Conditions: Alzheimer Disease
Keywords: Alzheimer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 351
Healthy volunteers: no

Brief summary:
The purpose of this study is to measure efficacy and safety of three different doses of buntanetap/Posiphen compared with placebo in participants with mild to moderate Alzheimer's disease.

Study details include:

The double-blind treatment duration will include a screening period of up to 42 days followed by 12 weeks of treatment at home.

The study duration will be 4-5 months. There will be 4 in-clinic visits and 1 phone call.

Detailed description:
320 mild to moderate AD participants will be randomized to 7.5 mg, 15 mg, 30mg of buntanetap/Posiphen once daily (QD) or placebo. If they provide informed consent, they will undergo a Screening Visit, and if they are considered eligible per the inclusion and exclusion criteria, they will proceed to participate in the treatment period. Randomized participants will visit the clinic for the first-time dosing in clinic, followed by an at home dosing period of 12 weeks, with daily administration of 7.5 mg, 15 mg or 30 mg of buntanetap/Posiphen or placebo. Participants will be required to visit clinics Day 0 (baseline), 6 weeks, and 12 weeks (end-of-trial), where they will undergo study procedures that include safety assessments (AE and concomitant medication monitoring, 12-lead ECGs, clinical laboratory testing, vital signs assessments, and physical examinations) and psychometric tests (Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog11), Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC), Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living Scale (ADCS-ADL), Digital Symbol Substitution Test (DSST), Mini Mental State Examination (MMSE)). At the end of blood sampling, the participants will need to stay for a minimum of 1 hour of observation. After all end-of-study procedures are complete, the subject will be discharged to home. A 24-hour follow-up call will occur after all clinical visits to assess the participants current condition and if there are any additional adverse events or questions.

The study will be a 12-weeks, placebo-controlled and double-blind trial: participants, investigators and the sponsor will be blinded to the participants' treatment.

Qualified participants will be randomly assigned at a 1:1:1:1 ratio to one of the four treatment arms: buntanetap/Posiphen 7.5 mg, buntanetap/Posiphen 15 mg, buntanetap/Posiphen 30mg, and placebo, through an Interactive Randomization System, after a screening period of up to 42 days.

ADAS-Cog 11, ADCS-CGIC, ADCS-ADL, DSST, and MMSE will be assessed by clinicians who have successfully completed the requisite certifications/trainings for each assessment.

One interim analysis is planned. It will take place when 90 enrolled subjects (\~30%) have completed the Week 6 assessments to re-assess the sample size. No interim analyses are planned for the purpose of stopping the study early for futility.

Arms:
arm 1: Buntanetap/Posiphen 7.5mg oral capsule with daily administration for a period of 12 weeks arm 2: Buntanetap/Posiphen 15mg oral capsule with daily administration for a period of 12 weeks arm 3: Buntanetap/Posiphen 30mg oral capsule with daily administration for a period of 12 weeks arm 4: Placebo oral capsule with daily administration for a period of 12 weeks

Interventions: intervention 1: Buntanetap/Posiphen intervention 2: Placebo
Intervention descriptions: intervention 1: HPMC (vegetarian source) capsule shells intervention 2: HPMC (vegetarian source) capsule shells

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Cover Page for ClinicalTrials.gov 
 
 
 
Sponsor name: 
Annovis Bio, Inc. 
NCT number: 
NCT05686044 
Sponsor trial ID: 
ANVS-22002 
Official title of study: 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, 
Multicenter Study of Buntanetap in Participants with Mild to 
Moderate Alzheimer’s Disease 
Document type: 
Protocol 
Document date: 
September 25, 2023 
 


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Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Multicenter Study of 
Buntanetap in Participants with Mild to Moderate Alzheimer’s Disease 
Protocol Short Title: 
A dose-ranging study to investigate efficacy of buntanetap in mild to moderate AD participants 
Protocol Number:  ANVS-22002 
Sponsor:  Annovis Bio, Inc., Berwyn, Pennsylvania 19312, USA 
US IND Number:  72,654 
Confidentiality Statement 
The information in this document is privileged or confidential and may not be disclosed unless 
such disclosure is required by applicable laws and regulations. It is the property of ANNOVIS Bio, 
Inc. and should not be copied by or distributed to persons not involved in the study. Persons to 
whom the information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply 
equally to all future information supplied to you, which is indicated as privileged or confidential. 
Any unauthorized review, use, disclosure, copying or distribution is strictly prohibited.  






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LIST OF ABBREVIATIONS  
5’UTR  
 
5’ untranslated regionαSYN Alpha-synuclein 
αSYN                          Alpha Synuclein 
Aβ 
 
 
Amyloid Beta 
AChE  
 
Acetylcholinesterase 
AD 
 
 
Alzheimer’s diseases 
ADAS-Cog 
 
Alzheimer’s Disease Assessment Scale–Cognitive Subscale 
ADCS-ADL 
Alzheimer's Disease Cooperative Study Activities of Daily Living 
Inventory 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study Clinician’s Global Impression of 
Change  
AE 
 
 
Adverse Event 
ANOVA 
Analysis of variance 
APP 
Amyloid Precursor Protein           
ATC 
Anatomical Therapeutic Chemical           
AUC 
Area under the curve 
BChE 
Butyrylcholinesterase  
BDNF 
Brain derived neurotrophic factor 
BP 
Blood pressure 
CA 
Competent Authority 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practice 
CI 
Confidence Interval  
CLBP 
Chronic low back pain 
Cmax 
Maximum plasma and CSF concentration  
ChE 
Cholinesterase 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CNS 
Central Nervous System 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficients of variation 
CVD 
Cerebrovascular Dementia 
DNA 
Deoxyribonucleic Acid 
DS 
Down Syndrome 
DSMB 
Data Safety Monitoring Board 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSST 
Digit Symbol Substitution Test 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FCR  
Fractional clearance rate 
FDA 
Food and Drug Administration 
FSR 
Fractional Synthesis Rate 
FWA 
Federal wide Assurance 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation  
GFAP 
Glial fibrillary acidic protein 


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GI 
Gastrointestinal 
GRAS  
Generally recognized as safe  
GWAS 
Genome Wide Association Studies 
HbA1c 
Hemoglobin A1C 
HEK 293 
Human embryonic kidney cells 
HEENT 
Head/ears/eyes/nose/throat 
hERG 
Human ether-a-go-go related gene  
HIPAA 
Health Insurance Portability and Accountability Act 
HPMC 
Hydroxypropyl methylcellulose  
ICH 
International Conference on Harmonization 
IDMB 
Independent Data Monitoring Board 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRE 
Iron-responsible element 
IRP1 
Iron Regulatory Protein 1 
LAR 
Legally authorized representative 
MAD 
Multiple Ascending Dose 
MCI 
Mild Cognitive Impairment 
MDS-UPDRS 
MDS-United Parkinson’s Disease Rating Scale 
MedRA 
Medical Dictionary for Regulatory Activities  
mITT 
modified Intent to Treat 
MMRM 
Mixed model for repeated measures 
MMSE 
Mini-Mental State Examination 
mRNA 
Messenger Ribonucleic Acid 
NFL 
Neurofilament light 
NG 
Neurogranin 
NIA 
National Institute on Aging 
NIA-AA 
National Institute on Aging and Alzheimer’s Association 
NIH 
National Institutes of Health 
NOAEL 
No observed adverse effect level 
NPH 
Normal Pressure Hydrocephalus 
OHRP 
Office for Human Research Protections 
p-tau  
Phosphorylated tau 
PD 
Parkinson’s disease  
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
POC 
Proof of Concept 
PS1 
Presenilin 1 
QD 
Once a Day 
QID 
4 Times a Day 
QT 
Interval seen in electrocardiogram (ECG) test 
QTc  
Interval seen in QT (ECG) test 
RA 
Regulatory Authority  
SAD 
Single Ascending Dose 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SH-SY-5Y 
Human Derived Cell Line 


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SILK™ 
Stable Isotope Labeling and Kinetics 
SNCAa53t 
Synuclein alpha 
SNRI 
Selective Norepinephrine Reuptake Inhibitor  
SOC 
Standard of care / System organ class 
SSRI 
Selective Serotonin Reuptake Inhibitor 
sTREM 
Soluble Triggering Receptor Expressed On Myeloid Cells  
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
t1/2 
Half-life 
tau 
Tau protein 
TEAE 
Treatment Emergent Adverse Event 
Tmax 
Time to peak drug concentration 
TMF 
Trial Master File 
TDP-43 
TAR DNA-binding Protein 43 
TG 
transgenic 
WAIS-IV 
Wechsler Adult Intelligence Scales, 4th edition 
WHO 
World Health Organization 
 
 
 
 


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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE: ...................................................................................................2 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE: ..................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1.0 
PROTOCOL SYNOPSIS ............................................................................................12 
2.0 
INTRODUCTION ......................................................................................................13 
2.1. 
OBJECTIVES .............................................................................................................14 
2.2. 
ENDPOINTS ..............................................................................................................16 
3.0 
COMPLETED STUDIES ...........................................................................................18 
3.1. 
Summary of Non-Clinical Findings ............................................................................18 
3.2. 
Summary of Clinical Findings ....................................................................................18 
4.0 
BACKGROUND AND STUDY RATIONALE.........................................................21 
4.1. 
Background .................................................................................................................21 
4.2. 
Study Overview...........................................................................................................21 
4.3. 
Outcome Measures ......................................................................................................22 
5.0 
POTENTIAL RISKS AND BENEFITS OF INVESTIGATIONAL PRODUCT AND 
STUDY PROCEDURES ............................................................................................23 
5.1. 
Risks and Benefits Associated with Buntanetap or Placebo .......................................23 
5.2. 
Risk/Benefit Associated with Blood Collections ........................................................24 
6.0 
SAMPLE SIZE AND STATISTICAL PLAN ............................................................24 
6.1. 
Randomization ............................................................................................................24 
6.2. 
Power and Sample Size Determination .......................................................................24 
6.3. 
Safety and Tolerability Analysis .................................................................................24 
6.4. 
PK Analysis.................................................................................................................25 
6.5. 
Criteria for Termination of the Trial ...........................................................................25 
6.6. 
Statistical Analysis ......................................................................................................25 
6.7. 
Study Participants and Demographics ........................................................................27 
6.7.1 
Population Analysis Set ..............................................................................................27 
6.7.2 
Disposition and Withdrawals ......................................................................................27 
6.7.3 
Protocol Deviations .....................................................................................................27 
6.7.4 
Demographics and Other Baseline Characteristics .....................................................27 
6.7.5 
Medical History and Concomitant Medications .........................................................27 


