LP), and blood draw, where applicable. BP and pulse will 
be measured after the subject is sitting for at least 5 minutes. All BP measurements should be 
performed in the same arm while sitting, preferably by the same person with an inflatable cuff and 
a calibrated manometer. Vital signs will be taken at the scheduled visits shown in the Schedule of 
Assessments [Appendix 2].  
After the last blood collection in a visit, subjects will be observed for approximately 15 minutes. 
BP and pulse will be measured and documented at the end of this observation period. 
7.1.10.6. Brain Imaging 
Brain MRI scans will be scheduled and performed within the window specified for each visit 
shown in the Schedule of Assessments [Appendix 2].  
The screening MRI report per central reader will be used to determine study eligibility, by 
excluding other neuropathologies, and as baseline for volumetric assessment of the imaging 
biomarkers. Post dose MRI will be used for safety monitoring and for volumetric MRI assessment 
of the imaging biomarkers. 
MRIs will be performed using either 1.5 or 3 Tesla scanners. Details of the MRI sequences are 
described in the MRI study manual.  
Sedation is permitted for claustrophobic subjects who have difficulty tolerating the MRI procedure 
according to local standard procedures. For those who cannot undergo MRI, CT is acceptable at 
Screening but requires prior approval by Medical Monitor. These subjects will not be scheduled 
for further CT imaging and will not contribute to the assessment of the volumetric imaging 
biomarkers. CT is not allowed for subjects at sites in Germany. 
7.1.10.7. Electrocardiogram 
ECGs will be performed as shown in the Schedule of Assessments [Appendix 2]. A standard 
triplicate 12-lead ECG will be performed at the Screening – Part 2 Visit, Week 6, and Week 13. 
At subsequent visits, a single 12-lead ECG will be performed unless there is evidence of QT 
prolongation previously or in or current visit, in which case a triplicate ECG must be performed. 
The ECG should be obtained after the subject has rested in a supine position for at least 5 minutes. 
This assessment may be performed any time before blood sampling or at least 30 min after blood 
sampling, if applicable. 
ECG intervals (e.g., interval representing the time for both ventricular depolarization and 
repolarization to occur [QT interval], QTcF interval, interval from the beginning of the Q wave to 
the termination of the S wave, representing the time for ventricular depolarization [QRS duration], 
and time from the onset of the P wave to the start of the QRS complex [PR interval]) and any 
clinically significant findings will be recorded. The tracings will be reviewed and reported by the 
central ECG reader.  
7.1.10.8. Columbia-Suicide Severity Rating Scale 
The C-SSRS will be performed prior to dosing to assess suicide risk at the visits shown in the 
Schedule of Assessments [Appendix 2]. 

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7.1.10.9. Safety Laboratory Assessments 
Safety laboratory tests are summarized in [Table 2]. Clinical chemistry, hematology, coagulation 
tests, and urinalysis will be performed in all subjects at the scheduled visits shown in the Schedule 
of Assessments [Appendix 2]. At each visit, blood tests will be done after the completion of all 
study procedures except for study drug dosing and dispensing.  
 
 

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Table 2 
Clinical Laboratory Tests 
Panel/Assessments 
Visits 
Parameters to be Analyzed 
Genotyping (Blood) 
Screening – Part 1 only 
APOE genotype 
Immunology  
Screening – Part 2 only 
HIV-1/-2 Ag and Ab 
Hep B S Ag 
Hep C Ab 
HCV RNA (if applicable) 
Clinical Chemistry 
Screening – Part 2 only 
HbA1c 
Vitamin B12 
TSH 
FSH (all females of non-childbearing potential only) 
hCG (all females of childbearing potential only) 
Clinical Chemistry 
Screening – Part 2,  
Weeks 6, 13, 26, 39, 52, 65, 
78, and ET 
Albumin 
ALP 
AST 
ALT 
GGT 
TBL 
Direct bilirubin 
Indirect bilirubin 
Lactate dehydrogenase 
Blood urea nitrogen 
Creatinine* 
Glucose 
Magnesium 
Potassium 
Sodium 
Total protein 
Calcium 
Chloride 
Phosphorus 
Uric acid 
Hematology 
Screening – Part 2,  
Weeks 6, 13, 26, 39, 52, 65, 
78, and ET 
Hemoglobin 
Hematocrit 
RBC count 
RBC MCV 
White blood cell count with differential (percentage of neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) 
Platelet count 
Coagulation Tests 
Screening – Part 2,  
Weeks 6, 13, 26, 39, 52, 65, 
78, and ET 
aPTT 
PT 
INR for PT 
Urinalysis 
Screening – Part 2,  
Weeks 6, 13, 26, 52, 78, 
and ET 
Color 
Appearance 
pH 
Specific gravity 
Glucose 
Protein 
Ketones 
Blood 
Microscopic examination (RBC, white blood cells, epithelial cells, 
casts, crystals, bacteria) 
Urine pregnancy test (all females of child bearing potential only) at 
all visits except Screening – Part 2 
ALT: alanine aminotransferase; ALP: alkaline phosphatase; aPTT: activated partial thromboplastin time; AST: aspartate 
aminotransferase; ET: early termination; FSH: follicle-stimulating hormone; GGT: γ-glutamyl transferase; HbA1c: glycosylated 
hemoglobin; hCG: human chorionic gonadotropin; HCV RNA: hepatitis C virus RNA; Hep B S Ag: hepatitis B surface 
antigen; Hep C Ab: hepatitis C antibody; HIV: human immunodeficiency virus; INR: International normalized ratio; 
MCV: mean corpuscular volume; PT: prothrombin time; RBC: red blood cells; TBL: total bilirubin; TSH: thyroid-stimulating 
hormone 
* Used to calculate glomerular filtration rate according to the Modification of Diet in Renal Disease formula. 

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It is preferred that urine samples for urinalysis and other urine testing is collected at the first void 
performed at the clinic. All clinical laboratory samples and urine samples for urinalysis will be 
analyzed at a central laboratory. The urine pregnancy test, if applicable, will be analyzed at the 
study site. 
All laboratory reports must be reviewed, initialed, and dated by the Principal Investigator or by a 
Sub-Investigator who is a physician or other qualified health care professional involved in the 
study conduct at the site. Each abnormal test will be evaluated as clinically significant or not 
clinically significant. All clinically significant abnormal laboratory values that represent an 
unexpected CBL should be assessed as AEs, and an AE eCRF must be completed. Any clinically 
significant abnormal values that persist should be followed until they have been resolved or the 
Investigator, in consultation with the Medical Monitor, assesses them to be chronic or stable. 
7.1.10.10. Serum FSH or hCG Test 
Serum FSH levels will be measured only for female subjects of non-childbearing potential at the 
Screening – Part 2 Visit. Serum human chorionic gonadotropin (hCG) levels will be measured 
only for female subjects of childbearing potential at the Screening – Part 2 Visit.  
Serum FSH levels for female subjects of non-childbearing potential should be in the 
postmenopausal range as determined by the laboratory for study entry. Serum hCG levels for 
female subjects of childbearing potential must indicate negative pregnancy results for study entry. 
7.1.10.11. Urine Pregnancy Test 
Urine pregnancy test will be performed at subsequent visits prior to dosing shown in the Schedule 
of Assessments [Appendix 2] for females of childbearing potential. Pregnancy tests must be 
negative to continue the study. 
7.1.10.12. Urine Drug Screen 
Urine drug screen will be performed at the Screening – Part 2 Visit as shown in the Schedule of 
Assessments [Appendix 2]. Drugs of abuse to be screened for include amphetamines, MDMA, 
barbiturates, benzodiazepines, cannabinoids, cocaine, phencyclidine, ethanol, and opiates.  
Subjects who use cannabidiol (CBD) oil must commit to withholding consumption for at least 24 
hours prior to all clinic visits. 
7.1.10.13. Screens for HIV and Hepatitis B and C 
HIV antigen and antibody, hepatitis B surface antigen (Hep B S Ag), and hepatitis C antibody 
(Hep C Ab) and HCV RNA (if applicable) tests will be conducted at the Screening – Part 2 Visit 
as shown in the Schedule of Assessments [Appendix 2]. 
7.1.11. 
Clinical Efficacy Assessments 
All clinical efficacy assessments will be collected on electronic tablets and will be considered 
source data. In the uncommon event that a tablet is not functional, assessments will be collected 
on paper and considered as the source data, and will be entered into the tablet later. 

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7.1.11.1. Alzheimer’s Disease Assessment Scale – Cognitive Subscale 
The ADAS-Cog is a brief neuropsychological assessment used to assess the severity of cognitive 
symptoms. The ADAS-Cog 13 consist of 13 questions including word recall task, naming objects 
and fingers, following commands, constructional praxis, ideational praxis, orientation, word 
recognition task, remembering test directions, spoken language, comprehension, word-finding 
difficulty, delayed word recall, and digit cancellation tasks. The total test score ranges from 0 to 
85. The worse the cognition (cumulative number of errors), the greater the score.  
The ADAS-Cog 11 includes all of above items except for delayed word recall and digit 
cancellation tasks with a total score ranging from 0 to 70.  
The ADAS-Cog will be administered, while audio-recorded, to the subject by properly certified 
site staff at the visits shown in the Schedule of Assessments [Appendix 2]. It is highly 
recommended that the same rater for a given subject perform the ADAS-Cog throughout the study. 
7.1.11.2. Amsterdam Instrumental Activities of Daily Living 
The A-IADL Questionnaire is a 70-item informant-based computerized questionnaire aimed at 
detecting deficits in complex functions at the early stages of AD [Sikkes et al. 2013]. It will be 
assessed at the visits shown in the Schedule of Assessments [Appendix 2]. Instrumental ADL can 
be described as the activities necessary to function independently in society. These activities 
include, but are not limited to, cooking, doing finances, and shopping. They are complex everyday 
tasks, determined by multiple cognitive processes and controlled processing. They can be 
distinguished from basic ADL, which include basic self-care skills. 
7.1.11.3. Disability Assessment for Dementia 
The DAD evaluates the basic and instrumental activities in daily activities of subjects with 
dementia. The proxy-respondent scale specifically measures daily living tasks in terms of 
executive functions. 
A 40-item scale is part of the DAD, which addresses a range of functional domains: eating, meal 
preparation, telephoning, hygienic, dressing, medication, corresponding, finance, leisure, and 
housework.  
The DAD will be administered to the subject by properly qualified and trained site staff at the 
visits shown in the Schedule of Assessments [Appendix 2]. 
7.1.11.4. Clinical Dementia Rating – Global Score and Sum of Boxes 
The CDR is a global rating scale used to assess the stage and severity of dementia. It uses a 
structured, clinician-rated interview that collects information on cognitive and functional capacity 
from both the subject and caregiver, on performance in six areas (memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care). Each of the six 
areas (boxes) is rated on a scale of 0, 0.5, 1, 2, or 3 where 0 is normal, 0.5 is Questionable and 3 is 
Severe. The scores of each of the areas are added together to determine the Sum of Boxes (SB) 
score. The CDR-SB is used as measurement of efficacy response. A Global Score will also be 
calculated.  