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6.8 
Analysis of Primary Endpoints ...................................................................................28 
6.9 
Multiplicity Adjustment ..............................................................................................28 
6.10 
Interim Analysis ..........................................................................................................29 
6.10.1 
 Re-estimation of Sample Size ....................................................................................29 
6.10.2 
Communication of Interim Results .............................................................................30 
6.11 
Safety and Tolerability Analyses ................................................................................30 
6.12               Adverse Events ........................................................................................................30 
6.12.1           Clinical Laboratory Evaluations ...............................................................................31 
6.12.2  
 Electrocardiogram (ECG) ..........................................................................................31 
6.12.3            Vital Signs ................................................................................................................31 
6.12.4            Physical Examination Findings................................................................................31 
6.12.5            Other Safety Parameters:  C-SSRS ..........................................................................31 
7 
STUDY DRUG AND CONCOMITANT MEDICATIONS ......................................32 
7.1 
Identity of IP and Comparator ....................................................................................32 
7.2 
Dosage .........................................................................................................................32 
7.3 
Packaging/Dispensing/Labeling ..................................................................................33 
7.4 
Storage ........................................................................................................................33 
7.5 
Drug Accountability ....................................................................................................33 
7.6 
Compliance .................................................................................................................33 
7.7 
Breaking the Blind ......................................................................................................34 
7.8 
Concomitant Medications ...........................................................................................34 
7.8.1 
Prohibited Concomitant Medications ..........................................................................34 
7.8.2 
Permitted Concomitant Medications ...........................................................................34 
8 
STUDY POPULATION .............................................................................................35 
8.1              Inclusion Criteria ......................................................................................................35 
8.2 
Exclusion Criteria .....................................................................................................37 
9 
DESCRIPTION OF STUDY VISITS .........................................................................40 
9.1 
Screening Visit ............................................................................................................40 
9.2 
Baseline Visit ..............................................................................................................40 
9.3 
Onsite Visit at 6 Weeks ...............................................................................................41 
9.4 
12 Weeks Visit (End of Trial Visit) ............................................................................42 
9.4.1 
End of Trial Visit ........................................................................................................42 


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9.4.2 
Post End of Trial Visit 24-Hour Phone Follow-up .....................................................43 
10 
EARLY TREATMENT/STUDY DISCONTINUATION ..........................................44 
10.1 
Reasons for Early Discontinuation .............................................................................44 
11 
STUDY-SPECIFIC INSTRUMENTS ........................................................................45 
12 
STUDY-SPECIFIC PROCEDURES ..........................................................................45 
12.1 
Safety Assessments .....................................................................................................45 
12.1.1 
Physical and Neurological Examination .....................................................................45 
12.1.2 
Electrocardiogram (ECG) ...........................................................................................45 
12.1.3 
Clinical Laboratory Evaluations .................................................................................46 
12.2 
Biofluids ......................................................................................................................46 
12.2.1 
Plasma for Biomarkers and Pharmacokinetics ............................................................46 
13 
PERSONNEL REQUIREMENTS ..............................................................................47 
14 
ADVERSE EVENTS (AES) .......................................................................................47 
14.1 
Definition ....................................................................................................................47 
14.2 
Following Up on AEs .................................................................................................48 
15 
SERIOUS ADVERSE EVENTS (SAE) .....................................................................48 
15.1 
Definition ....................................................................................................................48 
15.2 
Reporting SAEs...........................................................................................................48 
16 
SUSPECTED UNEXPECTED SERIOUS, ADVERSE REACTION ........................49 
16.1 
Definition ....................................................................................................................49 
16.2 
Reporting of Suspected Unexpected Serious Adverse Reactions ...............................49 
17 
ADVERSE EVENTS OF SPECIAL INTEREST .......................................................49 
18 
PRECAUTIONS/OVERDOSE ...................................................................................49 
19 
PREGNANCY ............................................................................................................49 
20 
DATA AND SAFETY MONITORING BOARD (DSMB) .......................................50 
21 
RECORDING AND COLLECTION OF DATA .......................................................50 
21.1 
Electronic Case Report Form (eCRF) .........................................................................50 
21.2 
Study Files and Source Documents ............................................................................51 
22 
ETHICS AND REGULATORY CONSIDERATIONS .............................................51 
22.1 
Good Clinical Practice ................................................................................................51 
22.2 
Institutional Review Board (IRB) ...............................................................................52 


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22.3 
Informed Consent and Health Insurance and Portability and Accountability Act 
(HIPAA) Compliance .................................................................................................52 
23 
STUDY MONITORING.............................................................................................53 
24 
AUDIT ........................................................................................................................53 
25 
RECORD RETENTION .............................................................................................53 
26 
LITERATURE CITED ...............................................................................................54 
APPENDIX 1: SCHEDULE OF EVENTS ...................................................................................56 
 
 


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1.0 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, 
Multicenter Study of Buntanetap in Participants with Mild to 
Moderate Alzheimer’s Disease  
STUDY DESIGN 
The study will be a 12-week, placebo-controlled and double-blind: 
participants, investigators and the sponsor will be blinded to the 
participants’ treatment.  
Qualified participants will be randomly assigned at a 1:1:1:1 ratio to 
one of the four treatment arms: buntanetap 7.5 mg, buntanetap 15 mg, 
buntanetap 30mg, and placebo, through an Interactive Randomization 
System, after a screening period of up to 42 days.  
ADAS-Cog 11, ADCS-CGIC, ADCS-ADL, DSST, and MMSE will 
be assessed by clinicians who have successfully completed the 
requisite certifications/trainings for each assessment.   All efforts will 
be made to ensure participants will be assessed by the same clinician 
throughout the study.   
One interim analysis is planned.  It will take place when 90 enrolled 
participants (~30%) have completed the Week 6 assessments to 
reassess the sample size. No interim analyses are planned for the 
purpose of stopping the study early for futility. 
DURATION OF STUDY 
PARTICIPATION 
Each participant will have up to a 42-day screening period, a baseline 
visit, followed by 12 weeks of treatment at home, followed by an in-
clinic visit. The total duration of study participation will be 4-5 
months.  
SUMMARY OF 
INVESTIGATIONAL 
PRODUCT 
Buntanetap 7.5mg, 15 mg, 30mg, or placebo capsules, taken orally 
once a day for 12 weeks. 
SUMMARY OF KEY 
ELIGIBILITY 
CRITERIA  
• Diagnosis of AD  
• Age 55 to 85 
• MMSE 14-24 
PRIMARY OUTCOME 
MEASURES 
Aim 1.  ADAS-Cog11 
Aim 2. ADCS-CGIC 
SECONDARY 
OUTCOME MEASURES 
Aim 1.  ADCS-ADL 
Aim 2.  DSST 
Aim 3.  MMSE 
EXPLORATORY 
OUTCOME MEASURES 
Aim 1.  Plasma Biomarkers  
Aim 2.  Pharmacokinetics 
 
 
 


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2.0 
INTRODUCTION 
Currently, there is no treatment available to stop or reverse the progression of Alzheimer’s 
(AD) and Parkinson’s disease (PD). Neurodegenerative diseases such as AD and PD share 
many common characteristics, including the central role of neurotoxic aggregating proteins 
in their pathogenesis. Amyloid β (Aβ) and tau aggregates (senile plaques and neurofibrillary 
tangles, respectively) have been traditionally associated with AD, while α-synuclein (αSYN) 
aggregates (Lewy bodies) have been associated with PD. However, it is becoming 
increasingly clear that all these proteins are involved in both diseases and that aggregation 
of one can lead to accumulation of another. Furthermore, in several studies of brains from 
older AD participants, a high percentage of all AD brains present mixed pathologies, such as 
Lewy body disease. Several clinical trials targeting just one (often Aβ) of the neurotoxic 
aggregating proteins have failed. Finally, other fragments of Amyloid β Precursor Protein 
(APP) have been implicated in AD pathology. Collectively, these facts point to the need for 
lowering multiple neurotoxic aggregating proteins simultaneously, if we are to have a good 
chance of at least halting disease progression. 
Buntanetap has a unique mechanism of action, in that it inhibits the translation and, therefore, 
reduces the levels of several neurotoxic aggregating proteins both in vitro and in vivo, including 
α-Synuclein (αSYN), Amyloid Precursor Protein (APP), its fragments, and tau. Although APP 
and its downstream products (Ab oligomers, c-terminus peptide, and amyloid plaques), and tau 
neurofibrillary tangles have been well documented to be culprits of AD, recent research has 
shown that other misfolded proteins are also part of the equation. For example, increased levels 
of αSYN and TDP-43 have been shown to be correlated with deficits in cognitive functions in 
AD participants. Therefore, it is reasonable to hypothesize that inhibiting expression of all the 
above neurotoxic proteins should lead to a better efficacy outcome in AD participants than 
inhibiting just one. 
αSYN, APP, tau, and TDP43 contribute to the progression of AD and PD in similar ways: they 
impair axonal transport and lower neurotransmitter and neurotrophic factor release, they cause 
inflammation, they form aggregates, and, finally, they lead to nerve cell death. In our in vitro and 
in vivo preclinical studies, buntanetap has normalized all those actions. 
Preclinical data proves buntanetap’s efficacy in restoring memory and learning in an APP/PS1 tg 
mouse model of AD, restoring axonal transport in DS trisomic mice, preserving memory, and 
learning in traumatic brain injury rats and in stroke mice, and preserving the retina in acute 
glaucoma. Buntanetap also restores colonic motility in a human SNCAA53T transgenic (tg) mouse 
model of early PD.  
Buntanetap’s safety has been established in three Phase 1 clinical studies by Maccecchini et al 
(2012). Importantly, buntanetap normalized levels of APP, tau and αSYN, as well as 
inflammatory markers in the cerebrospinal fluid (CSF) of mildly cognitively impaired (MCI) 
participants at a dose of 4x60 mg/day (Protocol QR12001). 
 