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The CDR will be administered by qualified and trained raters at the site during the Screening – 
Part 2 Visit to determine eligibility for entry into the study based on the global score, and at the 
visits shown in the Schedule of Assessments [Appendix 2]. 
It is important to ensure that a CDR rater is not influenced by knowledge of the ADAS-cog and/or 
MMSE scores. Therefore, for a given subject, the interview-based CDR should be administered 
by one rater, while the ADAS-Cog and/or MMSE should be administered by a different rater at 
the Screening – Part 2 Visit and beyond.  
• A CDR rater should not access the ADAS-cog and/or MMSE scores before administering 
the CDR interview.  
• For each subject, it is highly recommended that the CDR rater remains the same throughout 
the study period.  
• A CDR rater may administer clinical scales except for ADAS-cog and MMSE. 
• A CDR rater may have access to other clinical data except for ADAS-cog and MMSE. 
• A rater may be assigned to administer the CDR for one subject and be assigned to perform 
the ADAS-cog and/or MMSE for another subject.  
7.1.11.5. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) – 
Delayed Memory Index Score 
The RBANS identifies and characterizes abnormal cognitive decline in older adults and serves as 
a screening battery for younger subjects [Randolph et al. 1998]. The entire battery yields scaled 
scores for five cognitive domains: Immediate Memory, Visuospatial/Constructional, Language, 
Attention, and Delayed Memory. The Delayed Memory domain includes List Recall, List 
Recognition, Story Memory, and Figure Recall.  
The Delayed Memory test will be administered by qualified and trained raters at the site during 
the Screening – Part 2 Visit [Appendix 2]. The Delayed Memory Index Score will serve to 
determine eligibility for study enrollment.  
7.1.11.6. Mini-Mental State Examination 
The MMSE is a brief cognitive test assessing general cognitive function that has been used in 
numerous clinical studies of FDA products approved for the treatment of AD. It will be 
administered by qualified and trained raters at the site at the visits shown in the Schedule of 
Assessments [Appendix 2]. MMSE at the Screening – Part 1 Visit can be performed by any 
qualified rater, while at the Baseline Visit and beyond, the same rater for a given subject is 
preferred throughout. 
The MMSE score from the Screening – Part 1 Visit serves to assess subject eligibility for the study. 
The MMSE score from the Baseline Visit is used to stratify eligible subjects in the study. The 
MMSE will also be used as an exploratory measure of efficacy.  
7.1.11.7. Neuropsychiatric Inventory 
The NPI 12-item form is designed to be a self-administered questionnaire completed by caregivers 
about subjects for whom they care. Each of the 12 NPI domains contains a survey question that 

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reflects cardinal symptoms of that domain. Initial responses to each domain question are "Yes" 
(present) or "No" (absent). If the response to the domain question is "No", the informant goes to 
the next question. If "Yes", the informant then rates both the Severity of the symptoms present 
within the last month on a 3-point scale and the associated impact of the symptom manifestations 
on them (i.e., Caregiver Distress) using a 5-point scale. The NPI provides symptom Severity and 
Distress ratings for each symptom reported, and total Severity and Distress scores reflecting the 
sum of individual domain scores. 
The NPI will be administered to the subject by properly qualified and trained site staff at the visits 
shown in the Schedule of Assessments [Appendix 2]. 
7.1.11.8. Quality of Life in Alzheimer’s Disease 
The QoL-AD is a 13-item questionnaire designed to provide both subject and caregiver or study 
partner report of the QoL for subjects with AD. The 15-item QoL-AD includes an additional four 
items, including the ability to take care of oneself, live with others, make own life choices, and 
people who work within the residential setting. 
The QoL-AD will be administered to the subject and caregiver or study partner by properly 
qualified and trained site staff at the visits shown in the Schedule of Assessments [Appendix 2]. 
7.1.11.9. Resource Utilization in Dementia 
The RUD Lite consists of two sections: one about the caregiver (including questions about the 
caregiver, and time spent caring for the subject), and the other one about the subject (including 
questions about the subject’s living arrangements and their healthcare resource usage).  
The RUD Lite will be administered to the subject by properly qualified and trained site staff at the 
visits shown in the Schedule of Assessments [Appendix 2]. 
7.1.12. 
Biomarker Assessments 
7.1.12.1. Cerebrospinal Fluid Biomarkers 
The CSF sub-study will enroll approximately 120 subjects (60 per group). Subjects who participate 
in the CSF sub-study will undergo an LP according to the site’s standard procedures [Appendix 
2]. For each subject, all 3 LPs should be performed within a 2-hour time window. For example, if 
the first LP occurs at 10 AM and the second LP occurs at 12 PM, the third LP must occur between 
10 AM and 12 PM. If the first LP occurs at 10 AM and the second LP occurs at 8 AM, the third 
LP must occur between 8 AM and 10 AM. The actual date and time of CSF collection (not time 
of preparation) will be recorded. LPs should be performed via gravity drip method with atraumatic 
needles to reduce the risk of CSF leakage and post-LP headaches. This technique will allow for 
optimal biomarker collection and analysis. Further details about CSF biomarker sampling are 
provided in the Laboratory Manual. 
Assays will evaluate the effects of study drug on the following CSF biomarkers: p-tau181, p-tau217, 
Aβ40, Aβ42, NfL, t-tau, neurogranin, sTREM2, YKL-40, and GFAP.  
Other potential additional analyses of CSF biomarkers of importance in AD, such as Aβ oligomer 
assay, may be evaluated when assays become available. 

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7.1.12.2. Plasma Biomarkers 
Plasma biomarker samples will be collected at the visits shown in the Schedule of Assessments 
[Appendix 2]. For each subject, sampling for plasma biomarkers should be performed within the 
same 2-hour time window on each of the clinic visits regardless of dosing time and other 
assessments. The actual date and time of each sample will be recorded.  
The approximate amount of blood to be withdrawn is shown in [Table 3]. Further details about the 
handling, storage and transport of all samples will be specified in the Laboratory Manual.  
Assays will evaluate the effects of study drug on the following plasma biomarkers: p-tau181, 
p-tau217, Aβ40, Aβ42, NfL, and GFAP.  
Other potential additional analyses of plasma biomarkers of importance in AD may be evaluated 
when assays become available. 
7.1.12.3. Imaging Biomarkers 
All Subjects will undergo vMRI to evaluate the effects of ALZ-801 on hippocampal volume, 
cortical thickness, and whole brain volume at the visits shown in the Schedule of Assessments 
[Appendix 2].  
The actual date and time of the vMRI will be recorded. Further details about vMRI are provided 
in the MRI Study Manual. 
7.1.13. 
Pharmacokinetic Assessments 
Plasma PK samples will be collected at pre-dose at the visits shown in the Schedule of Assessments 
[Appendix 2]. Additionally, a PK sample at ≥ 1 hour post-dose during clinic visit should be 
collected at Week 65. The actual date and time of each sample will be recorded. The times of study 
drug administration that occurred the night prior to clinic visit and when taken at the study site 
will be recorded. 
The amount of blood to be withdrawn for PK sampling is shown in [Table 3]. Further details about 
plasma PK sampling are provided in the Laboratory Manual.  
CSF PK samples will be taken when CSF biomarker samples are collected from the subjects who 
participate in the CSF sub-study at the visits shown in the Schedule of Assessments [Appendix 2]. 
The actual date and time of CSF collection (not time of preparation) will be recorded. Further 
details about CSF PK sampling are provided in the Laboratory Manual. 
If a subject inadvertently takes the morning ALZ-801 dose prior to the clinic visit, a PK sample 
should still be drawn at the clinic, and the sampling and dosing times will be recorded.  
Plasma samples will be used to evaluate the PK of ALZ-801, tramiprosate, and its metabolite 
3-SPA in all study subjects. CSF samples will be used to evaluate CSF drug levels from subjects 
in the CSF sub-study. All sample collection, processing, storage and shipping instructions are 
provided in the Laboratory Manual.  
7.1.14. 
Total Volume of Blood Collection 
The total volume of blood collection for each subject will vary depending on the duration of study 
treatment and central laboratory requirements. At any time during the study, if any laboratory 

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abnormalities are found for a subject, additional blood may be drawn for safety monitoring. 
[Appendix 2].  
For subjects who complete the study, the total blood volume collected over 52 weeks will be 
approximately 210 mL, and over 78 weeks will be approximately 270 mL. The approximate total 
blood volume to be drawn at each visit is shown in [Table 3]. 
Table 3 
Approximate Blood Volume to be Drawn at Each Study Visit 
Time 
Point 
Chemistry 
Creatinine 
FSH/hCG 
TSH 
B12 
Chemistry 
Creatinine 
Hem. 
Coagulation 
(PT, INR, 
aPTT) 
APOE 
Genotype 
Future 
Potential 
Genomic 
Testing 
Immunology 
(HIV, Hep B S 
Ag, Hep C Ab, 
HCV RNA if 
applicable) 
Plasma 
Biomarkers 
PK 
Total Per 
Visit 
Screening 
– Part 1 
— 
— 
— 
— 
9 mL 
— 
— 
— 
— 
9 mL 
Screening 
– Part 2 
4 mL 
— 
3 mL 
3 mL 
— 
9 mL 
6 mL 
4 mL 
— 
— 
29 mL 
Baseline 
— 
— 
— 
— 
— 
— 
— 
16 mL 
4 mL 
20 mL 
Week 6 
— 
4 mL 
3 mL 
3 mL 
— 
— 
— 
16 mL 
4 mL 
30 mL 
Week 13 
— 
4 mL 
3 mL 
3 mL 
— 
— 
— 
16 mL 
4 mL 
30 mL 
Week 26 
— 
4 mL 
3 mL 
3 mL 
— 
— 
— 
16 mL 
4 mL 
30 mL 
Week 39  
— 
4 mL 
3 mL 
3 mL 
— 
— 
— 
16 mL 
4 mL 
30 mL 
Week 52 
— 
4 mL 
3 mL 
3 mL 
— 
— 
— 
16 mL 
4 mL  
30 mL 
Week 65 
— 
4 mL 
3 mL 
3 mL 
— 
— 
— 
16 mL 
4 mL×2 
34 mL 
Week 78 
— 
4 mL 
3 mL 
3 mL 
— 
— 
— 
16 mL 
4 mL 
30 mL 
Safety 
Follow-up 
at Week 
82 
— 
— 
— 
— 
— 
— 
— 
— 
— 
— 
 
 
Total Blood Volume per Subject over 52 Weeks: 208 mL 
Total Blood Volume per Subject over 78 Weeks: 272 mL 
aPTT: activated partial thromboplastin time; FSH: follicle-stimulating hormone; hCG: human chorionic gonadotropin; 
HCV RNA: hepatitis C virus RNA; Hep B S Ag: hepatitis B surface antigen; Hep C Ab: hepatitis C antibody; Hem: 
hematology; HIV: human immunodeficiency virus; INR: International normalized ratio; PK: pharmacokinetics; 
PT: prothrombin time; TSH: thyroid-stimulating hormone 
 
7.1.15. 
COVID-19 Related Special Consideration 
7.1.15.1. COVID-19 Infection 
If a subject contracts COVID-19 anytime during the study, he/she can start/resume study 
procedures (includes screening and study visits) after fulfilling required criteria per local 
guidelines.  
7.1.15.2. COVID-19 Vaccination 
If a subject receives a COVID-19 vaccine at anytime during the study (after signing the ICF), 
he/she may remain in the study provided that the in-clinic assessment occurs at least six weeks 

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after the first vaccine dose or at least two weeks after the last (including booster) vaccine dose, as 
applicable. 
7.2. 
Procedures by Visit 
The study procedures for each visit are shown in the Schedule of Assessments [Appendix 2]. 
7.2.1. 
Screening – Part 1 Visit – (Up to 13 weeks prior to Baseline Visit)  
Screening – Part 1 Visit will be conducted to determine eligibility status based on MMSE score, 
APOE genotype, prohibited medications, and demographics, and medical history to determine 
initial eligibility of the subject, and to schedule MRI for those subjects who qualify (except for 
APOE genotype if not known yet) based on these criteria.  
Previous evidence of APOE4/4 status may be used as a reference and allow the Screening – Part 1 
and Screening – Part 2 Visits to occur together at the same day if preferable. Alternatively, 
screening procedures may be conducted over several visits provided that the results are available 
to evaluate inclusion and exclusion criteria before randomization. 
The following procedures should be performed in this order: 
• Informed consent for the Screening – Part 1 Visit from subject (or the subject’s legally 
authorized representative with the subject’s assent)  
Note: Signed and dated informed consent for the Screening – Part 1 Visit must be obtained 
before any study procedures listed below are perfrormed. 
• Demographics, medical history 
• MMSE 
• Blood sample for APOE genotype testing 
• Prohibited medications 
• Note: Any untoward medical event that occurs after signing the initial ICF will be recorded 
as an AE. 
If a subject fails the Screening – Part 1 Visit, one re-screening is allowed. Any additional re-
screening (Screening – Part 1) requires sponsor approval.  
7.2.2. 
Screening – Part 2 Visit  
Eligible subjects after the Screening – Part 1 Visit will enter the Screening – Part 2 Visit. 
Procedures may be conducted over several visits during the Screening period provided that the 
results are available before randomization. 
The following procedures will be performed. The recommended order is shown below: 
• Informed consent from subject (or the subject’s legally authorized representative with the 
subject’s assent) and caregiver/study partner 
Note: Signed and dated informed consent for the Screening – Part 2 Visit must be obtained 
before any study procedures listed below are perfrormed. 