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Recently, we also tested buntanetap in the DISCOVER study at 1x60, 2x60 and 3x60 mg/day for 
up to 25 days to see if it changes the synthesis and degradation kinetics of Aβ in a stable isotope 
labelling kinetic (SILK) study.  The DISCOVER study is conducted by the ADCS and was 
completed with 16 treated participants (Protocol QR15001). The study officially finished in 
December 2021, with 7 patients treated in cohort 1 (1x60mg/day), 6 patients in cohort 2 
(2x60mg/day), and 2 patients in cohort 3 (3x60mg/day). The CSF measurements of Aβ showed 
in a dose-dependent fashion that buntanetap slows the synthesis and lowers the total amount of 
Aβ synthesized by half. It also showed improvement in cognition as measured by the ADAS-
Cog11 scale. 
We recently completed a double Phase 2a study (ANVS-12003) in both early AD and early PD 
populations. In AD, 14 participants were recruited and randomized into 80mg QD buntanetap or 
placebo for 25±2 days. CSF biomarker results show that buntanetap lowered multiple neurotoxic 
proteins levels (sAPPa, sAPPb, total Tau, phosphorylated Tau), reduced inflammation (shown by 
GFAP, YKL-40, sTREM and Complement C3), preserved axonal integrity shown by 
neurofilament light (NFL) and improved synaptic density shown by neurogranin (NG). 
Buntanetap also improved AD participants ADAS-Cog 11 score as well as WAIS coding score 
(Fang 2022). 
In PD, 54 participants were recruited and randomized into 0, 5, 10, 20, 40 and 80mg QD 
buntanetap for 25±2 days. CSF biomarkers were collected and analyzed. MDS-UPDRS and 
WAIS coding were tested. CSF biomarker results show that buntanetap lowered αSYN level, 
reduced inflammation (shown by GFAP, YKL-40, sTREM and Complement C3), preserved 
axonal integrity shown by NFL and improved synaptic density shown by NG. Although sample 
size was not powered to see efficacy, buntanetap improved PD participants WAIS coding scores 
at all doses including 5mg QD. Buntanetap also improved PD participants MDS-UPDRS Part III, 
IV and Total score (Fang 2022).  
In this study, we want to confirm buntanetap’s efficacy in a diverse population of mild to 
moderate AD participants. We only tested 80mg QD in our Phase2a study in AD participants. 
During the dose-finding Phase 2a PD study, we saw a dose-response curve between 0 and 10/20 
mg QD. Therefore, we want to do a similar dose-ranging trial to test the efficacy of 7.5mg, 15mg 
and 30 mg QD buntanetap.  
2.1. 
OBJECTIVES 
Study objectives include assessing buntanetap’ s efficacy and safety in participants with mild to 
moderate AD.   
Study drugs will be 7.5 mg, 15mg, 30mg of buntanetap, or matching placebo capsules, taken 
once per day in the morning right before food. Eligible participants will be randomly assigned at 
a 1:1:1:1 ratio to one of the four treatment arms: buntanetap 7.5 mg, buntanetap 15 mg, 
buntanetap 30mg, and placebo, through an Interactive Randomization System, after a screening 
period of up to 42 days. The total duration of the study will be 4-5 months. ADAS-Cog11, 
ADCS-CGIC, DSST, ADCS-ADL, MMSE will be assessed by clinicians who have successfully 


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completed the requisite certifications/trainings for each assessment. All efforts will be made to 
ensure participants will be assessed by the same clinician throughout the study.   
 
 


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2.2. 
ENDPOINTS 
Primary Endpoints: 
1. ADAS-Cog11 
Change in Alzheimer’s Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog 11) 
from baseline to the end of treatment period (12 weeks). ADAS-Cog 11 measures cognitive 
functions and non-cognitive functions such as mood and behavior. Total scores range from 0-
70, with higher scores indicating greater cognitive impairment.  
2. Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-
CGIC)  
ADCS-CGIC is a validated categorical measure of change in the participant’s clinical 
condition between baseline and follow-up visits. It measures whether the effects of active 
treatment are substantial enough to be detected by a skilled and experienced clinician on the 
basis of a clinical interview and examination. It relies on both direct examination of the 
participant and an interview of the study partner. A skilled and experienced clinician who is 
blinded to treatment assignment rates the participant on a 7-point Likert scale, ranging from 1 
(marked improvement) to 7 (marked worsening). Lower scores indicate better improvement. 
 
Secondary Endpoints: 
1. Alzheimer’s Disease Cooperative Study-Instrumental Activities of Daily Living Scale 
(ADCS-ADL) 
The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire 
answered by the participant‘s study partner. The ADCS-ADL measures both basic and 
instrumental activities (instrumental activity items 6a, 7-23) of daily living by participants 
with a lower score indicating greater severity. 
2. Mini Mental State Examination (MMSE) Score 
MMSE is a brief screening instrument used to assess cognitive function (orientation, 
memory, attention, ability to name objects, follow verbal/written commands, write a 
sentence, and copy figures). Total score ranges from 0 to 30 with a lower score indicating 
greater disease severity. 
3. Digital Symbol Substitution Test (DSST) 
In the digital symbol substitution test (DSST) individuals are asked to record associations 
between different symbols and numbers within time limits. The total score is the sum of all 
the correctly coded numbers and higher scores indicate better performance. 
Exploratory Endpoints: 
1. Plasma biomarkers 


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Potential biomarkers to be measured in plasma are A42/40 ratio, pTau181, pTau217, 
Neurofilament Light (NFL), Glial fibrillary acidic protein (GFAP), TDP43. 
 
2. Pharmacokinetics 
The following PK parameters will be determined: Area under the curve (AUC), Cmax, 
Tmax, t½, and CL. 


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3.0 
COMPLETED STUDIES 
The following is a summary of the available information on buntanetap. Detailed information 
can be found in the current buntanetap Investigational Drug Brochure. 
3.1. 
Summary of Non-Clinical Findings 
In APP transgenic AD mice, buntanetap led to a decrease in APP levels, improved neuronal stem 
cell survival and increased levels of brain-derived neurotrophic factor (BDNF) (Marutle 2007, 
Kadir 2008, Lilja 2013). Chronic administration of buntanetap to APP transgenic mice totally 
prevented decline in memory and learning as well as in long-term potentiation at brain and 
plasma concentrations that are 10 times lower than originally published (Teich 2018). In alpha-
synuclein (αSYN) transgenic PD mice, buntanetap restored gut motility to normal and lowered 
aSYN in the brain and gut of the tg PD mice. Again, the efficacious levels were 10 times lower 
than originally published (Kuo 2019). In DS trisomic mice buntanetap fully restored axonal 
transport in vitro and in vivo (Chen 2020). In summary, buntanetap is a translational inhibitor of 
APP and aSYN and fully restores function at doses that are very low and very safe, and the 
plasma levels seen are attainable with low oral dosing in humans. 
Buntanetap was not mutagenic or clastogenic as assessed by in vitro assays.  
The cardiac electrophysiological properties of buntanetap tartrate were negative in vitro using 
human ether-a-go-go related gene (hERG) transfected human embryonic kidney cells (HEK 
293). Buntanetap did not adversely affect the interval seen in an electrocardiogram (ECG) test 
(QT (or QTc)) interval.  
Four-week toxicity studies in dogs showed brain toxicity (ataxia and tremors/twitching) and 
gastrointestinal (GI) toxicity at 30 mg/kg/day, which was dose-dependent and reversible. The no 
observed adverse effect level (NOAEL) was 20 mg/kg/day in dogs. The signs/symptoms noted at 
high doses of buntanetap may be related to cholinergic manifestations. In in vitro assays, 
buntanetap showed minimal inhibition of AChE or BChE (Butyrylcholinesterase) activity, 
however, a metabolic product of buntanetap, N1-norposiphen demonstrated acetyl cholinesterase 
inhibitory activity (Yu 2013). There were no effects on the reproductive organs associated with 
4-week exposure to buntanetap in male or female rats or dogs.  
Repeat Oral dose Toxicity Study of buntanetap in male and female rats giving 10, 20 and 40 
mg/kg for 26 weeks showed that NOAEL dose was 40 mg/kg for both male and female rats. 
Repeat Oral dose Toxicity Study of buntanetap in male and female dogs giving 5, 10 and 20 
mg/kg for 39 weeks showed that NOAEL dose was 20 mg/kg for both male and female dogs.  
3.2. 
Summary of Clinical Findings  
Three Phase 1 studies and two Phase 2a study have been conducted with buntanetap. For the 
three Phase 1 studies, the first was a single ascending dose (SAD) study in healthy volunteers; 
the second was a multiple ascending dose (MAD) study in healthy volunteers, and the third one 
was a pharmacokinetic (PK)/pharmacodynamic study of CSF in mild cognitively impaired 
participants (Protocol QR12001). One Phase1/2 study (Discover) was to test the safety, 