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• Vital signs (prior to blood draw), and BP and pulse approximately 15 minutes after last 
blood draw 
• Physical examination  
• Neurological examination  
• Height 
• Weight 
• AE assessment 
• Prior medications taken within 24 weeks prior to the Baseline Visit and all current 
medications 
• RBANS 
• CDR 
• C-SSRS 
• AD diagnostic criteria 
• Evidence of progressive memory loss over the last 12 months per investigator assessment 
as captured on the diagnostic verification form 
• Triplicate 12-lead ECG 
• Safety laboratory tests: clinical chemistry, hematology, and coagulation 
• Serum FSH/hCG test 
• Serum immunology screens for HIV and hepatitis B and C 
• Blood sample for future potential genomic testing 
• Urine for urinalysis  
• Urine for drug screen 
• MRI: For subjects with acceptable screening tests performed as above, MRI will be 
scheduled prior to Baseline Visit.  
If a subject fails the Screening – Part 2 Visit, one re-screening is allowed. Any additional re-
screening (Screening – Part 2) requires sponsor approval. If a subject fails screening due to 
RBANS Delayed Memory score, the subject may be re-screened after discussion with the Sponsor. 
7.2.3. 
Visit 2 – Baseline Visit (Day 1) 
The following procedures will be performed. The recommended order is shown below: 
• Inclusion/exclusion criteria 
• Vital signs (prior to blood draw) 
• Physical examination 
• Weight 

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• AE assessment 
• All medications taken since last visit (whether currently being taken or discontinued) 
• ADAS-Cog 
• MMSE 
• A-IADL 
• DAD 
• NPI 
• QoL-AD 
• RUD Lite 
• C-SSRS 
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine pregnancy test (female subjects of childbearing potential) 
• Randomization to treatment  
• Study drug dosing (exact time of dosing will be recorded). The first dose of study drug 
must be administered only after all the above assessments have been completed. Except on 
clinic visits when the study drug will be administered at the site, the subject will be 
instructed to start taking the study drug BID with morning and evening meals (or within 
30 minutes after each meal) with approximately 10 to 12 hours between doses. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• Study drug dispensing 
• BP and pulse approximately 15 minutes after last blood draw  
For subjects in the CSF sub-study: 
• Site may schedule the LP up to 10 days prior to the Baseline Visit. 
• LPs should be performed via gravity drip method with atraumatic needles to reduce the 
risk of CSF leakage and post-LP headaches. This technique will allow for optimal 
biomarker collection and analysis. 
• Pre-dose CSF sample collection for biomarker assessment (exact time will be recorded) 
• Pre-dose CSF sample collection for PK assessment (exact time will be recorded) 

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7.2.4. 
Visit 3 (Phone) – Week 2 (Day 15 ± 2 days) 
The following items will be assessed via a telephone call 2 weeks after the Baseline Visit (Day 1). 
Ideally, the contact is made directly with the subject himself or herself; the caregiver/study partner 
may provide information to support the subject’s self-report.  
• AE assessment 
• Change in medications since last visit 
7.2.5. 
Visit 4 – Week 6 (Day 43 ± 7 days) 
The following procedures will be performed. The recommended order is shown below: 
• Vital signs (prior to blood draw) 
• Physical examination 
• Weight 
• AE assessment 
• Change in medications since last visit 
• C-SSRS 
• Triplicate 12-lead ECG 
• Safety laboratory tests  
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine for urinalysis  
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug return, accountability, and compliance 
• Study drug dosing (morning only). Exact times of dosing that occurred the night prior to 
clinic visit and during clinic visit will be recorded. The subject will be instructed not to 
take an evening dose on the day of the clinic visit. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• Study drug dispensing 
• BP and pulse approximately 15 minutes after last blood draw 
7.2.6. 
Visit 5 – Week 13 (Day 92 ± 14 days) 
The following procedures will be performed. The recommended order is shown below: 
• Vital signs (prior to blood draw) 
• Physical examination 

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• Weight 
• AE assessment 
• Change in medications since last visit 
• ADAS-Cog 
• MMSE 
• C-SSRS 
• Triplicate 12-lead ECG 
• Safety laboratory tests  
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine for urinalysis  
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug return, accountability, and compliance.  
• Study drug dosing (morning only). Exact times of dosing that occurred the night prior to 
clinic visit and during clinic visit will be recorded. The subject will be instructed not to 
take an evening dose on the day of the clinic visit. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• Study drug dispensing 
• BP and pulse approximately 15 minutes after last blood draw 
7.2.7. 
Visit 6 (Phone) – Week 20 (Day 141 ± 2 days) 
The following items will be assessed via a telephone call 7 weeks after Visit 5. Ideally, the contact 
is made directly with the subject himself or herself; the caregiver/study partner may provide 
information to support the subject’s self-report.  
• AE assessment 
• Change in medications since last visit 
7.2.8. 
Visit 7 – Week 26 (Day 183 ± 14 days) 
The following procedures will be performed. The recommended order is shown below: 
• Vital signs (prior to blood draw)  
• Physical examination 
• Neurological examination  
• Weight 

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• AE assessment 
• Change in medications since last visit 
• ADAS-Cog 
• MMSE 
• A-IADL 
• CDR 
• DAD 
• NPI 
• C-SSRS 
• Single 12-lead ECG (triplicate if corrected QT [QTc] prolongation observed previously or 
in current visit) 
• Safety laboratory tests  
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine for urinalysis 
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug return, accountability, and compliance 
• Study drug dosing (morning only). Exact times of dosing that occurred the night prior to 
clinic visit and during clinic visit will be recorded. The subject will be instructed not to 
take an evening dose on the day of the clinic visit. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• Study drug dispensing 
• BP and pulse approximately 15 minutes after last blood draw 
• MRI (within the visit window) 
7.2.9. 
Visit 8 – Week 39 (Day 274 ± 14 days) 
The following procedures will be performed. The recommended order is shown below: 
• Vital signs (prior to blood draw)  
• Physical examination 
• Weight 
• AE assessment 
• Change in medications since last visit 

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• MMSE 
• C-SSRS 
• Safety laboratory tests  
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug return, accountability, and compliance 
• Study drug dosing (morning only). Exact times of dosing that occurred the night prior to 
clinic visit and during clinic visit will be recorded. The subject will be instructed not to 
take an evening dose on the day of the clinic visit. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• Study drug dispensing 
• BP and pulse approximately 15 minutes after last blood draw 
7.2.10. 
Visit 9 – Week 52 (Day 365 ± 14 days) 
The following procedures will be performed. The recommended order is shown below: 
• Vital signs (prior to blood draw)  
• Physical examination 
• Neurological examination  
• Weight 
• AE assessment 
• Change in medications since last visit 
• ADAS-Cog 
• MMSE 
• A-IADL 
• CDR 
• DAD 
• NPI 
• QoL-AD 
• RUD Lite 
• C-SSRS 

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• Single 12-lead ECG (triplicate if QTc prolongation observed previously or in current visit) 
• Safety laboratory tests  
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine for urinalysis 
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug return, accountability, and compliance 
• Study drug dosing (morning only). Exact times of dosing that occurred the night prior to 
clinic visit and during clinic visit will be recorded. The subject will be instructed not to 
take an evening dose on the day of the clinic visit. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• Study drug dispensing 
• BP and pulse approximately 15 minutes after last blood draw 
• MRI (within the visit window) 
For subjects in the CSF sub-study: 
• MRI should be performed and results available prior to LP. 
• LPs should be performed via gravity drip method with atraumatic needles to reduce the 
risk of CSF leakage and post-LP headaches. This technique will allow for optimal 
biomarker collection and analysis. 
• Site may schedule the LP ± 14 days of the window specified. 
• Pre-dose CSF sample collection for biomarker assessment (exact time will be recorded) 
• Pre-dose CSF sample collection for PK assessment (exact time will be recorded) 
7.2.11. 
Visit 10 – Week 65 (Day 456 ± 14 days) 
The following procedures will be performed. The recommended order is shown below: 
• Vital signs (prior to blood draw)  
• Physical examination 
• Weight 
• AE assessment 
• Change in medications since last visit 
• MMSE 
• C-SSRS 

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• Safety laboratory tests  
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug return, accountability, and compliance 
• Study drug dosing (morning only). Exact times of dosing that occurred the night prior to 
clinic visit and during clinic visit will be recorded. The subject will be instructed not to 
take an evening dose on the day of the clinic visit. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• Study drug dispensing 
• One post-dose plasma PK sample at ≥ 1 hour post-dose (exact time will be recorded) 
• BP and pulse approximately 15 minutes after last blood draw 
7.2.12. 
Visit 11 – Week 78 (Day 547 ± 14 days) [End of Treatment] 
Week 78 visit is considered the end of treatment (EOT) visit. The following procedures will be 
performed. The recommended order is shown below: 
• Vital signs (prior to blood draw)  
• Physical examination 
• Neurological examination  
• Weight 
• AE assessment 
• Change in medications since last visit 
• ADAS-Cog 
• MMSE 
• A-IADL 
• CDR 
• DAD 
• NPI 
• QoL-AD 
• RUD Lite 
• C-SSRS 
• Single 12-lead ECG (triplicate if QTc prolongation observed previously or in current visit) 

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• Safety laboratory tests  
• Pre-dose plasma sample collection for biomarker assessment (exact time of sampling will 
be recorded) 
• Pre-dose plasma sample collection for PK assessment (exact time will be recorded)  
• Urine for urinalysis 
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug return, accountability, and compliance 
• Study drug dosing (morning only). Exact times of dosing that occurred the night prior to 
clinic visit and during clinic visit will be recorded. The subject will be instructed not to 
take an evening dose on the day of the clinic visit. 
Note: Study drug dosing will not occur until all of study procedures listd above are 
perfrormed. 
• BP and pulse approximately 15 minutes after last blood draw 
• MRI (within the visit window)I 
For subjects in the CSF sub-study: 
• MRI should be performed and results available prior to LP. 
• LPs should be performed via gravity drip method with atraumatic needles to reduce the 
risk of CSF leakage and post-LP headaches. This technique will allow for optimal 
biomarker collection and analysis. 
• Site may schedule the LP ± 14 days of the window specified. 
• Pre-dose CSF sample collection for biomarker assessment (exact time will be recorded) 
• Pre-dose CSF sample collection for PK assessment (exact time will be recorded) 
7.2.13. 
Safety Follow-up Visit – Week 82 (Day 574 ± 7 days) [End of Study] 
The Safety Follow-up Visit is considered the end of study (EOS). It will occur approximately 4 
weeks after the Week 78 visit. The following procedures will be performed. The recommended 
order is shown below: 
• Vital signs (prior to blood draw)  
• Physical examination 
• Neurological examination  
• Weight 
• AE assessment 
• Change in medications since last visit 
• C-SSRS 

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7.2.14. 
Early Termination Visit 
Early Termination is also considered an EOT visit. An ET Visit should be completed if a study 
subject discontinues prematurely from the study, or is discontinued from the study by the 
Investigator [see Section 5.5].  
If a study subject prematurely discontinues from study treatment, an ET Visit should be conducted 
at the time of discontinuation. Every effort should be made to conduct all ET procedures as 
specified below and in the Schedule of Assessments [Appendix 2]. Every attempt should be made 
to follow study subjects who have an SAE for 4 weeks after their ET Visit. For subjects who 
continue to be followed for safety, SAEs should continue to be reported as described in [Section 
8.4.2]. 
The following procedures will be performed. The recommended order is shown below: 
• Vital signs (prior to blood draw)  
• Physical examination 
• Neurological examination  
• Weight 
• AE assessment 
• Change in medications since last visit 
• ADAS-Cog 
• MMSE 
• A-IADL 
• CDR 
• DAD 
• NPI 
• QoL-AD 
• RUD Lite 
• C-SSRS 
• Single 12-lead ECG (triplicate if QTc prolongation observed previously or in current visit) 
• Safety laboratory tests  
• Plasma sample collection for biomarker assessment (exact time of sampling will be 
recorded) 
• Plasma sample collection for PK assessment (exact time will be recorded)  
• Urine for urinalysis 
• Urine pregnancy test (female subjects of childbearing potential) 
• Study drug dosing from the last dose prior to the visit (time of dosing will be recorded) 

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• Study drug return, accountability, and compliance 
• BP and pulse approximately 15 minutes after last blood draw 
• MRI (as soon as possible, no later than 2 weeks after the ET visit) 
For subjects in the CSF sub-study: 
• MRI should be performed and results available prior to LP. 
• LPs should be performed via gravity drip method with atraumatic needles to reduce the 
risk of CSF leakage and post-LP headaches. This technique will allow for optimal 
biomarker collection and analysis. 
• Site should schedule the LP as soon as possible, no later than 2 weeks after the MRI. 
• CSF sample collection for biomarker assessment (exact time will be recorded) 
• CSF sample collection for PK assessment (exact time will be recorded) 
7.2.15. 
Retrieved Dropout Visit 
In addition to the ET visit, subjects who discontinue the study drug during the trial will be 
encouraged to remain in the study (off study drug) for continued RDO visits by attending Week 
52 (if applicable) and Week 78 (EOT) visits. The RDO visits will include the following procedures, 
in the recommended order shown below: 
• Vital signs 
• AE assessment 
• Change in medications since last visit 
• ADAS-Cog 
• A-IADL 
• MMSE 
• NPI 
For subjects who prematurely withdraw from the study,, they will be encouraged to return at Week 
78 to finish study-related procedures. 
7.2.16. 
Unscheduled Visit 
Unscheduled Visit, at the discretion of the Investigator, may occur at any time, and appropriate 
procedures and evaluations will be conducted and documented in the eCRF. 
8. 
ADVERSE EVENTS 
8.1. 
Specification of Safety Parameters 
All of the following safety endpoints will be recorded on the eCRF. 
• Occurrence and severity of TEAEs and SAEs 

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• Occurrence of clinically significant abnormal findings in laboratory tests, as determined by 
the Investigator 
• Occurrence of clinically significant abnormal findings in ECG, as determined by the central 
ECG reader 
• Occurrence of abnormal findings in physical examination, including weight and vital signs 
(pulse rate, body temperature, respiratory rate, and BP) 
• Occurrence of abnormal findings in MRI central readings for ARIA-E or ARIA-H 
• Occurrence of abnormal findings in C-SSRS 
• Pregnancy for females of childbearing potential 
8.1.1. 
Definition of Adverse Event (AE) 
Adverse Event: An AE is any untoward medical event that occurs in a subject or clinical 
investigation subject administered a pharmaceutical product, and which does not necessarily have 
to have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including clinically significant abnormal laboratory findings), symptom, or 
disease temporally associated with the use of an investigational product, whether or not considered 
related to the product. Examples include the following: 
• Any treatment-emergent signs and symptoms (events that are marked by a change from the 
subject’s baseline/entry status [e.g., an increase in severity or frequency of pre-existing 
abnormality or disorder]); 
• All reactions from study drug, abuse of drug, withdrawal phenomena, sensitivity, or 
toxicity to study drug; 
• Apparently unrelated illnesses; 
• Injury or accidents; 
• Exacerbations of the underlying disease (indication); 
• Extensions or exacerbations of symptomatology, subjective events reported by the study 
subject, new clinically significant abnormalities in clinical laboratory, physiological 
testing, or physical examination. 
The following is not considered an AE: 
• Elective procedure unless related to the AD diagnosis  
• Pre-existing conditions found as a result of screening procedures 
Treatment-emergent Adverse Event: A TEAE is defined as any new AE that begins, or any 
preexisting condition that worsens in severity, after at least one dose of study treatment has been 
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8.1.2. 
Definition of Serious Adverse Event (SAE) 
Serious Adverse Event: An SAE is defined as any untoward medical event that results in any of 
the following outcomes: 
• Death 
• A life-threatening AE 
Note: This means that the subject is at immediate risk of death at the time of the event; it 
does not mean that the event hypothetically may have caused death if it were more severe. 
• Inpatient hospitalization or prolongation of existing hospitalization 
o Hospitalization is defined by the Sponsor as a full admission to the hospital for 
diagnosis and treatment. This includes prolongation of an existing inpatient 
hospitalization. Hospitalization may include social hospitalization, defined as 
inadequate family support or care at the study subject’s primary residence that results 
in the study subject being admitted to the hospital (i.e., wound care, nutrition). 
o Exceptions: Emergency Room visits that do not result in a hospital admission; 
outpatient surgery; preplanned or elective procedures; and/or protocol procedures. 
These events would not be reported as SAEs unless the event triggering the hospital 
visit is an SAE as defined by other SAE criteria such as life-threatening, resulting in 
disability or incapacity, or per the medical judgment of the Investigator.  
o Any other event fulfilling the definition of serious that develops as a result of the 
in-hospital procedure or extends the hospital stay is an SAE.  
• A persistent or significant disability or incapacity or substantial disruption of the ability to 
conduct normal life functions 
o Disability is defined as a substantial disruption in a person’s ability to conduct normal 
life functions.  
• A congenital anomaly or birth defect 
• Important medical event(s) 
o Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
Pregnancy: In addition, and for the purposes of monitoring, the following should be reported via 
the Pregnancy eCRFs, as appropriate, according to the instructions provided in [Section 8.4.3]. 
• Any occurrence of pregnancy of female study subjects or female sexual partners of male 
study subjects (with or without AEs). 
• Any study subject who becomes pregnant during the study must be withdrawn from 
treatment and will be followed to term and/or other pregnancy outcome.  
• For all female study subjects, a serum pregnancy test must be performed at the Screening 
– Part 2 Visit.  

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• Females of non-childbearing potential are defined as follows: 
o Be postmenopausal with amenorrhea for at least 1 year prior to the first dose and FSH 
serum levels consistent with postmenopausal status, or 
o Have undergone one of the following documented sterilization procedures at least 
6 months prior to the first dose: 
− hysteroscopic sterilization,  
− bilateral tubal ligation or bilateral salpingectomy,  
− hysterectomy, or  
− bilateral oophorectomy. 
• Females of childbearing potential, defined as a premenopausal female capable of becoming 
pregnant, will be included if they are either sexually inactive (sexually abstinent for 14 days 
prior to the first dose and confirm to continue through 28 days after the last dose) or using 
one of the following highly effective contraceptives (i.e., results in < 1% failure rate when 
used consistently and correctly) 14 days prior to the first dose continuing through 28 days 
after the last dose: 
o IUD,  
o surgical sterilization of the partner (vasectomy for 6 months minimum),  
o combined (estrogen or progestogen containing) hormonal contraception associated 
with the inhibition of ovulation (either oral, intravaginal, or transdermal),  
o progestogen only hormonal contraception associated with the inhibition of ovulation 
(either oral, injectable, or implantable),  
o IUS, or 
o bilateral tubal occlusion.  
8.1.3. 
Definition of Unanticipated Problems 
The Office of Human Research Protection (OHRP) considers unanticipated problems (UPs) 
involving risks to participants or others to include, in general, any incident, experience, or outcome 
that meets all of the following criteria:  
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and ICF; and (b) the characteristics of the participant population being studied 
• Related to participation in the research 
• Research placing participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized 
This study will use the OHRP definition of UPs. 

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8.2. 
Classification of an Adverse Event 
8.2.1. 
Severity of Event 
Investigators should assess the severity of AEs according to the National Cancer Institute CTCAE 
version 5.0. In general, CTCAE severity grades are defined as follows: 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL. Instrumental ADL refer to preparing meals, shopping 
for groceries or clothes, using the telephone, managing money, etc.  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
• Grade 4: Life-threatening consequences; urgent intervention indicated.  
• Grade 5: Death related to AE. 
These five categories are based on the Investigator’s clinical judgment, which in turn depends on 
consideration of various factors such as the study subject’s reports, the physician’s observations, 
and the physician’s prior experience. The severity of the AE should be recorded in the appropriate 
section of the eCRF. The evaluation of severity is distinguished from the evaluation of 
“seriousness.” A severe event may not meet the criteria for seriousness and a serious event may be 
evaluated as mild.  
8.2.2. 
Causality 
The following should be considered when assessing causality:  
• temporal associations between the agent and the event; 
• cessation or rechallenge; 
• compatibility with known class effect; 
• known effects of concomitant medications; 
• pre-existing risk factors; 
• a plausible mechanism; and 
• concurrent illnesses. 
The Investigator will assess the causality/relationship between the study drug and the AE. One of 
the following categories should be selected based on medical judgment, considering the definitions 
and all contributing factors: 
Categories of attribution for “Related” 
• Definitely related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. 

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• Possibly related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the study drug). However, the 
influence of other factors may have contributed to the event (e.g., the study subject’s 
clinical condition, other concomitant events). 
Categories of attribution for “Unrelated” 
• Unlikely to be related: There is little evidence to suggest there is a causal relationship. 
There is another reasonable explanation for the event. 
• Not related: An AE will be considered “not related” to the use of the product if any of the 
following tests are met: 
o An unreasonable temporal relationship exists between administration of the product 
and the onset of the AE (e.g., the event occurred either before or too long after 
administration of the product for it to be considered product related). 
o A causal relationship between the product and the AE is biologically implausible (e.g., 
death as a passenger in an automobile accident). 
o A clearly more likely alternative explanation for the AE is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related event). 
8.2.3. 
Expectedness 
Sponsor will be responsible for determining whether an SAE is expected or unexpected. An SAE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information described in the Investigator’s Brochure. 
8.3. 
Time Period and Frequency for Event Assessment and Follow-up 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care, or upon review by a study 
monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate eCRF. Information to be collected includes event description, dates 
and times of onset and resolution, clinician’s assessment of severity, assessment of relatedness to 
study drug (assessed only by those with the training and authority to make a diagnosis), and action 
taken. All AEs occurring while on study must be documented appropriately regardless of 
relationship. 
Any medical condition that is present at the time that the participant is screened will be considered 
as baseline and not reported as an AE. However, if the study participant’s condition deteriorates 
at any time during the study, it will be recorded as an AE. UPs will be recorded in the data 
collection system throughout the study.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.  
The Investigator or designee will record all reportable events with start dates occurring any time 
after informed consent is obtained until the AE has resolved, stabilized, or a new chronic baseline 
has been established. At each study visit, the Investigator or designee will inquire about the 

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occurrence of AE/SAEs since the last visit. Events will be followed for outcome information until 
resolution or stabilization. 
8.4. 
Collecting, Reporting, and Recording Procedures 
8.4.1. 
Collecting, Reporting, and Recording Adverse Events  
All AEs will be collected and recorded in the eCRF for each subject from the day of signed ICF 
until the end of Safety Follow-up Visit. All AEs regardless of relatedness to the study drug, must 
be fully and completely documented on the AE eCRF and in the subject’s medical notes. AEs may 
be volunteered spontaneously by the study subject or discovered by the study staff during physical 
and neurological examinations or by asking an open-ended non-leading question such as: “How 
have you been feeling since you were last asked?” The Investigator will document the nature of 
AE, date of onset of the AE (and time, if known), date of outcome of the AE (and time, if known), 
severity of the AE, action taken with study drug as a result of the AE, assessment of the seriousness 
of the AE, and assessment of the causal relationship of the AE to study drug and/or study 
procedure. All AEs experienced by a subject, irrespective of the suspected causality, will be 
monitored until the AE has resolved, stabilized, or a new chronic baseline has been established, 
abnormal laboratory values have returned to baseline or normal levels, there is a satisfactory 
explanation for the changes observed, the subject is lost to follow-up, or the subject has died. 
All AEs should be recorded individually in the subject’s own words (verbatim) unless, in the 
opinion of the Investigator, the AEs constitute components of a recognized condition, disease, or 
syndrome. In the latter case, the condition, disease, or syndrome should be named rather than each 
individual symptom. 
Concomitant illnesses that existed before entry into the study will not be considered an AE unless 
the illness worsens during the treatment period. Pre-existing conditions will be recorded in the 
eCRF on the Medical History or appropriate page as well as on the SAE Report Form (Medical 
History section). 
8.4.2. 
Collecting, Reporting, and Recording Serious Adverse Events 
In addition to the severity rating, each AE is to be classified by the Investigator as “serious” or 
“not serious.” The seriousness of an event is defined according to the applicable regulations and 
generally refers to the outcome of an event. An SAE is one that meets one or more of the criteria 
listed in [Section 8.2.1]. 
The reporting of SAEs by the Sponsor to the Regulatory Authorities is a regulatory requirement. 
Each Regulatory Authority has established a timetable for reporting SAEs based upon established 
criteria. It is the responsibility of the principal Investigator to report to the Pharmacovigilance and 
Safety Services group and to document the SAE in the eCRF within 24 hours of learning of 
occurrence. 
The SAE (initial and/or follow-up) must be reported by completing the SAE eCRFs, as appropriate 
(refer to the eCRF Completion Guidelines for details). Calls related to fatal/life-threatening SAEs 
should first be directed to the Medical Monitor (refer to the contact list in this protocol for contact 
information). If the Medical Monitor is not available, please contact the Sponsor Medical Officer. 