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tolerability, PK and PD of  buntanetap in subjects with early Alzheimer's disease  (Protocol 
QR12005). The other Phase 2a study was a double study for both early AD and early PD 
participants to test buntanetap’s safety, pharmacokinetics, biomarkers, and efficacy (Protocol 
ANVS-12003). 
In the SAD trial, buntanetap was administered orally in doses of 10, 20, 40, 80, and 160 mg. 
Limiting side effects observed following the 160 mg dose resulted in curtailment of the study 
without administration of the 320 mg dose. The 160 mg dose was associated with an increased 
incidence of nausea and vomiting (four participants were nauseous and three vomited). Adverse 
events were either mild or moderate; none were severe. Buntanetap 80 mg was determined as the 
no observed adverse effect level. 
Following oral administration, peak concentration was achieved rapidly, with mean observed 
Tmax between 1.3 and 1.6 hours for both males and females at all doses. Cmax increased with 
increasing dose, as did the various measures of AUC. Differences in mean observed Cmax and 
AUC between males and females at each dose appeared to be related to body weight rather than 
gender differences. 
In the MAD trial, buntanetap was administered orally in doses of 20, 40, and 60 mg 4 times a 
day (QID). The first two treatments were dosed for 7 days, and the third, for 10 days. Single 
doses were given on the first and last day to determine the pharmacokinetics of the drug. In 
general, the drug was well tolerated, resulting in no serious or severe adverse events and only 
one premature discontinuation, a participant in the 60 mg group discharged because of nausea, 
vomiting, dizziness and “feeling warm.” The incidence of adverse events, all either mild or 
moderate severity, also occurred with similar frequency in the placebo group. The most common 
AEs were dizziness, headache, and nausea/vomiting.  
Buntanetap was absorbed rapidly after oral administration, achieving maximum plasma and CSF 
concentration (Cmax) within 1.2-1.5 hours. For the 40 and 60 mg doses, with fully defined plasma 
profiles, the mean terminal t½’s were 3.80 ±0.88 and 5.23±1.24 hours, respectively after a single 
dose and 3.53±1.03 and 4.104±0.91 hours, respectively, after repeat dosing. The half-life (t½) of 
the plasma concentrations at the lower doses could not be calculated accurately. The Cmax 
increased with dose (24, 144, and 2310 ng.h/mL after a single dose of 20, 40, and 60 mg, 
respectively and 110, 134, and 2101 ng.h/mL after multiple doses of 20, 40, and 60 mg, 
respectively). 
In the proof of mechanism of action study (Protocol QR12001), the PK of buntanetap was 
measured after 10 days of administration (4x60 mg) over 12 hours in CSF and plasma of the 
MCI participants. The pharmacodynamics of a number of biomarkers was compared for 12 hours 
before the first dose at day 0 and after the last dose at day 11 of buntanetap administration. We 
found that the plasma concentrations of buntanetap overlapped with the plasma concentrations 
found in the MAD study. In this study, the N1-metabolite reached about 10 to 15%, while the 
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Because a substantial proportion of the adverse events observed in AD participants treated with 
cholinesterase inhibitors appear to reflect the cholinomimetic properties of molecules in this 
class, buntanetap’s highest tolerated dose is determined by the levels of the N1-metabolite in 
blood and brain. 
While the t1/2 of buntanetap in plasma was 4-5 hours as seen in the SAD and MAD studies, the 
t1/2 in CSF/brain was longer than 12 hours. The concentrations of buntanetap in the brain, 
extrapolated from blood and CSF, were 8 times higher than in plasma. 10 days of treatment with 
buntanetap normalized CSF levels of sAPPα and β, tau, αSYN and a series of inflammatory 
markers. The concentration and persistence of buntanetap in the brain suggests that much lower 
doses of drug administered once daily could achieve the desired pharmacological effect. 
For the Phase 2a trial (Protocol ANVS-12003), there are two parts of the study. In part one, early 
AD participants were given 80 mg QD buntanetap or placebo for 25 days.  In the second part, 
early PD participants were given 5 mg, 10 mg, 20 mg, 40 mg, 80mg QD buntanetap or placebo 
for 25 days. In all doses and in both AD and PD participants, buntanetap was safe and well 
tolerated. No SAE was reported.  
Buntanetap was absorbed rapidly after oral administration, achieving maximum plasma and CSF 
concentration (Cmax) within 1-2 hours. For the 80 mg doses, with fully defined plasma profiles, 
the mean terminal t½’s were 2.76 ± 2.668 hours. The half-life (t½) of the plasma concentrations at 
the lower doses (5 & 10 mg) could not be calculated accurately. The Cmax increased with dose 
(15.31, 40.19 and 112.31 ng.h/mL after a single dose of 20, 40 and 80 mg, respectively). 
Consistent with Phase 1 POC study, 80mg QD buntanetap reduced AD participants’ CSF levels 
of sAPP, sAPP, total tau, phosphorylated tau (tau181), αSYN and a series of inflammatory 
markers (YKL-40, GFAP, sTREM2, Complement C3). Buntanetap also improved axonal 
integrity shown by Neurofilament light (NFL) and synaptic function shown by neurogranin 
(NG). Similarly, 80 mg QD buntanetap reduced PD participants’ CSF levels of αSYN and a 
series of inflammatory markers (YKL-40, GFAP, sTREM2, Complement C3). Buntanetap also 
improved PD participants’ axonal integrity shown by NFL and synaptic function shown by NG.  
Further, buntanetap treatment improved AD participants’ cognition shown by ADAS-Cog11 and 
WAIS coding test and improved PD participants’ movement shown by MDS-UPDRS and WAIS 
coding test in our Phase2a studies. 
 
 


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4.0 
BACKGROUND AND STUDY RATIONALE 
4.1. 
Background 
Although APP and its downstream products (Aβ oligomers, c-terminus peptide, and amyloid 
plaques), and tau neurofibrillary tangles have been well documented to be culprits of AD, recent 
research has shown that other misfolded proteins are also part of the equation. In AD, in addition 
to Aβ and tau, increased levels of αSYN and TDP-43 have been shown to be correlated with 
deficits in cognitive functions. A high load of inflammation and microglia activating factors that 
contribute to neurodegeneration are also common in AD. 
Buntanetap (Posiphen) is the (+) enantiomer of phenserine, but while phenserine inhibits AChE, 
buntanetap has no AChE activity itself and develops some activity in vivo with the metabolism 
to N1-bisnorposiphen. In vivo, phenserine has about 10-20 times more AChE inhibitory activity 
than buntanetap’s metabolite N1-bisnorposiphen.  
Buntanetap has been found to significantly reduce soluble APP and Aβ as well as tau, p-tau and 
αSYN in the rodent brain and in human CSF. In preliminary studies in animals and humans, 
inhibition of APP, Aβ, tau, p-tau and αSYN occurs at levels 8 to 16 times lower than the levels 
causing cholinomimetic effects. 
Buntanetap acts at the 5’UTR of the aSYN and APP mRNA and lowers their protein expression 
levels in animal models; it decreased sAPPα and β, tau, p-tau and aSYN levels in human CSF. 
Our data suggests that these effects are achieved via the same mechanism: the 5’UTRs of these 
mRNAs form a complex with iron regulatory protein 1 and buntanetap stabilizes the complex, 
thereby inhibiting the translation of these mRNAs. 
As buntanetap inhibits the synthesis of APP and aSYN, as well as other neurotoxic aggregating 
proteins, it might have a broader spectrum of activity than AD and PD. By protecting neurons 
from dying, it has a disease-modifying effect in AD, PD as well as other neurodegenerative 
disorders.  
4.2. 
Study Overview 
Study population: The study will be conducted in a diverse population of participants with mild 
to moderate AD. 
Dose selection: Qualified participants will be randomly assigned at a 1:1:1:1 ratio to one of the 
four treatment arms: buntanetap 7.5 mg, buntanetap 15 mg, buntanetap 30mg, and placebo.  
Study Design:  320 mild to moderate AD participants will be randomized to 7.5 mg, 15 mg, 
30mg of buntanetap QD or placebo.  If they provide informed consent, they will undergo a 
Screening Visit, and if they are considered eligible per the inclusion and exclusion criteria, they 
will proceed to participate in the treatment period.  Randomized participants will visit the clinic 
for the first-time dosing in clinic, followed by an at home dosing period of 12 weeks, with daily 
administration of 7.5 mg, 15 mg, or 30 mg of buntanetap or placebo.  Participants will be 
required to visit clinics Day 0 (baseline), 6 weeks, and 12 weeks (end-of-trial), where they will 


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undergo study procedures that include safety assessments (AE and concomitant medication 
monitoring, 12-lead ECGs, clinical laboratory testing, vital signs assessments, and 
physical/neurological examinations) and psychometric tests (ADAS-Cog11, ADCS-CGIC, 
ADCS-ADL, DSST, MMSE). At the end of blood sampling, the participants will need to stay for 
a minimum of 1 hour of observation. After all end-of-study procedures are complete, the 
participant will be discharged to home. A 24-hour follow-up call will occur after all clinical 
visits to assess the participants current condition and if there are any additional adverse events or 
questions.   
Participants who drop out during the initial 9 weeks at home treatment period will be 
discontinued and complete an early discontinuation visit as soon as possible following 
discontinuation.  Participants that drop out after the initial 9 weeks will be scheduled for an end 
of trial visit.  If 4 participants are discontinued due to severe adverse events a DSMB safety 
review will be conducted without interrupting the study.  
4.3. 
Outcome Measures 
Efficacy outcome measures: Buntanetap has shown to improve AD participants’ cognition. 
ADAS-Cog 11 and MMSE will be measured to assess its improvement on AD participants’ 
cognition, ADCS-ADL will be measured to assess its improvement on AD participants daily 
living functions. ADCS-CGIC will also be measured to assess its effect in AD participants’ 
performance. DSST will be measured to assess AD participant’s CNS dysfunction.  
Safety outcome measures: Reports of adverse events (AEs) and serious adverse events (SAEs) 
during exposure to buntanetap will be collected to evaluate if there are any significant clinical 
safety issues for the study population. Extensive clinical and laboratory safety data already exist 
for buntanetap; therefore, these safety measures will be sufficient in the proposed study. 
Clinical, functional and cognitive assessment measures: The participants will be administered 
the MMSE (Folstein 1975) for determination of inclusion into the study. The ADAS-Cog11 
(Rosen 1984) and MMSE will be administered for participants’ cognitive function.  The ADCS-
ADL (Galasko 1997) will be administered for participants’ daily activity. ADCS-CGIC (Guy 
1976) will be administered for participants cognitive and daily functions.  The DSST (WAIS-IV; 
Wechsler 2008) will serve as a sensitive measure of CNS dysfunction.  
Exploratory measures: Buntanetap has shown to reduce neurotoxic proteins, reduce 
inflammation and preserve axonal integrity and synaptic functions in previous Phase 2a studies. 
In this study we potentially plan to measure plasma A42/42 ratio, GFAP, NFL, p-Tau 181, p-
Tau217 and TDP43. 
 
 


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5.0 
POTENTIAL RISKS AND BENEFITS OF INVESTIGATIONAL PRODUCT 
AND STUDY PROCEDURES  
5.1. 
Risks and Benefits Associated with Buntanetap or Placebo 
There are no benefits to the participants other than receiving medical and selective functional and 
cognitive evaluations. 
The clinical investigator must advise all potential participants of the possibility of unexpected 
side effects and carefully evaluate each person exposed to Investigational Product for possible 
AEs. 
Side effects to placebo are not uncommon but are obviously not due to a pharmacological agent 
as an industry standard placebo (inactive ingredients) will be provided. The placebo used for the 
study consists of standard (non-lactose) pharmaceutical excipients which are generally 
recognized as safe (GRAS), with no known side effects anticipated. 
Buntanetap has been tested in animal safety studies. No adverse effects were observed in rats 
given doses up to 40 mg/kg/day for 26 weeks. Drug-related effects observed in dogs included 
severe tremors at ≥20 mg/kg/day, ataxia, and gastrointestinal erosion/ulcer/inflammation at ≥30 
mg/kg/day, convulsions at ≥60 mg/kg/day, and duodenal necrosis and death at 100 mg/kg 
(equivalent to a human dose of 3,350 mg). No adverse effects were observed in dogs given doses 
up to 20 mg/kg/day for 36 weeks. 
In clinical studies to date, buntanetap has been well tolerated with single doses of 80 mg or less 
and QID doses of 60 mg up to 25 days. A higher single dose of 160 mg was associated with an 
increased incidence of nausea and vomiting. Aside from nausea and vomiting, which are well-
known responses to treatment with AChE inhibitors, the only consistent pattern of AEs entailed 
dizziness/fainting, headache, and reduction in total serum protein. These effects were seen to 
varying degrees at all doses of buntanetap and in the placebo group. There was a tendency, but 
no definitive pattern of increased incidence of AEs with increasing dose of buntanetap. There 
have been no SAEs in prior clinical studies with buntanetap. 
Definitive reproductive and developmental toxicity studies have not been conducted with 
buntanetap. As a result, women of childbearing potential will be excluded from participating in 
this study unless they agree to be on contraceptive for the whole duration of the trial and four 
weeks after. Female partners of male participants of childbearing potentials will also need to 
agree to be on contraceptive for the whole duration of the trial plus an additional four weeks.  
Male study participants should not donate sperm and female study participants should not donate 
eggs during the whole duration of the trial and four weeks after.  
At this time, there is no controlled clinical data available for anyone receiving SARS-CoV-2 
(COVID19) vaccination while being treated with buntanetap. However, based on the intended 
mechanism of actions and currently available data for these vaccine candidates and for 
buntanetap, it is not believed that there are specific risks to consider in participants participating 
in this study who have received SARS-CoV-2 (COVID19) vaccination or who are planning to 