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Suspected Unexpected Serious Adverse Reaction (SUSAR) is the term used to refer to a serious 
adverse event that occurs in a clinical trial subject, which is assessed by the Sponsor as being 
unexpected and having a reasonable possibility of a causal relationship with the study drug 
(adverse reaction). Reports of these reactions are subject to expedited submission to health 
authorities. 
SAEs are to be reported via the electronic data capture (EDC) system when it is available the SAE 
eCRFs are to be completed with all the current information (refer to the eCRF Completion 
Guidelines for details). 
If the EDC system is unavailable, SAEs can be reported on a paper form. This form (for initial 
and/or follow-up information) and cover sheet will include all available supporting documentation 
relevant to the event. This form is to be emailed (within 24 hours of discovery) to the following: 
SAE REPORTING CONTACT INFORMATION 
Department: Pharmacovigilance and Safety Services 
Company: ICON plc 
Email address: icon-safety-centralreceipt@iconplc.com 
Telephone: +1 281 295 4889 
Fax: +44 (0)208 100 5005 (Europe); +1 215 616 3096 (North America) 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits and phone contacts. All SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the subject is lost to follow-up. In the event of any SAE (other 
than death), the study subject will be instructed to contact the Investigator (or designee) using the 
telephone number provided in the ICF. All study subjects experiencing an SAE will be seen by the 
Investigator or designee as soon as is feasible following the report of the SAE. 
All SAEs will continue to be followed until the end of the study or until such events have resolved 
or the Investigator, in conjunction with the Sponsor, deems them to be chronic or stable.  
SAEs occurring up to the safety follow-up visit should be reported. 
8.4.3. 
Collecting, Reporting, and Recording Pregnancy 
Females of childbearing potential will be required to take pregnancy test before IMP 
administration. The results of the pregnancy testing must be negative in order to be in the study. 
• Females of non-childbearing potential are defined as follows: 
o Be postmenopausal with amenorrhea for at least 1 year prior to the first dose and FSH 
serum levels consistent with postmenopausal status, or 
o Have undergone one of the following documented sterilization procedures at least 
6 months prior to the first dose: 
− hysteroscopic sterilization,  
− bilateral tubal ligation or bilateral salpingectomy,  

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− hysterectomy, or  
− bilateral oophorectomy. 
• Females of childbearing potential, defined as a premenopausal female capable of becoming 
pregnant, will be included if they are either sexually inactive (sexually abstinent for 14 days 
prior to the first dose and confirm to continue through 28 days after the last dose) or using 
one of the following highly effective contraceptives (i.e., results in < 1% failure rate when 
used consistently and correctly) 14 days prior to the first dose continuing through 28 days 
after the last dose: 
o IUD,  
o surgical sterilization of the partner (vasectomy for 6 months minimum),  
o combined (estrogen or progestogen containing) hormonal contraception associated 
with the inhibition of ovulation (either oral, intravaginal, or transdermal),  
o progestogen only hormonal contraception associated with the inhibition of ovulation 
(either oral, injectable, or implantable),  
o IUS, or 
o bilateral tubal occlusion.  
In the event that a female subject or a male subject whose female partner does become pregnant at 
any time through 28 days after the last dose, the Investigator must notify the Medical Monitor or 
designee within 48 hours of learning about the pregnancy. Any study subject that becomes 
pregnant during the study must be withdrawn from treatment and will be followed to term and/or 
other pregnancy outcome. 
The Investigator will be required to complete the Pregnancy Report/Outcome Form and any 
additional documents provided by the Sponsor, follow the subject through the pregnancy term, and 
report to the Medical Monitor or designee the course of the pregnancy, including perinatal or 
neonatal outcome.  
Information on the status of the mother and the child will be forwarded to the Medical Monitor or 
designee using the Pregnancy Report/Outcome Form. Any premature termination of the pregnancy 
will also be reported on this form. 
Although pregnancy occurring in a clinical study is not considered to be an SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded as an AE 
and will be followed as such. A spontaneous abortion is considered to be an SAE. 
8.5. 
Safety Oversight 
This study will have an independent DSMB to oversee subject safety and well-being as detailed in 
[Section 13.5]. In addition, the Study SMC consisting of the Sponsor and contract research 
organization personnel will regularly monitor all aspects of subject safety throughout this study, 
including but not limited to all SAEs, AEs, clinical laboratory data, ECG data, MRI, weight loss, 
and other relevant safety data such as physical examination findings. The Study SMC will meet at 
regular intervals, but no less than monthly to review the emerging safety data. The details of the 

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safety reviews and composition of the SMC will be detailed in the Safety Management Plan and 
the SMC charter, respectively.  
9. 
CLINICAL MONITORING AND COMPLIANCE 
9.1. 
Study Monitoring 
Monitoring procedures approved by the Sponsor will be followed in order to comply with GCP 
guidelines. Remote and on-site checking of the eCRFs for completeness and clarity, cross-
checking with source documents, and clarification of administrative matters will be performed. 
The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
visits, whenever possible, from a representative of the Sponsor who will review the eCRFs and 
source documents. This CRA will be qualified by training, education and experience to monitor 
the progress of sites participating in a clinical study and to ensure that it is conducted, recorded, 
and reported in accordance with the protocol, standard operating procedures (SOPs), GCP and the 
applicable regulatory requirements. 
The interval between monitoring visits will depend on the recruitment rate and the complexity of 
the study. Source data verification (SDV) is an essential part of the monitoring process and the 
Investigator must grant direct access to the original subject’s source documents. The extent and 
nature of monitoring will be described in detail in the monitoring plan. 
In the event of pandemics, alternative monitoring measures may be required if on-site monitoring 
is not permitted and deviations to the study monitoring schedule are necessary. If it is not possible 
to follow the recommended monitoring schedule of onsite visits due to national, local, or 
site-specific restrictions, possible temporary, alternative measures may be implemented to 
maintain proper oversight of the clinical trials. All monitoring deviations related to the pandemic 
should be well-documented to enable appropriate evaluation of the clinical trials. 
Remote SDV will be allowed if the site and Principal Investigator agree to this method of 
monitoring due to pandemic restrictions for onsite monitoring visits. To facilitate remote SDV, 
scans of source document worksheets, assessment forms, and other required documentation will 
be sent to the monitor. Monitors should be trained on remote SDV procedures. No protected health 
information should be scanned and sent to the monitors. If a site allows the monitors to have access 
to their electronic medical records, this should only be available to the monitor during the time of 
the remote visit. Site staff should be available to respond to monitors questions during the remote 
monitoring visit.  
9.2. 
Data Quality Assurance 
The Sponsor’s representatives and regulatory authority inspectors are responsible for contacting 
and visiting the Investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (e.g., eCRFs and other pertinent data), provided that 
subject confidentiality is respected. 
The Study Monitor is responsible for inspecting the eCRFs at regular intervals throughout the 
study to verify the following: adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research. The CRA should 

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have access to study subject medical records and other study-related records needed to verify the 
entries on the eCRFs. The Investigator must agree to cooperate with the CRA to ensure that any 
problems detected in the course of these monitoring visits are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for an 
audit. Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records may occur in order to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
9.3. 
Audits and Inspections 
Regulatory authorities, the IRB/IEC, and/or the Sponsor’s clinical quality assurance group, or its 
designee, may request access to all source documents, eCRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
9.4. 
Archiving Study Documents 
Investigators are required to maintain all study documentation, including documents created or 
modified in electronic format, for at least 15 years following the completion of the study. ICFs and 
adequate records for the receipt and disposition of all study drug must be retained for a period of 
2 years following the date a marketing application is approved for the drug for the indication for 
which it is being investigated, or, if no application is to be filed or if the application is not approved 
for such indication, until 2 years after the investigation is discontinued and the FDA and other 
applicable Regulatory Authorities are notified, unless a longer period is required by applicable law 
or regulation. The Investigator must not discard any records unless given written authorization by 
the Sponsor. 
Investigators are responsible for all study records and the accuracy of the subject data and source 
documents. It is required that Investigators contact the Sponsor or its designee for the following: 
• If the study files are relocated to another facility or the custodian of the records is changed 
at any time while the records are being stored. 
• If the Investigator delegates responsibility for these documents to another person. 
Subject identity information will be maintained for 15 years unless applicable law or regulation 
requires a longer period. 
10. 
STATISTICAL METHODS AND DATA ANALYSIS 
10.1. 
General Considerations 
All statistical processing will be performed using the most current version of SAS® at the time of 
the analysis. Data summaries and listings will be provided for all baseline variables collected 
(subject disposition, all demographic and baseline characteristics, prior and concomitant 
medications, and study drug compliance), all efficacy outcomes, all safety outcomes (deaths, AEs, 
clinical laboratory values, vital signs, ECG assessments, physical examination, and neurological 
examination), all fluid and imaging biomarker outcomes, and CSF and plasma concentrations of 

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ALZ-801, tramiprosate, and 3-SPA. Individual data will be listed and sorted by treatment, subject 
ID, visit, and time point. 
Summary statistics for continuous measurements will be reported using the number of study 
subjects with data values, mean, median, standard deviation (SD), minimum, and maximum. For 
continuous efficacy outcomes 95% confidence intervals will be provided. 
Summary statistics for categorical variables will be reported using the number and percentage of 
study subjects within each level of the variable. 
Baseline values for a given variable are defined as the last values collected prior to the first 
administration of ALZ-801. 
A detailed SAP will be developed and finalized prior to the final database lock, and submitted to 
regulatory authorities per local guidelines. Any analyses after database lock that represent 
deviations from the final approved SAP will be described and justified in the clinical study report. 
10.2. 
Endpoints for Statistical Considerations 
See Section 4.2 for endpoints for statistical considerations. 
10.3. 
Determination of Sample Size 
10.3.1. 
Primary Clinical Outcome 
The total study sample size will be approximately 300 subjects or 150 subjects per treatment group 
(TRT). The sample size was determined based on efficacy data from an AD study with 
tramiprosate, the active agent in ALZ-801. These efficacy data were observed with tramiprosate 
150mg BID, which provides plasma exposures similar to ALZ-801 at 265mg BID, the dose used 
in this study. In the previous 78-week AD study, the APOE4/4 subpopulation treated with 
tramiprosate showed approximately 5.0 point difference from placebo (benefit) on ADAS-Cog 11 
in Mild AD subjects with baseline MMSE scores of 22-26 [Abushakra et al. 2017].  
For the primary efficacy outcome of ADAS-Cog 13, this study is powered to detect a 3.0 point 
difference between ALZ-801 and placebo in the CBL to Week 78. This assumes a within-treatment 
SD of approximately 8.1 in the drug arm and 5.6 in the placebo arm.  
A sample size of 125 subjects per arm will provide approximately 90% power to show a 3-point 
difference between the two treatment groups at a significance level of α = 0.05 (2-sided). The 
drop-out rate is estimated to be approximately 17% at 78 weeks, thus a total of 300 subjects 
enrolled would provide approximately 250 completers or approximately 125 per arm. 
10.3.2. 
Fluid Biomarker Outcome 
CSF Sub-study: For CSF p-tau181, the primary fluid biomarker outcome, sample size 
determination was based on data from two Early AD studies with anti-amyloid antibodies that 
showed significant (13% to 17%) reduction in CSF p-tau over 78 weeks [Tolar et al. 2020b]. We 
therefore assumed the following: 
• Expected baseline mean CSF p-tau181 level in each study arm : 90 to 110 pg/mL 