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receive the vaccination. As such, SARS-CoV-2 (COVID19) vaccination is not prohibited. If 
appropriate, SARS-CoV-2 (COVID19) vaccination should be considered as a concomitant 
medication. 
5.2. 
Risk/Benefit Associated with Blood Collections 
Phlebotomy is associated with mild to moderate discomfort due to piercing of the skin. This can 
be minimized with the use of a well-trained phlebotomist/nurse. Sometimes the blood draw site 
may become discolored with a “bruised” appearance that is transient and not painful. Rarely, the 
blood draw site may become infected and require antibiotic treatment. 
6.0 
SAMPLE SIZE AND STATISTICAL PLAN 
A sample size of up to 320 participants (1:1:1:1 randomized to 7.5mg, 15mg, 30mg buntanetap 
and placebo respectively) is planned to be randomized.  
Definitions of the analysis populations and a detailed description of the analysis rules will be 
presented in a separate Statistical Analysis Plan (SAP). 
6.1. 
Randomization 
Participants who have signed an informed consent and meet screening eligibility requirements 
will be randomly assigned to the active and placebo treatment groups at 1:1:1:1 ratio. The 
randomization methodology used is permuted block randomization. 
6.2. 
Power and Sample Size Determination 
Qualified participants will be randomized at a 1:1:1:1 ratio to one of the following three 
treatment groups: 7.5 mg, 15 mg, 30 mg QD buntanetap and placebo. A sample size of 280 (210 
combining all three buntanetap-treatment groups and 70 in control) will have a 90% power to 
detect a treatment difference for the primary efficacy variable ADAS-Cog11 at a two-sided 
significance level of 0.05, assuming a delta of 2.7 between the treatment (pooling all three 
treatment arms together) and placebo, and a common standard deviation of 6.0.  This sample size 
will also have an 89% power to detect a significant difference for the co-primary efficacy 
variable ADCS-CGIC at a two-sided significance level of 0.05, assuming a delta difference 0.23  
between the treatment (pooling all three treatment arms together) and placebo,  and a common 
standard deviation of 0.5. Approximately 320 participants will be randomized (approximately 80 
per arm) to account for an expected 12.5% dropout rate. 
6.3. 
Safety and Tolerability Analysis 
Safety and tolerability will be assessed with physical examinations, vital signs, clinical 
laboratory values, 12-lead ECG, use of concomitant medications, and AE reports. The 
frequencies of adverse events, serious adverse events, and laboratory abnormalities between the 
participants across the treatment groups will be compared.  


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Participants who dropout during the initial 9 weeks at-home treatment period will be 
discontinued and invited to an Early Discontinuation visit. Participants that drop out after the 
initial 9 weeks will be scheduled for an end-of-trial visit. If 4 participants are discontinued due to 
serious adverse events a DSMB safety review will be conducted without interrupting the study.   
6.4. 
PK Analysis 
Plasma concentration-time data will be analyzed by non-compartmental methods using SAS 
version 9.4 or greater. Calculations will be based on the actual sampling times recorded during 
the study. Since the study is blinded, all participants’ plasma will be included in the PK 
analysis. From the plasma concentration-time data, the following PK parameters will minimally 
be determined, as data permit: Area under the curve (AUC), Cmax, Tmax, t½, and CL. Dose-
proportionality may be calculated on Cmax and AUC as appropriate. 
Plasma concentration-time data for buntanetap will be listed and summarized descriptively 
(number of participants (N), mean, median, standard deviation (SD), minimum (min), and 
maximum (max)) and graphically presented. PK parameters will be listed and summarized 
descriptively (N, mean, median, SD, min, max, and 95% CI) by each dose regimen. In addition, 
geometric means, and between-participant coefficients of variation (CV) will be calculated. 
6.5. 
Criteria for Termination of the Trial  
The trial may be terminated by the Sponsor based on issues of safety, and Data Safety 
Monitoring Board (DSMB) recommendations. 
An independent Data Monitoring Board (DSMB or IDMB) will be formed to safeguard the 
participants’ wellbeing. The responsibilities of IDMB will be established in the IDMB Charter. 
The study will have a safety analysis when 90 randomized participants (about 30% of the 
targeted sample size) have been treated for 6 weeks.  
6.6. 
Statistical Analysis 
Continuous variables will be summarized using the following descriptive statistics: number of 
subjects, mean, median, standard deviation (SD), standard error (SE), minimum, and maximum. 
Unless otherwise specified, means, medians and confidence intervals (CIs) will be presented to 
one more decimal place than the raw data, and the SD and SE will be presented to two more 
decimals than the raw data. In general, the maximum number of decimal places is 4. Wherever 
possible, data will be decimally aligned.  
Categorical variables will be summarized by the number of subjects and the percentage of 
subjects in each category. Categories with zero counts will not have zero percentages displayed. 
For demographic summaries, percentages will be calculated by using the total number of subjects 
in the given treatment group as the denominator. Percentages will be presented with one decimal 
place.   


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Unless otherwise specified, all statistical tests will be 2-sided at the significance level of 5% and 
all the Cis will be 2-sided 95%. P-values will generally be presented to 4 decimal places; values 
less than 0.0001 will be presented as <0.0001.  
 
 
 


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6.7. 
Study Participants and Demographics 
6.7.1 Population Analysis Set 
Enrolled Analysis Set: The enrolled population will include all participants who signed Informed 
Consent and meet all inclusion and exclusion criteria. 
Randomized Analysis Set: The Randomized Analysis Set (RAS) consists of all participants who 
were randomized. Subjects will be classified according to the randomized treatment assignments.  
Safety Analysis Set: The Safety Analysis Set (SAS) consists of all randomized participants who 
received at least one dose of study drug. Subjects will be analyzed according to the actual 
treatment. 
Full Analysis Set: The Full Analysis Set (FAS) consists of all participants who were randomized, 
received at least one dose of study drug, and have both a baseline and at least one post-baseline 
value for the ADAS-Cog11 or ADCS-CGIC score after taking study drug. Subjects will be 
analyzed according to the treatment they were randomized.  
Per Protocol Analysis Set:  The Per-protocol Analysis Set consists of all participants in the FAS 
who do not have major protocol deviation. The membership of this analysis set will be 
determined prior to database lock.  
6.7.2 Disposition and Withdrawals 
The numbers of participants screened, randomized, completing, discontinuing treatment, and 
withdrawing, along with reasons for discontinuation or withdrawal, will be tabulated overall and 
by treatment group. The number of participants in each analysis population will be reported. 
6.7.3 Protocol Deviations 
Major protocol deviations will be classified and documented before database lock and will be 
discussed in the CSR. All protocol deviations, both minors and majors, will be presented in a data 
listing. 
6.7.4 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race/ethnicity, weight, and height) 
will be summarized for each treatment group and for the overall population by descriptive 
statistics. 
6.7.5  Medical History and Concomitant Medications 
Medical history will be listed. Prior and concomitant medications will be summarized by treatment 
group, by the number and percentage of participants taking each medication, classified using 
World Health Organization (WHO) Drug Dictionary Anatomical Therapeutic Chemical (ATC) 
classes and preferred terms. 


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6.8 Analysis of Primary Endpoints 
The co-primary endpoints are the change from baseline to 12 weeks in ADAS-Cog11 scores and 
the ADCS-CGIC scores at 12 weeks. The ADAS-Cog11 will be analyzed via mixed models for 
repeated measures (MMRM). The model for ADAS-Cog11 will include treatment, timepoint, 
treatment-by-timepoint interaction as the fixed effects, baseline ADAS-Cog11as the covariate,  
and subjects as random effect. The Model for ADCS-CGIC will include treatment, timepoint, 
treatment-by-timepoint interaction as the fixed effects ,  and subjects as random effect. An 
unstructured covariance matrix will be used and the Kenward-Roger approximation will be used 
to adjust the denominator degrees of freedom. The change from baseline and the differences in 
the change from baseline between treatments will be based on the Least Square Means from this 
model. The two-sided 95% confidence intervals of the treatment differences will be presented. 
6.9 Multiplicity Adjustment 
The primary study hypothesis is that, the buntanetap-treatment (pooling three treatment arms 
together) is superior to placebo in reducing the cognitive impairment of AD patients, as assessed 
by the two co-primary endpoints: change from baseline in the ADAS-Cog11 score at 12-weeks 
and ADCS-CGIC score at 12-weeks. The two co-primary endpoints will be tested at a two-sided 
significance level of 5% without multiplicity adjustment. If both test hypotheses are rejected at 
the 5% level, the test will continue onto secondary endpoints in a gatekeeping sequential order, 
at a two-sided significance level of 5%.  
The study is also designed to explore the effectiveness of three buntanetap-treatment dose level. 
Nominal p-values will be provided for these test hypotheses of each dose arm vs. placebo, 
without multiplicity adjustment.  
 
 


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6.10 Interim Analysis 
An interim sample size re-estimation will be performed after a total of 𝑛1 = 90 evaluable 
participants across four treatment arms have 6 weeks of assessments for the co-primary efficacy 
endpoints ADAS-Cog11 and ADCS-CGIC. Evaluable participants are defined as randomized 
subjects who received the study drug and have baseline and Week 6 values of one or both co-
primary efficacy endpoints. The aim of the interim sample size review is to re-assess the size of 
the estimated mean difference between the treatment (pooling three treatment arms together) and 
placebo, and standard deviations of the co-primary endpoints ADAS-Cog11 and ADCS-CGIC to 
ensure sufficient power at the final analyses.  
No Interim analyses are planned for the purpose of stopping the study early for success or 
futility. 
6.10.1 
 Re-estimation of Sample Size 
The initial planned sample size was determined for ADAS-Cog11 based on a targeted power of 
90% to detect a delta of 2.7 between the treatment (pooling three arms together) and placebo, 
with a common standard deviation of 6.0 at a two-sided significance level alpha of 5%.  This 
sample size will also have a power of 89% to detect a significant difference for the co-primary 
effectiveness variable ADCS-CGIC at a two-sided significance level of 5%, assuming a delta of 
0.22 with a common standard deviation of 0.5. Accounting for an expected drop-out rate of 
12.5%, a sample size of approximately 320 participants (80 per treatment arm) was calculated to 
achieve 280 evaluable participants (70 per treatment arm).  
To guarantee sufficient power for the primary trial objectives, sample size will be re-estimated 
based on the calculated conditional power at the interim analyses. The conditional power for 
each co-primary endpoint will be calculated at the significance level of 0.05 separately, 
according to the methodology and equation from Mehta and Pocock (2011). The sample size will 
only be increased if the conditional powers for both co-primary endpoints are >50% (and <90%), 
otherwise, the trial will continue as planned, i.e., no decrease in sample size or stopping the trial 
early for futility or efficacy success at the interim analysis. The target power is 90% and 
maximum sample size per group is set to be 100 participants per arm. Specifically, if both 
conditional powers at interim analysis are >50%, then each arm will be increased to 100 
participants. Otherwise, the trial will continue as is.  
Chen, Lan and Demets (2004) have shown that, when conditional power >=50%, one may 
increase sample size to 𝑛2∗ and the conventional test statistics and critical values can be used at 
the final analysis, the overall type I error rate will not be inflated. Further, Chen, Yuan and Li 
(2018) demonstrated that the conventional maximum likelihood estimate, and coverage error of 
its conventional confidence interval are generally small following sample size adjustment. 
Therefore, conventional point estimate and confidence interval are recommended to be used 
when applying the 50% conditional power principle for sample size re-estimation, to keep 
consistent statistics in both hypothesis test and statistical inference.  