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• CSF p-tau181 levels at week 78 are expected to be approximately 15% lower than baseline 
in the ALZ-801 arm and to remain stable in the placebo arm, with approximately 
15% difference in CBL between ALZ-801 and placebo  
• Expected difference: ∆ = 15 pg/mL  
• Confidence level: 1-α = 95% 
• 2-sided test on paired samples 
A sample size of 45 subjects per arm provides > 90% power to detect a delta of 15 pg/mL 
(decrease) in CSF p-tau181 at 78 weeks, assuming a SD of 25 pg/mL; and provides power of 
approximately 90% assuming a SD of 30 pg/mL. A total of 60 subjects enrolled would provide 
approximately 48 completers per arm, assuming 20 % drop out rate in the CSF sub-study.  
For plasma p-tau181, it is assumed that the difference in CBL between ALZ-801 and placebo CBL 
will be similar to CSF, namely a 15% difference. A sample size of 125 completers per arm is 
therefore expected to provide > 90% power. 
10.3.3. 
Imaging Biomarker Outcome 
For total hippocampal volume, the power calculation is based on the assumption that the placebo 
arm experiences hippocampal atrophy of 6% while the drug arm experiences approximately 
4% atrophy over 78 weeks. The baseline hippocampal volume is assumed to be approximately 
3100 mm3, the delta is expected to be 68 mm3, with SD of 165 mm3 and 147 mm3 for the drug arm 
and placebo arms, respectively. A sample size of 125 per arm provides > 90% power to detect a 
40% attenuation in hippocampal atrophy compared to placebo at 78 weeks, at a significance level 
of α = 0.05 (2-sided).  
10.4. 
Subject Stratification 
Randomization will be stratified by use of concomitant AD medications (AChEI or none), age 
(50 through 65 years or > 65 years at the Screening – Part 1 Visit), gender, and disease stage 
(MMSE ≤ 26 or > 26 at the Baseline Visit). It is expected that approximately 60% will be AD 
subjects with MMSE 22-26 (inclusive), and approximately 40% will be AD subjects with MMSE 
27–30 (inclusive). 
10.5. 
Study Populations 
The criteria for study populations are described below and in the SAP. A subject classification 
document will be prepared and signed before database lock. 
10.5.1. 
Safety Population 
The Safety population will include all study subjects who received at least one dose of study drug. 
All safety analyses will be conducted on this population. 
10.5.2. 
Modified Intent-to-Treat Population (mITT) 
The mITT population will include all study subjects who have received at least one dose of study 
drug, have one baseline assessment, and have also completed at least one scheduled post-baseline 

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visit with at least one valid post baseline efficacy assessment. All primary and secondary efficacy 
analyses will be conducted on this population.  
10.5.3. 
Per Protocol Population (PPP) 
The PPP will include all study subjects who have completed the study and who are at least 80% 
compliant with study drug for the duration of their study participation. The PPP will be used for 
sensitivity analyses of the primary and secondary efficacy endpoints. 
10.5.4. 
Completer Population (CP) 
The CP will include all randomized subjects who receive at least one dose of study drug, being on 
treatment until Week 78 and have completed the study, regardless of compliance with study drug. 
Subjects who discontinue treatment prematurely will not be included in this population even if 
they adhere to the scheduled visits. The CP will be used for sensitivity analyses of the primary and 
secondary efficacy endpoints. 
10.5.5. 
Pharmacokinetic Population 
The PK population will include all treatment assigned study subjects who have received at least 
one dose of active treatment and have at least one evaluable post-dose PK sample. 
10.5.6. 
Populations for Exploratory Analyses 
Populations for exploratory analyses will be described in the SAP. 
10.6. 
Demographics, Baseline Characteristics, and Other Background 
Information 
10.6.1. 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be listed and summarized overall, by the two 
categories of disease severity, and by region (North America and Europe). 
10.6.2. 
Prior and Concomitant Medications 
All prior and concomitant medications will be listed and summarized by anatomical therapeutic 
chemical classification levels 2 and 4. The number and percentage of subjects who are on drugs 
that could affect behavior and cognition will be summarized. 
10.6.3. 
Subject Disposition 
The number and percentage of study subjects who discontinue will be reported overall and by 
reason for discontinuation. 
10.6.4. 
Study Drug Compliance 
Study drug compliance will be listed. 

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10.7. 
Efficacy Analyses 
10.7.1. 
Hierarchical Hypothesis Testing 
A fixed sequence hierarchical testing approach will be used to test multiple endpoints in a 
predefined order to control the family-wise type 1 errors arising from multiple comparisons. Only 
after a success on the testing of the previous endpoint will the next endpoint be tested.  
If the primary endpoint is significant at the 0.05 significance level, the key secondary endpoints 
will be analyzed using a fixed-sequence step-down procedure to control for multiplicity in the 
secondary endpoints. The three key secondary endpoints (CBL to week 78 in A-IADL, CDR and 
DAD) will be tested in sequential order at significance levels of 0.05. The order of testing will be 
A-IADL, followed by CDR-SB, followed by DAD [Figure 9]. The hypothesis testing for the 
additional clinical endpoints will be considered exploratory. 
The order of the hierarchical tests is: 
1. Primary efficacy endpoint: CBL to Week 78 in ADAS-Cog 13  
2. Key secondary endpoint: CBL to Week 78 in A-IADL 
3. Key secondary endpoint: CBL to Week 78 in CDR-SB 
4. Key secondary endpoint: CBL to Week 78 in DAD 

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Figure 9  
Hierarchical Testing Process in Study ALZ-801-AD301 
 
ADAS-Cog 13: 13-item Alzheimer’s Disease Assessment Scale – cognitive subscale; A-IADL: Amsterdam 
Instrumental Activities of Daily Living; CDR-SB: Clinical Dementia Rating – Sum of Boxes; DAD: Disability 
Assessment for Dementia 
10.7.2. 
Primary Efficacy Analysis 
Unless otherwise specified, all primary efficacy analyses will be performed using the mITT 
population. Analyses of the primary endpoint of ADAS-Cog 13 will be performed with a 
likelihood based linear MMRM on treatment observed case (OC) data. The OC data set will consist 
of actual observations recorded at each visit during the double-blind treatment period and no 
missing data will be imputed. The model terms will include treatment, the stratification factors of 
use of concomitant AD medications (AChEI or none), age group (50 through 65 years or > 65 at 
the Screening – Part 1 Visit), gender, disease severity based on MMSE at the Baseline Visit, 
baseline ADAS-Cog 13 values, visit (VISIT), and treatment by visit interaction. The visit variable 
will be used to define the within-subject repeated measures over time. The least squares mean 
(LSM) for each treatment at each visit will be generated together with its 95% confidence interval, 
and the LSM difference between the active treatment and placebo will also be calculated; together 

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with its standard error, and the 2-sided 95% confidence interval. For the primary endpoint at 
78 weeks, treatment comparisons will be done at the 0.05 significance level.   
All data collected during the study will be used in the statistical analysis. Additional details will 
be described in the final SAP. Sensitivity testing of the primary endpoint will include MMRM 
analyses for the PPP, and the CP.   
For subjects who discontinue treatment prior to trial completion, every attempt will be made to 
have them continue with clinic visits and study assessments. Particular attention will be given to 
collecting Week 78 ADAS-Cog 13 assessments, regardless of when subjects discontinued 
treatment. These data from retrieved dropouts data will be used to impute missing data using 
multiple imputation method as a sensitivity analysis for the primary endpoint. This method 
assumes that the best reflection of what happened to the early dropout patients at Week 78 are the 
retrieved dropouts. For those subjects who terminate treatment prematurely but have Week 78 
assessments, and the intermediate missing off-treatment data will be imputed by interpolation for 
analyses. 
10.7.3. 
Secondary Endpoint Analyses 
The same MMRM method applied to the primary efficacy endpoint will be used to evaluate the 
between-treatment difference for the key secondary endpoints. No explicit missing data imputation 
will be performed except for that which is inherent in the MMRM. Differences between treatments, 
the p-values, and the 2-sided 95% CIs will be calculated within the framework of MMRM. 
Note that only the post-baseline visits on which the endpoints are scheduled to be measured will 
be included in the model. The secondary endpoint analyses will be analyzed using the mITT 
population, PPP, and CP. 
All other secondary efficacy endpoints will be analyzed using either MMRM, analysis of 
covariance (ANCOVA), or nonparametric inferential statistical methods and will be described in 
the SAP. 
10.7.4. 
Subgroup Analyses 
Efficacy analyses in the sub-groups of subjects with baseline MMSE ≤ 26 or > 26 may be 
performed using the MMRM method.  
It is expected that approximately 80% of all subjects would be on stable doses of AChEI, 
approximately 90% in Mild AD and 70% in MCI. It is expected that the use of AChEI will be 
similar between the ALZ-801 and placebo arms. Subgroup analysis of efficacy by use of AChEI 
will be performed. 
10.8. 
Biomarker Analyses 
10.8.1. 
Cerebrospinal Fluid Biomarker Analyses 
Serial CSF samples from the baseline, Week 52 and Week 78 visits will be stored and batched for 
analyses. Samples from multiple subjects and study sites will be analyzed in batches, at a single 
central laboratory, using standardized procedures and validated assays, or well performing, widely 
accepted CSF assays if not validated.  

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The CSF biomarker analyses will be performed on subjects (CSF sub-study) who have a baseline 
and at least one post-baseline CSF biomarker sample. The change from baseline and percent 
change from baseline in CSF biomarkers will be summarized by visit and treatment group. The 
between groups comparisons of change from baseline in each CSF biomarker will be analyzed 
using an MMRM model with treatment, the use of concomitant AD medications (AChEI or none), 
age group (50 through 65 years or > 65 years from the result of the Screening – Part 1 Visit), 
gender, disease severity based on MMSE at the Baseline Visit, baseline CSF biomarker level, visit, 
and treatment by visit interaction in the model. 
10.8.2. 
Plasma Biomarker Analyses 
Serial plasma samples from screening and each subsequent visit will be stored and batched, under 
GLP conditions, for analyses. Samples from multiple subjects and study sites will be analyzed at 
a single central laboratory using validated assays, or well performing, widely accepted plasma 
assays if not validated. 
The plasma biomarker analyses will be performed on subjects who have a baseline and at least one 
post-baseline biomarker sample. The change from baseline and percent change from baseline in 
plasma biomarkers will be summarized by visit and treatment group. The change from baseline in 
each plasma biomarker will be analyzed using an MMRM model. The model will include 
treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 
years or > 65 years at the Screening – Part 1 Visit), gender, disease severity based on MMSE at 
the Baseline Visit, baseline plasma biomarker level, visit, and treatment by visit interaction in the 
model. 
10.8.3. 
Imaging Biomarker Analyses 
Analysis of hippocampal volume and cortical thickness will be performed using the same MMRM 
approach described for analysis of the primary clinical endpoint. The MMRM model will include 
treatment, the use of concomitant AD medications (AChEI or none), age group (50 through 65 
years or > 65 years at the Screening – Part 1 Visit), gender, disease severity based on MMSE at 
the Baseline Visit, baseline plasma biomarker level, visit, and treatment by visit interaction. The 
MRI magnet strength (1.5 or 3 Tesla) will also be included as a covariate in the model. 
The imaging biomarker analyses will be performed on the subjects who have a baseline and at 
least one post-baseline vMRI assessment. 
10.9. 
Tests of Cognition and Function 
Tests of cognition and function will be evaluated using the same approach described for the 
analysis of the fluid biomarkers. 
10.10. 
Safety Analyses 
Continuous safety data will be analyzed descriptively with summary statistics; and categorical 
safety data will be summarized using counts and percentages. The safety assessments will also 
include analyses of MRI findings (ARIA-E and ARIA-H) based on the central readings. 

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10.10.1. 
Adverse Events 
For data summarization, AEs will be classified into standard terminology using the Medical 
Dictionary for Regulatory Activities (MedDRA), and reported by system organ class and preferred 
term. 
TEAEs are defined as AEs that either started or worsened after administration of the first dose of 
study drug. 
The number and percentage of the following types of AEs will be reported: 
• TEAEs; 
• TEAEs that led to study discontinuation;  
• TEAEs related to study drug; 
• TEAEs by maximum severity;  
• SAEs; and  
• SAEs related to study drug. 
A listing of AEs will also be compiled. 
10.10.2. 
Clinical Laboratory Evaluations 
Clinical laboratory test results will be summarized and listed. Summary statistics for the CBL and 
the percentage out of range (normal reference range as established by the central laboratory) will 
be presented for each post-baseline time point. 
Clinically notable changes in LFTs will be summarized and listed for individual study subjects. 
The criteria for clinically significant LFT results are as follows: 
• ALT > 5 × ULN,  
• AST > 5 × ULN, or 
• TBL > 3 × ULN 
10.10.3. 
MRI Safety Evaluations 
The Screening – Part 2, Week 26, Week 52, and Week 78 MRIs will be assessed for occurrence 
of ARIA-E, ARIA-H, and macrohemorrhage by the central imaging provider (Bioclinica). Listings 
of these findings will be provided and summarized using descriptive statistics. 
10.10.4. 
Vital Signs 
Changes from baseline in vital sign measurements will be summarized. 
Clinically notable systolic and diastolic BP while sitting will be listed for individual study subjects 
and summarized using descriptive statistics. Clinically notable criteria are indicated in [Table 4]. 

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Table 4 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic BP 
> 30 mm Hg increase from baseline 
> 30 mm Hg decrease from baseline 
Diastolic BP 
> 20 mm Hg increase from baseline 
> 20 mm Hg decrease from baseline 
Pulse rate 
> 120 beats/min and an increase in pulse 
rate of ≥ 15 beats/min from baseline 
< 40 beats/min and a decrease in pulse rate of 
≥ 15 beats/min from baseline 
Body temperature 
> 39.0°C (≥ 102.2°F) 
< 35.0°C (≤ 95.0°F) 
BP: blood pressure 
10.10.5. 
Electrocardiograms 
All ECG intervals and durations will be reviewed for notable abnormalities according to the 
criteria in [Table 5]. Clinically notable abnormalities and ECG findings considered to be clinically 
significant will be listed. The number and percentage of study subjects who have a clinically 
notable ECG interval abnormality or other clinically significant ECG finding will be summarized. 
Assessment of clinically notable abnormalities will be based on the average of triplicate ECG 
readings. The criteria for QTcF are based on the upper threshold in elderly subjects [Reardon & 
Malik, 1996], and from other recent AD studies. 
Table 5 
Criteria for Clinically Notable Electrocardiogram Interval Abnormalities 
Interval/Duration 
High Threshold 
Low Threshold 
PR interval 
PR interval ≥ 220 msec 
PR interval ≤ 120 msec 
QRS duration 
QRS duration ≥ 120 msec and an increase in QRS duration 
of ≥ 20 msec from baseline 
– 
QT interval 
QT interval > 500 msec 
– 
QTcF interval 
 
QTcF interval > 500 msec and an increase in QTcF interval 
of ≥ 60 msec from baseline 
– 
QRS duration: interval from the beginning of the Q wave to the termination of the S wave, representing the time for 
ventricular depolarization; QT interval: interval representing the time for both ventricular depolarization and 
repolarization to occur; QTcF: corrected QT interval using Fridericia’s correction; PR interval: time from the onset 
of the P wave to the start of the QRS complex. 
10.10.6. 
Physical Examination 
The number and percentage of subjects with abnormal physical examination findings will be 
summarized. Analyses of subjects with weight loss of > 6% from baseline will be provided for 
subjects with weight loss without intentional dieting. 
10.10.7. 
Neurological Examination 
The number and percentage of subjects with abnormal neurological examination findings will be 
summarized.  
10.10.8. 
Deaths 
A listing of reported deaths, or SAEs of deaths and their narratives, will be provided. 

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10.11. 
Pharmacokinetic Analyses 
10.11.1. 
Descriptive Pharmacokinetic Analysis 
The plasma and CSF concentrations of ALZ-801, tramiprosate, and the metabolite (3-SPA) will 
be summarized and tabulated. 
10.12. 
Interim Analyses 
No formal interim efficacy analyses will be performed. Regular safety analyses will be performed 
by the DSMB and SMC, according to the schedule in their respective charters.  
10.13. 
Measures to Minimize Bias 
10.13.1. 
Enrollment/ Randomization/ Blinding Procedures 
Subjects who meet the enrollment criteria will be randomly assigned to receive either ALZ-801 or 
placebo in a 1:1 ratio. The study will be conducted in a double-blinded manner. Unless otherwise 
specified, the Investigator and site personnel, study subjects, and Sponsor personnel will be 
unaware of whether subjects receive ALZ-801 or placebo until the study is formally unblinded.  
During the conduct of the study, the personnel who perform the unblinded safety analysis for the 
DSMB will be shielded from the study team, by a firewall and other appropriate procedures. These 
steps are further described and documented in the DSMB charter. 
10.13.2. 
Blinding at the Study Site and Sponsor Personnel 
Study treatment group information (active drug vs placebo) will remain blinded to the subject and 
the study team at the study site.  
During this study, Sponsor staff and designees will be blinded to treatment allocation, except as 
described in this section. The periodic SMC reviews will be performed in a blinded manner.  
Procedures for emergency unblinding are described in Section 10.13.3. These procedures ensure 
that the study monitoring staff from the Clinical Research Organization, the Investigator, and other 
site staff do not have premature access to the study subjects’ treatment assignments. Upon 
notification of an unblinding event, the Sponsor will assess the need for potentially removing the 
unblinded site personnel from the trial. 
10.13.3. 
Breaking the Study Blind/Participant Code 
In the event of a medical emergency, where knowledge of a subject’s treatment assignment 
(ALZ-801 or placebo) must be known to facilitate appropriate medical treatment, the site 
investigator may break the blind to obtain immediate access to the subject’s treatment assignment. 
The responsibility to break the treatment code in emergency situations resides solely with the 
investigator. Each instance of unblinding must be reported to Sponsor within 24 hours. 
The Medical Monitor or designee may break the blind in the event of an SAE that requires 
expedited reporting to regulatory authorities. Any other requests to reveal a subject’s treatment 
identity, apart from a medical or safety need identified by the investigator, must be approved by 
the Medical Monitor or designee. Upon notification of an unblinding event, the Sponsor will assess 

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the need for potentially removing the unblinded personnel from the trial. If a subject’s treatment 
identity is unblinded, the subject may be withdrawn from the study and may complete the ET visit. 
Details of the unblinding process to be followed are provided in the study manual(s). In the event 
that the treatment assignment is unblinded, Sponsor or designee will be notified immediately that 
the blind has been broken, and will be informed of the actual treatment assignment as required for 
SAE reporting or other specific reason. Other study team personnel will remain blinded unless 
unblinding is necessary for the safety of the subject. 
The Investigator or designee is responsible for ensuring that unblinding procedures are followed, 
and that access is only available to the relevant staff for appropriate safety management. 
11. 
DATA HANDLING AND RECORD KEEPING 
11.1. 
Data Collection and Management 
Data collection is the responsibility of the clinical study staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
If source documents are used, they should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Data reported in the eCRF, if derived from source documents, should be 
consistent with the source documents or the discrepancies should be explained and maintained in 
the participant’s official study record. 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into a 21 CFR Part 11-compliant data capture system. The 
data system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
11.2. 
Access to Source Data/Case Report Forms 
Every clinical site participating in this study is required to submit clinical data for each enrolled 
study subject via an EDC system using an eCRF. Site personnel will be trained on the EDC system 
before receiving access to it. The Sponsor or its designee is responsible for maintaining a record 
of all system users. The study subjects will not be identified by name on any study documents to 
be collected by the Sponsor. 
All clinical information requested in this protocol will be recorded on the eCRFs provided by the 
Sponsor (or via other data collection methods, such as electronic laboratory data transfer). The 
Principal Investigator is responsible for reviewing all eCRFs, verifying them for accuracy, and 
approving them via an electronic signature. Copies of the completed eCRFs, saved to disk in PDF 
format, will be sent to the Investigator’s site at the completion of the study. 
The Investigator must make study data accessible to the Site Monitor (CRA), other authorized 
representatives of the Sponsor, Ethics Committees, and Regulatory Agency inspectors upon 
request. A file for each subject must be maintained that includes the signed ICF and the 
Investigator’s copies of all source documentation related to that subject. The Investigator must 

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ensure the reliability and availability of source documents from which the information on the eCRF 
was derived. 
11.3. 
Subject Confidentiality and Data Protection 
Subject confidentiality and data protection will be handled according to applicable local laws 
including the General Data Protection Regulation (European Union [EU] 2016/679). Furthermore, 
the Investigator must ensure that each subject’s privacy is protected as described below. On the 
eCRFs or other documents submitted to the Sponsor or its designee, subjects must be identified by 
no more than a Subject Identification Number. This coded information and/or samples submitted 
to the Sponsor may also be transferred to other countries including the US and the UK, where 
personal data protection laws may not be as strict as in the EU. The Sponsor and its designees are 
obligated to respect confidentiality and to ensure an adequate standard of personal data protection. 
Documents that are not for submission to the Sponsor and/or its designee (e.g., signed ICFs) should 
be kept in strict confidence by the Investigator in compliance with applicable regulations and ICH 
GCP Guidelines. The Investigator and institution must permit authorized representatives of the 
Sponsor (and/or its designee), representatives of regulatory agencies, and the IRB/IEC direct 
access to review the subject’s original medical records for verification of study-related procedures 
and data. Direct access includes examining, analyzing, verifying, and reproducing any records and 
reports that are needed for the evaluation of the study. The Investigator is obligated to inform the 
subject in the ICF that the above named representatives may review the subject’s study-related 
records. 
12. 
QUALITY MANAGEMENT 
The Sponsor and designee are implementing and maintaining quality assurance (QA) and quality 
control (QC) systems with written SOPs to ensure that studies are conducted and data are 
generated, documented, recorded, and reported in compliance with the protocol, GCP and 
applicable regulatory requirement(s). Where applicable, the QA and QC systems and written SOPs 
of the clinical research organization will be applied. 
The Sponsor or Sponsor’s designee may arrange to audit the study at any or all study sites and 
facilities. The audit may include on-site review of regulatory documents, eCRFs and source 
documents. Direct access to these documents will be required by the auditors. 
13. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS 
13.1. 
Ethical Conduct of the Study 
The study will be conducted according to the protocol and in compliance with GCP, with the 
Declaration of Helsinki (as amended October 2013), and with other applicable regulatory 
requirements.  
13.2. 
Informed Consent 
At Screening – Part 1 Visit, prior to stated procedures (APOE genotyping, MMSE, demographics, 
medical history and prohibited medications) are performed, the site staff will obtain the signed ICF 

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from each participant. Complete signed ICF from subject and caregiver/study partner will be 
obtained prior to any other procedures at the Screening – Part 2 Visit or at the Screening – Part 1 
visit if APOE4/4 status is known or confirmed using a rapid genotype test. A separate ICF will be 
obtained for those subjects who will participate in the CSF sub-study. The Principal Investigator 
and the Sponsor or designee must agree upon the format and content of the ICF before it is 
submitted to the IRB or IEC for approval. A written IRB/IEC-approved ICF, any other required 
forms to meet local or country-specific regulations must be obtained from each subject before any 
study-related activities are conducted. 
The Investigator or Investigator’s designee will explain the nature of the study to the subject, the 
subject’s caregiver/study partner, and the subject’s legally authorized representative (if 
applicable), and answer all questions regarding this study. Signed and dated written informed 
consent must be obtained from (a) the subject or (b) the subject’s legally authorized representative 
with the subject’s assent if the subject is unable or is deemed not competent, and in accordance 
with local regulations. The subject’s caregiver/study partner must also consent to participate in the 
study. The Investigator must retain all original signed and personally dated ICFs (together with 
any subsequent IRB/IEC-approved amended versions) in the subject’s file. A copy of the original 
signed and dated ICF (and any amendments) must be given to the subject and caregiver/study 
partner.  
Subjects will be informed of findings from earlier or concurrent ALZ-801 clinical and nonclinical 
studies (including AEs) if it is determined that these could potentially affect the subject’s 
willingness to participate or continue in the study. Depending on the nature, severity, and 
seriousness of these AEs, the ICF may be amended as deemed appropriate. 
13.3. 
Regulatory Approval 
The Sponsor or its designee will make the appropriate applications to the Regulatory Authority for 
regulatory approval of the study and, if necessary, approval to import relevant study materials. The 
study will not start until all required regulatory approvals have been obtained. 
13.4. 
Ethics Committee Approval 
The Investigator at the site and/or Sponsor (or designee) are responsible for obtaining IRB/IEC 
approval for the final protocol, ICF, advertisements to recruit subjects, and/or any other subject 
facing documents. Written approval of these documents must be obtained from the IRB/IEC before 
any subject is enrolled at a site. 
The Principal Investigator and/or Sponsor (or designee) are responsible for the following 
interactions with the IRB/IEC: 
• Obtaining IRB/IEC approval for any protocol amendments and ICF revisions before 
implementing the changes; 
• Providing the IRB/IEC with any required information before or during the study; 
• Submitting progress reports to the IRB/IEC, as required, during the conduct of the study; 
requesting re-review and approval of the study, as needed; providing copies of all IRB/IEC 
re-approvals and relevant communication to the Sponsor; and 

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• Notifying the IRB/IEC of all serious and unexpected AEs related to the study drug reported 
by the Sponsor, as required by local regulations. 
13.5. 
Data and Safety Monitoring Board Review and Approval 
The DSMB is a group of experienced AD clinical, drug safety, and statistical experts that advises 
the National Institute on Aging (NIA) Director, the Sponsor, and the study investigators. DSMB 
members serve in an independent capacity and provide their expertise and recommendations to the 
NIA and Sponsor, while being completely independent of the Sponsor, study Investigators, and 
the NIA. DSMB members will have no financial, scientific, or other conflict of interest with the 
trial. 
The purpose of the DSMB in this study is to provide oversight of subject safety and well-being 
during the study conduct while maintaining strict data confidentiality. The DSMB responsibilities 
are to review and discuss the study data, and provide recommendations on the following: 
• Overall conduct of the trial, including screening, enrollment, drop-out rates, and reasons 
for subject drop-out 
• Aggregate and individual subject data related to safety, tolerability, and data integrity 
• Recommendations to the Sponsor regarding continuation, termination or other 
modifications to the study, based on observed adverse effects of ALZ-801 
• Evaluation of emergent data from other ALZ-801 studies or other AD clinical trials, that 
may impact subject safety, change the benefit risk profile of ALZ-801, or alter the ethics 
of the trial design 
• Protection of subjects’ safety and well-being throughout the study 
• Additional recommendations, as appropriate, if unexpected findings arise 
• Advice to the NIA leadership on any aspect of the study 
13.6. 
Protocol Amendments and Study Termination 
Protocol amendments must be made only with the prior approval of the Sponsor and/or designee 
and the applicable regulatory authorities, as appropriate. The IRB/IEC must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the study subjects 
or the conduct of the study. The Investigator must send a copy of the approval letter from the 
IRB/IEC to the Sponsor and/or designee. 
The study may be terminated in accordance with the terms of the Clinical Trial Agreement (CTA). 
The Investigator should notify the IRB/IEC in writing of the study’s completion or ET and send a 
copy of the notification to the Sponsor and/or designee. Regulatory notifications of study 
termination or completion will be filed in accordance with applicable local regulations. 