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6.10.2 
Communication of Interim Results 
The study team at the Sponsor will be blinded to the interim results and only decisions on sample 
size re-estimation will be communicated to the sponsor. A blinded Sponsor clinical scientist may 
have access to blinded aggregated ADAS-Cog11 and ADCS-CGIC results (pooled trial data) for 
the purpose of data review and will have no other responsibilities associated within the study. 
These results will be provided by the external unblinded statistician.  
 
6.11 
Safety and Tolerability Analyses 
All safety summary analyses will be performed using the actual treatment for the Safety Analysis 
by each treatment group and by the pooled buntanetap-treatment group.  
Safety and tolerability will be assessed through TEAEs; hematologic, biochemical, and 
urinalysis laboratory parameters; physical examination findings; and vital signs measurements.  
No formal statistical comparisons will be performed for safety endpoints. 
6.12               Adverse Events 
Adverse events (AEs) will be coded using MedDRA dictionary, Version 25.1 or newer.  
An AE will be considered as a treatment-emergent AE (TEAE) if started after first dose and no 
later than last dose date + 30 days, or started prior to first dose, but worsened in severity post 
dose.  
The event counts, number and percentage of subjects reporting TEAEs in each treatment group 
will be tabulated by system organ class (SOC) and preferred term (PT); by SOC, PT and 
maximum severity; by SOC, PT and relationship to study drug and by descending frequency of 
PT (within treatment group). If more than one TEAE occurs with the same PT for the same 
subject, then the subject will be counted only once for that preferred term using the most severe 
and most related occurrence for the summary. The display in these tables will be sorted 
alphabetically by SOC and then by descending frequency of PT (within treatment group) within 
each SOC.  
The incidence of most frequently reported (PT frequency >=5% in any group) TEAEs, SAEs 
reported after treatment start, TEAEs leading to drug withdrawn, and TEAEs related to study 
drug will be summarized by SOC and PT.  
An AE listing by subject will display all events, and will include the verbatim term in addition to 
the MedDRA SOC and PT. This listing will also include all relevant eCRF data associated with 
the event: date of onset, date resolved, date of last dose, severity, frequency, outcome and 
relationship to study drug and action taken with study drug. Separate listings will be presented 
for subjects with treatment-emergent SAEs, related TEAEs, TEAEs leading to drug withdrawn, 
fatal TEAEs (if any).  


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6.12.1           Clinical Laboratory Evaluations 
For continuous laboratory parameters, descriptive statistics will be presented for each visit and 
for the changes from Baseline to each subsequent visit by treatment group, and the pooled 
buntanetap-treatment group.  
 
Additionally, clinical laboratory parameters will be categorized as low, normal, or high 
according to laboratory range specifications and the number and percentage of participants in 
each category will be presented in shift tables. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. 
6.12.2   
Electrocardiogram (ECG) 
12-lead ECGs are collected throughout the study. Observed change from baseline of ECG 
endpoints at each assessment timepoint will be summarized by each treatment group, and the 
pooled buntanetap-treatment group. Observed QTc will also be categorized into the following 
categories (msec) and the number and percentage of subjects in each category will be 
summarized at each timepoint and the overall post-baseline maximum:  
• Observed: <=450, 451-480, 481-500, and >500; >450; >480 
• Change from Baseline: <=10, 11-30, 31-60, and >60; >30 
For ECG interpretations, the number and percentage of subjects with ECG results that are 
determined as normal, abnormal will be summarized at each timepoint. The overall post-baseline 
worst interpretation will also be summarized. Shift tables from baseline to each timepoint and 
from baseline to overall post-baseline worst interpretation will also be presented.  
6.12.3            Vital Signs 
Descriptive summaries (mean, SD, SE, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for systolic blood pressure, diastolic blood pressure, 
pulse, respiratory rate, and oral temperature. 
6.12.4            Physical Examination Findings 
Physical examination data will be presented in the listings. 
6.12.5            Other Safety Parameters:  C-SSRS 
The number and percentage of participants with suicidal ideation or suicidal behavior based on 
the C-SSRS will be summarized by treatment group and the pooled buntanetap-treatment group. 
The distribution of responses for most severe suicidal ideation and most severe suicidal behavior 
during the participant’s lifetime, during the double-blind treatment period, and during the safety 
follow-up period will also be presented by treatment group for the Safety Population. Supportive 


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listings will be provided and will include the participant number, study center number, lifetime 
history, and post-baseline values. Intensity of suicidal ideation, suicidal behavior type, and 
lethality of suicidal behavior will also be included in these listings. A listing of all AEs occurring 
in participants who have suicidal ideation or suicidal behavior will also be provided. 
7 
STUDY DRUG AND CONCOMITANT MEDICATIONS 
7.1 Identity of IP and Comparator 
Buntanetap will be provided in size 1 orange opaque hydroxypropyl methylcellulose (HPMC, 
vegetarian source) capsule shells.  Capsules contain buntanetap (either 7.5mg, 15mg or 30mg) 
formulated with inert inactive (non-lactose) pharmaceutical excipients generally recognized as 
safe for human pharmaceutical use. Matching placebo capsules will be prepared with the same 
inert inactive ingredients and look exactly like the buntanetap capsules. 
7.2 Dosage 
The study drug is to be taken orally; one capsule, once a day in the morning right before food, 
for 12 weeks at home.  Participants are encouraged to take at least 80% of all doses (across the 
12 weeks).  Bottles will be examined in clinic at each clinical visit to assess compliance.  


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7.3 Packaging/Dispensing/Labeling 
The study drug (buntanetap capsules and placebo capsules) is manufactured under cGMP, in a 
manner to preserve the blind, i.e., identical color and shape orange opaque HPMC hard capsule 
shells and packaged 50 capsules per bottle.  
The investigational drug supply will be shipped directly to the clinical sites to dispense to 
participants.  
Sites should order IP only after successful confirmation of all eligibility criteria (including lab 
results) during screening period and well ahead of baseline visit.  
The dosing schedule and storage requirements will be clearly explained to the participants and 
study partner before dispensing the study drug.  
All packaging and labelling as well as the production of study medication will be in accordance 
with cGMP regulations. 
7.4 Storage 
Both buntanetap capsules and the matching placebo capsules must be stored at room temperature 
(not to exceed 25°C/77°F), protected from light and moisture, in a locked, temperature-
controlled area with restricted staff access. 
7.5 Drug Accountability  
The investigator is responsible for investigational product reconciliation and records 
maintenance.  In accordance with all applicable regulatory requirements, the investigator or 
designated site staff must maintain investigational product accountability records throughout the 
course of the study.  The responsible person(s) will document the amount of investigational 
product dispensed to and returned by participants.  All used and unused study drug containers 
must be returned to the site for accountability.  Once authorized by a clinical monitor, unused 
study drug (including partially used bottles) will be shipped back to the contracted depot for 
destruction.  
7.6 Compliance 
Site personnel will assess compliance based on the amount of study drug dispensed to and 
returned by the participants, together with any related information, including the administration 
of study drug by study staff during the end of trial visit. Participants are encouraged to maintain a 
minimum of 80% compliance with study drug administration across the 12 weeks at home 
dosing period.  
Prior to the end of trial visit, site personnel will also contact the participant to remind them of the 
dose regimen, to ensure that a good level of compliance has been achieved.  
 


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7.7 
Breaking the Blind  
Only in the case of an emergency, when knowledge of whether the participant has received the 
investigational product is essential for the clinical management or welfare of the participant, may 
the investigator request to unblind a participant’s treatment assignment. If the investigator needs 
the blind to be unmasked for a participant for SAE, the investigator can open the blind without 
prior consulting with the Medical Monitor. If the blind is broken, whether it be by accident or for 
the welfare of the participant, the investigator MUST contact the Medical Monitor at the earliest 
opportunity and the entire process shall be recorded in the study documents, together with the 
procedures for the management of the SAE.  Refer to the study procedures manual for detailed 
procedures related to breaking the blind and reporting. 
7.8     Concomitant Medications 
7.8.1 
Prohibited Concomitant Medications 
Investigational agents are prohibited 4 weeks or five half-lives, whichever is greater, prior to 
entry and for the duration of the trial.  
Aducanumab/Aduhelm and Lecanemab/Leqembi are prohibited for 4 weeks or five half-lives, 
whichever is greater, prior to entry and for the duration of the trial. 
Initiation of prohibited medications during the course of the study is discouraged, however, if an 
excluded medication is initiated after screening, the site should consult with the Medical Monitor 
for further guidance. 
Buntanetap is mainly metabolized by CYP3A4 in vitro. Therefore, we recommend avoiding 
concomitant use of strong and moderate CYP3A4 inhibitor/inducers, examples see below 
according to FDA guidance on drug development and drug interactions. 
CYP3A4 inhibitors Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil 
CYP3A4 inducers 
Rifampicin 
7.8.2 
Permitted Concomitant Medications 
Use of the following medications is allowed only if the participants have been stabilized for at 
least 4 weeks before screening and will continue to be stable throughout the study: 
• tricyclic antidepressants  
• antipsychotics prescribed for any reason. However, the dosage must not exceed the 
following for these medications: 
Quetiapine ≤50 mg/day, risperidone ≤1.5 mg/day, olanzapine ≤5 mg/day, and 
aripiprazole ≤10 mg/day 
If the subject is on other antipsychotics besides the ones mentioned above, please consult              
the MM before screening the subject. 
• psychostimulants 


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Discontinuation and/or change of any of the above medication during the course of the study is 
discouraged, however, if necessary, the site should consult with the Medical Director and 
Sponsor for further guidance. 
This protocol allows concomitant treatment with anti-cholinesterase for 4 weeks or greater prior 
to screening. 
If participants are taking any anticonvulsant medications used for epilepsy or mood stabilization, 
neuropathic pain indications, dosing must be stable for at least 4 weeks prior to screening. 
Mood-stabilizing psychotropic agents, including but not limited to lithium, are permitted. Dosing 
must be stable for at least 4 weeks prior to Screening. 
Use of short acting benzodiazepines and hypnotics for treatment on an as-needed basis for 
insomnia or daily dosing as anxiolytics is permitted but should be avoided for 8 hours before 
administration of cognitive tests. If sedating medication is given for any short-term use, then all 
cognitive assessments must be administered at least 24 hours after administration of the sedative.  
At this time, there is no controlled clinical data available for anyone receiving SARS-CoV-2 
(COVID19) vaccination while being treated with buntanetap. However, based on the intended 
mechanism of actions and currently available data for these vaccine candidates and for 
buntanetap, it is not believed that there are specific risks to consider in participants participating 
in this study who have received SARS-CoV-2 (COVID19) vaccination or who are planning to 
receive the vaccination. As such, SARS-CoV-2 (COVID19) vaccination is not prohibited. If 
appropriate, SARS-CoV-2 (COVID19) vaccination should be considered as a concomitant 
medication. 
8 STUDY POPULATION 
Participants in this study must be in accordance with the criteria specified below. Participants 
who do not meet all inclusion criteria, disease diagnostic criteria, or who meet any exclusion 
criteria will not be included in the clinical trial.   
 8.1    Inclusion Criteria 
Participants must meet the following criteria:  
1.  Diagnosis of Alzheimer’s disease according to NIA and NIA-AA criteria for probable AD 
(McKhann 2011). 
2. Male or female aged 55 – 85 years.  
3. MMSE 14-24. 


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4.  Have a study partner who will provide written informed consent to participate, is in frequent 
contact with the participant (defined as at least 10 hours per week) and will accompany the 
participant to study visits at designated times. 
5. Female participants of childbearing potential* must have a negative urine pregnancy test at 
Screening, must be non-lactating and must agree to use a highly effective method of 
contraception (i.e., a method resulting in a failure rate of less than 1% per year when used 
consistently and correctly) during the trial and for 4 weeks after the last dose of trial 
treatment, such as: 
• 
Oral, intravaginal, or transdermal combined (estrogen plus progestogen) hormonal 
contraception associated with inhibition of ovulation 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion  
• 
Vasectomized partner (a vasectomized partner is a highly effective contraception 
method provided that the partner is the sole male sexual partner of the participant, and 
the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used) 
• 
Sexual abstinence (sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk 
associated with the study treatment. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant) 
*Non-childbearing potential includes surgically sterilized or postmenopausal with no 
menstrual bleeding for at least one year prior to study start. 
6. 
Male participants must be sterile or sexually inactive or agree not to father a child during 
the study and one month after the last dose of study medication and must agree to use a 
barrier method for contraception. Female partners of male participant must adopt a highly 
effective method of contraception with a failure rate of less than 1% per year when used 
consistently and correctly such as: 
• 
Oral, intravaginal, or transdermal combined (estrogen plus progestogen) hormonal 
contraception associated with inhibition of ovulation 
• 
Oral, injectable, or implantable progestogen-only hormonal contraception associated 
with inhibition of ovulation 


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• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion  
7. 
Participants can provide written informed consent. If PI deems that participant cannot fully 
understand ICF to give consent, their legally authorized representatives (LARs) can 
provide written informed consent. Participants can comply with scheduled visits, and other 
study-related procedures to complete the study with the help of the study partner. 
 
8. 
No evidence of current suicidal ideation or previous suicide attempt in the past 2 months as 
evaluated in the Columbia Suicide Severity Rating Scale nor suicidal behavior in the past 6 
months as per investigator.  
9. 
Stability of permitted medications for at least 4 weeks prior to screening.  
a. Cholinesterase inhibitors and/or memantine medication 
 
b. Anticonvulsant medications used for epilepsy or mood stabilization, neuropathic pain 
indications.  
 
c. Mood-stabilizing psychotropic agents, including, but not limited to, lithium.  
10. Adequate visual and hearing ability (physical ability to perform all the study assessments) 
as per investigator.  
 
11. Good general health with no disease expected to interfere with the study as per investigator.  
 
8.2 Exclusion Criteria 
Participants meeting any of the following criteria must not be included in the study: 
1. 
Has a history of a psychiatric disorder such as schizophrenia, bipolar disorder, or 
major depression according to the criteria of the most current version of the Diagnostic 
and Statistical Manual of Mental Disorders (DSM). Mild depression or history of 
depression that is stable on treatment with a SSRI or SNRI medication at a stable dose is 
acceptable.  
 
2. 
Has non-AD dementia, such as vascular dementia, Lewy body dementia, 
frontotemporal disease, Parkinson disease dementia, B12 and thyroid deficiency caused 
dementia.  
 
3.      History of a seizure disorder, if stable on medication is acceptable.  


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4. 
Has a history or current evidence of long QT syndrome, Fridericia’s formula 
corrected QT (QTcF) interval ≥ 450 ms for men and 460 ms for women, or torsades de 
pointes.  
 
5. 
Has bradycardia (<50 bpm) or tachycardia (>100 bpm) on the ECG at screening.  
 
6. 
Has uncontrolled Type-1 or Type-2 diabetes. A participant with HbA1c levels up 
to 7.5% can be enrolled if the investigator believes the participant’s diabetes is under 
control.  
 
7. 
Has clinically significant renal (CKD-EPI <60 mL/min/BSA (body surface area) 
or hepatic impairment (ALP > 2.0 ULN and/or total bilirubin > 2.0 ULN).  
 
8. 
Has any clinically significant abnormal laboratory values. Participants with liver 
function tests (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) 
greater than twice the upper limit of normal will be excluded.  
 
9. 
Is at imminent risk of self-harm, based on clinical interview and responses on the 
C SSRS, or of harm to others in the opinion of the Investigators. Participants must be 
excluded if they report suicidal ideation with intent, with or without a plan or method (e. 
g. positive response to Items 4 or 5 in assessment of suicidal ideation on the C SSRS) in 
the past 2 months, or suicidal behavior in the past 6 months.  
 
10. 
Has cancer or has had a malignant tumor within the past year, except participants 
who underwent potentially curative therapy with no evidence of recurrence. (Participants 
with stable untreated prostate cancer or skin cancers are not excluded).  
11. 
Alcohol / Substance use disorder, moderate to severe, in the last 5 years according 
to the most current version DSM.  
 
12. 
Participation in another clinical trial with an investigational agent and have taken 
at least one dose of study medication, unless unblinded on placebo, within 4 weeks prior 
to the start of screening, or five half-lives of the investigational drug, whichever is 
greater.  
         The end of a previous investigational trial is the date the last dose of an 
investigational agent was taken. 
 
13. 
Participants with learning disability or developmental delay.  
 
14. 
Participants whom the site PI deems to be otherwise ineligible.  
 


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15. 
Participants with a known allergy to the investigational drug or any of its 
components. Here are all the inactive ingredients of the IMP:  
Silicified Microcrystalline Cellulose 
Dibasic Calcium Phosphate Dihydrate 
Mannitol 
Magnesium Stearate 
Hypromellosee (capsule shells structure) 
titanium dioxide (opacifier of the capsule shells) 
 
16. 
Participant is currently pregnant, breast-feeding and/or lactating. 
17.    Participant is currently taking strong and moderate CYP3A4 inhibitors and/or 
inducers. See examples below: 
CYP3A4 
inhibitors 
Itraconazole, Ketoconazole, Azamulin, Troleandomycin, 
Verapamil 
CYP3A4 
inducers 
Rifampicin 
 
 
 


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9 DESCRIPTION OF STUDY VISITS 
Each participant will have a 42-day screening period followed by 12 weeks of treatment at home. 
The study visits are described below and outlined in the Schedule of Events in Appendix 1.  
9.1 Screening Visit 
The screening visit should occur up to 42 days before the baseline visit. The screening visit 
procedures may be completed over multiple days, but all must be done within a week. At PI’s 
discretion, re-testing can be done within 30 days. If the investigator deems re-screening is 
justified, they must contact Medical Monitor and sponsor for discussion on a case-by-case basis. 
If/when rescreening MMSE, the test has to be done at least 3 weeks apart from the previous one. 
Potential participants or their legally authorized representatives (LAR) if PI deems that 
participant cannot fully understand ICF to give consent, must sign an informed consent form 
prior to administration of any study-related procedures. The informed consent process must be 
performed by the principal investigator or medically qualified sub-investigator. Information 
regarding the participant’s demographics, concurrent medications, and medical history will be 
collected along with cognitive assessments, physical examination, and neurological examination. 
Safety assessments will include an ECG that will need to be read locally and reviewed by the site 
investigator to confirm eligibility. The clinical safety laboratory blood and urine tests will be sent 
to a central lab for analysis. The screening safety laboratory tests will be comprised of a 
metabolic panel, complete blood count, and urinalysis as listed in Section 12.1.3. Urine dipstick 
pregnancy test will be completed for female participants of childbearing potential. Fasting is 
required for safety laboratory tests. 
Cognitive and functional assessments should not be administered when the participant is in a 
fasted state. Once all screening visit procedures are completed, all information related to 
eligibility, including screening lab results, must be reviewed by the site investigator to assess the 
participant’s eligibility before proceeding to Baseline. 
9.2 Baseline Visit 
Sites should remind participants 1-3 days prior to their onsite visit through a telephone call. 
Baseline procedures include functional, cognitive, and behavioral assessments, safety 
assessments and a review of concurrent medications and potential adverse events that might 
occur.  To avoid the learning effect, MMSE should be done at least three weeks after the 
participant’s last MMSE test. The visit will consist of the following: admission procedures, 
including genetic material collection (blood for ApoE genotype), PK Sampling / administration 
of first dose, and finally, discharge procedures.   
Fasting state is required for safety laboratory tests, however, cognitive, and functional 
assessments should not be administered when the participant is in a fasted state. 
All baseline assessments should be performed on the same day. Details as below. 