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13.7. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki (http://private.ich.org/LOB/media/MEDIA482.pdf) The study will conform to ICH GCP 
Guidelines and all applicable FDA, Health Canada, EU, and national laws and regulations. 
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of the subjects. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, Investigator’s Brochure, ICF, advertisements (if 
applicable), written information given to the subjects, safety updates, annual progress reports, and 
any revisions to these documents will be provided to the IRB/IEC by the Investigator and/or 
Sponsor (designee). 
13.8. 
Finance, Insurance, and Indemnity 
Finance, insurance, and indemnity terms are delineated in the CTA. 
14. 
PUBLICATION PLAN 
Publication rights are delineated in the CTA.  
15. 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence by the Sponsor or 
pharmaceutical industry is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this study will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the study. The 
study leadership has established policies and procedures for all study group members to disclose 
all conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest. 

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16. 
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Viola KL, Klein WL (2015). Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, 
and diagnosis. Acta Neuropathol. 129:183-206.  
 
Wang L, Gao T, Cai T, et al. (2020).Cerebrospinal fluid levels of YKL-40 in prodromal 
Alzheimer’s disease. Neurosci Lett. 715:134658. doi: 10.1016/j.neulet.2019.134658. 
 
Winter JE, MacInnes RJ, Nowson CA (2017). The influence of age and BMI and all-cause 
mortality association: a meta-analysis. J Nutr Health Aging. 21:1254-8. 
 
 
 

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17. 
APPENDIX 
Appendix 1 
Key Personnel 
Function 
Personnel and Contact Information 
24-hour Contact for Serious Adverse 
Events (SAEs) 
 
See [Section 8.4.2 Collecting, Reporting, and 
Recording Serious Adverse Events] 
Please fax or email the SAEs to: 
ICON plc  
Department: Pharmacovigilance and Safety Services 
South Country Business Park 
Leopardstown 
Dublin 18 
Ireland 
Telephone: +1 281 295 4889 
Fax: +44 (0)208 100 5005 
Email: icon-safety-centralreceipt@iconplc.com 
Medical Monitor/Study Physician 
Heber  Varela, MD 
Email: Heber.Varela@iconplc.com 
Backup Medical Monitor/Study Physician 
Dominika Brykajlo, MD 
Email: Dominika.Brykajlo@iconplc.com 
Sponsor Study Physician 
and Medical Officer 
Susan Abushakra, MD 
Chief Medical Officer 
111 Speen Street, Suite 306 
Framingham, MA 01701  
USA 
Telephone: +1-650-438-7637 
Email: susan.abushakra@alzheon.com 
 

Protocol ALZ-801-AD301 (APOLLOE4) Amendment 2 
 
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Appendix 2 
Schedule of Assessments 
 
Screening* 
 
Double-Blind Treatment 
 
Visit (V) 
V 1a 
V 1b 
V 2 
V 3 
Phone 
V 4 
V 5 
V 6 
Phone 
V 7 
V 8 
V 9 
V 10 
V 11 
EOT 
ET 
Safety 
FU 
EOS 
Visit Time 
Scr – 
Part 1 
Scr – 
Part 2 
Bsl 
Day1 
W 2 
Day15  
W 6 
Day43 
W 13 
Day92  
W 20 
Day141  
W 26 
Day183 
W 39 
Day274  
W 52 
Day365 
W65 
Day456 
W 78 
Day547 
TBD 
W 82 
Day574 
Window 
Up to -13 
weeks 
– 
– 
± 2 d 
± 7 d 
± 14 d 
± 2 d 
± 14 d 
± 14 d 
± 14 d 
± 14 d 
± 14 d 
– 
± 7 d 
Informed consent/ 
caregiver/study partner 
consent1 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE Score 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Prohibited medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
APOE testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs2 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Neurological 
examination 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AD diagnostic criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
RBANS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Evidence of 
progressive memory 
loss over the last 12 
months 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead ECG3 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Future potential 
genomic testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol ALZ-801-AD301 (APOLLOE4) Amendment 2 
 
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Screening* 
 
Double-Blind Treatment 
 
Visit (V) 
V 1a 
V 1b 
V 2 
V 3 
Phone 
V 4 
V 5 
V 6 
Phone 
V 7 
V 8 
V 9 
V 10 
V 11 
EOT 
ET 
Safety 
FU 
EOS 
Visit Time 
Scr – 
Part 1 
Scr – 
Part 2 
Bsl 
Day1 
W 2 
Day15  
W 6 
Day43 
W 13 
Day92  
W 20 
Day141  
W 26 
Day183 
W 39 
Day274  
W 52 
Day365 
W65 
Day456 
W 78 
Day547 
TBD 
W 82 
Day574 
Window 
Up to -13 
weeks 
– 
– 
± 2 d 
± 7 d 
± 14 d 
± 2 d 
± 14 d 
± 14 d 
± 14 d 
± 14 d 
± 14 d 
– 
± 7 d 
Safety lab tests4 
 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Serum FSH/hCG test5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Immunology (HIV, 
Hep B S Ag, Hep C 
Ab, HCV RNA if 
applicable) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
 
Urine Pregnancy test6 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Urine drug screen 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MRI7 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
Inclusion/ 
exclusion criteria 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
ADAS-Cog 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
 
A-IADL 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
CDR8 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
DAD 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
NPI 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
QoL-AD 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
RUD Lite 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
C-SSRS9 
 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
CSF sampling10 
 
 
X 
 
 
 
 
 
 
X 
 
X 
X 
 
Plasma biomarkers 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
PK sample collection11 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 

Protocol ALZ-801-AD301 (APOLLOE4) Amendment 2 
 
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Screening* 
 
Double-Blind Treatment 
 
Visit (V) 
V 1a 
V 1b 
V 2 
V 3 
Phone 
V 4 
V 5 
V 6 
Phone 
V 7 
V 8 
V 9 
V 10 
V 11 
EOT 
ET 
Safety 
FU 
EOS 
Visit Time 
Scr – 
Part 1 
Scr – 
Part 2 
Bsl 
Day1 
W 2 
Day15  
W 6 
Day43 
W 13 
Day92  
W 20 
Day141  
W 26 
Day183 
W 39 
Day274  
W 52 
Day365 
W65 
Day456 
W 78 
Day547 
TBD 
W 82 
Day574 
Window 
Up to -13 
weeks 
– 
– 
± 2 d 
± 7 d 
± 14 d 
± 2 d 
± 14 d 
± 14 d 
± 14 d 
± 14 d 
± 14 d 
– 
± 7 d 
Time of last dose prior 
to clinic visit 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Study drug return, 
accountability, 
compliance 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Study drug dosing on 
site12 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Dispense study drug13 
 
 
X 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
ADAS-Cog: Alzheimer’s Disease Assessment Scale – cognitive subscale; A-IADL: Amsterdam Instrumental Activities of Daily Living; APOE: apolipoprotein 
E; BP: blood pressure; Bsl: baseline; CDR: Clinical Dementia Rating; CSF: cerebrospinal fluid; C-SSRS: Columbia-Suicide Severity Rating Scale; CT: 
computed tomography; d: Day; DAD: Disability Assessment for Dementia; ECG: electrocardiogram; EOS: end of study; EOT: end of treatment; ET: early 
termination; FSH: follicle-stimulating hormone; FU: Follow-up; hCG: human chorionic gonadotropin; HCV RNA: hepatitis C virus RNA; Hep B S Ag: 
hepatitis B surface antigen; Hep C Ab: hepatitis C antibody; HIV: human immunodeficiency virus; LP: lumbar puncture; MMSE: Mini-Mental State 
Examination; MRI: magnetic resonance imaging; NPI: Neuropsychiatric Inventory; PK: pharmacokinetics; QoL-AD: Quality of Life in Alzheimer’s Disease; 
QTc: corrected QT (interval); Scr: Screen; RBANS: Repeatable Battery for the Assessment of Neuropsychological Status; RUD Lite: Resource Utilization in 
Dementia Lite version; TBD: to be determined; V: visit; W: week. 
* Previous evidence of APOE4/4 status may be used as a reference and allow subjects to combine Screening – Par 1 Visit and Screening – Part 2 Visit together 
at the same day if the site and subject prefer. Screening procedures may be conducted over several visits during the Screening period provided that the results 
are available to evaluate inclusion and exclusion criteria before randomization. 
1. Informed consent at Screening – Part 1 Visit is for APOE genotyping, MMSE, demographics, medical history and prohibited medications. Complete 
consent from subject and caregiver/study partner at the Screening – Part 2 Visit or at the Screening – Part 1 Visit if APOE4/4 status is known or confirmed 
using a rapid genotype test. 
2. Vital sign measurements (BP, pulse, respiratory rate, and body temperature) will occur prior to dosing, LP, and blood draw, where applicable. BP and 
pulse will be measured after the subject has been sitting for 5 minutes. All BP measurements should be performed on the same arm, preferably by the 
same person, using an inflatable cuff and calibrated manometer. After last blood collections, subjects will be observed for approximately 15 minutes. BP 
and pulse while sitting will be measured and documented at the end of this observation period. 
3. ECGs should be obtained after the subject has rested quietly in the supine position for at least 5 minutes. Triplicate ECG will be performed at screening, 
Week 6, and Week 13. Triplicate ECG at Week 26, Week 52, Week 78, and ET will be performed only if QTc prolongation observed in current and prior 
visits.  
4. Lab tests include clinical chemistry, hematology, and coagulation tests, and will be done after ADAS-Cog and CDR-SB assessments. 

Protocol ALZ-801-AD301 (APOLLOE4) Amendment 2 
 
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5. Serum FSH levels will be measured only for female subjects of non-childbearing potential. Serum hCG levels will be measured only for female subjects 
of childbearing potential.  
6. Urine pregnancy tests will be conducted only for female subjects of childbearing potential.  
7. For those who cannot undergo MRI, CT is acceptable at Screening but requires prior approval by Medical Monitor. These subjects will not be scheduled 
for further CT imaging and will not contribute to the assessment of the volumetric imaging biomarkers. Note: CT is not allowed for subjects of sites at 
Germany. 
8. At screening, CDR global score and memory box score are calculated for screening purposes; the sum of boxes score is recorded at subsequent visits. 
9. C-SSRS: B/S = baseline/screening version, SLV = since last visit version. 
10. This CSF sub-study intends to enroll 60 subjects per treatment group. For each subject, LP will be performed within the same 2-hour window on each of 
the 3 visits regardless of dosing time and other assessments. In other words, for any two of the three CSF collections, the maximal time difference, in 
terms of the time of day, is within 2 hours from each other. Time of CSF collection (not time of preparation) will be recorded. 
11. Plasma PK samples will be collected at pre-dose at each clinic visit. Additional, a PK sample at ≥ 1 hour post-dose during clinic visit will be collected at 
Week 65.  
12. The times of study drug administration when taken at the study site will be recorded. 
13. Last study drug administration will occur on the morning of the Week 78 visit. One dose is administered at the site during clinic visits; the evening dose 
is skipped on clinic visit days.