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Participants should arrive fasted in the morning after an overnight fast. Clinical safety labs will 
be drawn and sent to the central lab for analysis.  
After safety lab, participants will be provided low-fat light meal before completing functional 
and cognitive evaluations, a physical and neurological exam, collecting vital signs, ECG, and 
reviewing and recording adverse events and concurrent medications. Sites should take detailed 
notes of the contents of all meals provided to the participants. Following completion of all these 
procedures, participants who continue to meet all protocol inclusion criteria and no exclusion 
criteria should be randomized.  
If no medical or compliance concerns are identified, the participant will move on to the PK 
sampling phase, which will entail the following procedures: 
1) Collect initial samples of blood (hour 0) (12ml) with venipuncture unless PI deems 
inappropriate with 2ml in a tube for ApoE genotype* and 10ml in a separate tube for PK. 
2) Administer first dose of assigned study drug after the hour 0 sampling. 
3) Collect blood (10mL) at the 1hr, 2hrs and 4hrs timepoints. Blood should be taken within 
± 10 mins of times. 
4) Perform the final safety monitoring.  
* ApoE genotype sample can be collected along with any other blood draw during this visit, as deemed appropriate 
by PI.  
Prior to discharge from the clinic, vital signs should be recorded, and a review of AE(s) and 
concomitant medications should be conducted. Participants will be educated of the study drug 
compliance and study drug return. Upon determination by the Investigator (or qualified 
designee) that the participant is stable, the participant will be discharged. If a participant 
experiences an unstable AE, please contact the Medical Monitor for guidance on the appropriate 
course of action to be taken. 
 
9.3 Onsite Visit at 6 Weeks  
Sites should remind participants 1-3 days prior to their onsite visit through a telephone call. At 6 
weeks from the baseline visit, a clinic visit should occur. Clinic visit procedures include 
functional, and cognitive assessments, safety assessments, and review of concurrent medications 
and adverse events. Fasting is required for safety laboratory tests.  
After safety lab, participants will be provided low-fat light meal before completing functional 
and cognitive evaluations, a physical and neurological exam, collecting vital signs, ECG, and 
reviewing and recording adverse events and concurrent medications. Sites should take detailed 
notes of the contents of all meals provided to the participants. 


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Study medication compliance will be reviewed and discussed, and reminders given about the 
upcoming end of trial visit. The participant should be scheduled for the 12-week clinic visit. 
 
9.4 12 Weeks Visit (End of Trial Visit) 
Sites should remind participants 1-3 days prior to their onsite visit through a telephone call. 
Admission for the end of trial visit should occur 12 weeks following the first dose of study 
medication. A pre-visit phone call will be conducted 1-3 days prior to admission and a post-visit 
phone follow-up will be conducted approximately 24 hours following discharge. End of trial visit 
procedures include functional, and cognitive assessments, safety assessments, and review of 
concurrent medications and adverse events that occur in clinic and blood collection. Fasting state 
is required for safety laboratory tests, however, cognitive, and functional assessments should not 
be administered when the participant is in a fasted state. 
9.4.1 End of Trial Visit 
This constitutes the participants’ last clinical visit during the study. The end of trial visit will 
consist of the following: admission procedures, blood sampling, all psychometric and safety 
tests, and discharge procedures. Fasting is required for safety laboratory tests. 
Participants should arrive fasted in the morning after an overnight fast. Clinical safety labs will 
be drawn and sent to the central lab for analysis.  
After safety lab, participants will be provided a low-fat light meal before completing functional 
and cognitive evaluations, a physical and neurological exam, collecting vital signs, ECG, and 
reviewing and recording adverse events and concurrent medications. Sites should take detailed 
notes of the contents of all meals provided to the participants.  
If no medical or compliance concerns are identified, the participant will move on to the PK 
sampling phase, which will entail the following procedures: 
1) 
Collect initial samples of blood 10ml (hour 0) with venipuncture unless PI deems 
inappropriate. 
2) 
Administer last dose of assigned study drug after the hour 0 sampling. 
3) 
Collect blood (10mL) at the 1hr, 2hrs and 4hrs timepoints. Blood should be taken within 
± 10 mins of times. 
4) 
Perform the final safety monitoring. 
Prior to discharge from the clinic, vital signs should be recorded, and a review of AE(s) and 
concomitant medications should be conducted. Upon determination by the Investigator (or 
qualified designee) that the participant is stable, the participant will be discharged. If a 
participant experiences an unstable AE, please contact the Medical Monitor for guidance on the 
appropriate course of action to be taken. 


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9.4.2 Post End of Trial Visit 24-Hour Phone Follow-up 
Approximately 24 hours following the end of trial visit the participant will be contacted by 
phone to confirm the participant’s well-being and to query about any new AEs. 


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10 EARLY TREATMENT/STUDY DISCONTINUATION 
The investigators at each site will make every reasonable effort to maximize participant 
retention. However, if an investigator removes a participant from treatment or study, or if a 
participant declines further treatment or study participation, an early discontinuation visit will be 
completed as soon as possible following discontinuation.  
Participants who discontinue from the study prior to completing all protocol procedures may be 
replaced in consultation with the Sponsor. 
10.1 
Reasons for Early Discontinuation 
Participants or their LARs may withdraw from the study at any time as stated in the informed 
consent document given to the participant at the time of enrollment. Participants or their LARs 
should inform sites as soon as such a withdraw decision is made. Participants must also be 
discontinued from treatment/study for reasons such as the following: 
• Adverse experience: The participant has experienced an adverse event that, in the opinion 
of the investigator, requires early discontinuation. This may include abnormal laboratory 
values. 
• Death. 
• Safety risk: Any participant who becomes a safety risk to themselves during the trial will 
be withdrawn. 
• Protocol violation: The participant fails to meet protocol entry criteria during the study 
after being randomized or does not adhere to protocol requirements. * 
• Development of suicidal or homicidal ideation requiring hospitalization or confinement. 
• Consent is withdrawn. The participants or their LARs wishes to withdraw from the study. 
• The study is terminated by the Sponsor/Coordinating Center, alone or at the 
recommendation of the Data Safety Monitoring Board. 
• Lost to follow up.  Participant could not be recalled back to conduct follow up visits. 
* The line item above requires the participant to continue to meet study entry criteria after 
randomization. This means that assessments conducted at visits post-randomization, such as vital 
signs, ECG, and laboratory tests, with results that fall outside of the parameters outlined in the 
Inclusion/Exclusion criteria must be discussed with the Medical Monitor and Study Team.  
The investigator and Medical Monitor will review the case to determine whether the participant 
must be discontinued from the study based on the abnormal value or if it is safe for the 
participant to continue treatment.  
 


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11 STUDY-SPECIFIC INSTRUMENTS  
The following instruments will be employed to measure states of function, dementia, and 
movement.   
• Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) 
• Mini-Mental State Examination (MMSE) 
• Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) 
• Clinical Global Impression of Change (ADCS-CGIC) 
• Digital Symbol Substitution Test (DSST)  
12 STUDY-SPECIFIC PROCEDURES  
12.1 Safety Assessments 
Safety will be evaluated by monitoring for changes in the parameters summarized below, 
including any AEs/SAEs as reported by participants or observed by the clinical staff, or using 
concomitant medication during the study. 
12.1.1 Physical and Neurological Examination 
A medically qualified professional will perform a physical examination that consists of a review 
of the major body systems (i.e., skin, head/ears/eyes/nose/throat (HEENT), cardiovascular, 
pulmonary, abdomen, musculoskeletal, and extremities) and a neurological examination which 
will include an assessment of cranial nerves, strength, coordination, reflexes, sensation, tremor, 
gait and mental status. Assessments of height, weight, and vital signs (systolic and diastolic 
blood pressure, pulse, temperature, and respiration) are included. 
12.1.2 Electrocardiogram (ECG) 
An appropriately qualified individual will conduct a standard 12-lead supine resting ECG. The 
ECG report must be reviewed, signed, and dated by the site PI (or a medically qualified 
individual delegated by the site PI). Those with clinically significant ECG findings will be 
referred for follow-up as deemed appropriate by the investigator and may be excluded from the 
study. 
 
 




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13 PERSONNEL REQUIREMENTS  
The site PI is responsible for the overall conduct of the study at the site. The PI is to supervise 
project personnel and ensure that clinical raters maintain a high level of skill and accuracy in 
conducting assessments. The site PI should keep the same rater for the same subject for the same 
scales during the whole study. Additionally, the PI will perform or supervise clinical evaluation 
of all participants and ensure protocol adherence. Additional key personnel will be required, as 
outlined in the procedure manual.  
14 ADVERSE EVENTS (AES)  
14.1 Definition 
An AE is defined as per the US Code of Federal Regulation, Title 21, Part 312.32 (2016) and 
ICH E2A: International Conference on Harmonization - Tripartite Guideline: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting (1994).  
Any untoward medical occurrence in a participant or clinical investigation participant 
administered a pharmaceutical product which does not necessarily have to have a causal 
relationship with this treatment. 
Collection of adverse events will begin once informed consent is signed and will continue until 
the 24-hour phone follow-up after the participant is discharged from the clinic at the end of study 
visit or discontinues from the study.  Adverse events include but are not limited to: (1) worsening 
or change in nature, severity, or frequency of conditions or symptoms present at the start of the 
study; (2) Participant deterioration due to primary illness; (3) intercurrent illness; and (4) drug 
interaction. An abnormal laboratory value will only be reported as an AE if the investigator 
considers it clinically significant, or if it leads to the Participant being withdrawn from the study. 
The investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs or symptoms. Symptoms and conditions present at the beginning of 
the study will be characterized, so that AEs can be defined as any new symptom, or any increase 
in frequency or severity of an existing symptom. Adverse events should be described with 
medical terminology so that the event can be matched against a medical coding dictionary, such 
as MedDRA (Medical Dictionary for Regulatory Activities). 
Investigators should report their assessment of the potential relatedness of each AE to the 
protocol procedure, and to the investigational product, and/or drug delivery system used in the 
protocol.  
Following questioning and evaluation, all AEs, whether determined to be related or unrelated to 
the study drug by a medically qualified site PI or clinician must be documented in the 
Participant’s records, in accordance with the investigator’s normal clinical practice, and on the 
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14.2 
Following Up on AEs 
The investigator is obliged to follow participants with AEs until the events have subsided, the 
conditions are considered medically stable, or the participants are no longer available for follow 
up. Participants who discontinue due to adverse experiences will be treated and followed 
according to established medical practice. All pertinent information will be entered into the 
eCRF. Adverse events will be reported to the Medical Monitor, Sponsor, and DSMB, per 
Coordinating Center SOPs and the DSMB Charter. 
15 SERIOUS ADVERSE EVENTS (SAE) 
15.1 
Definition  
An SAE is defined as per the US Code of Federal Regulation, Title 21, Part 312.32 (2016) and 
ICH E2A: International Conference on Harmonization - Tripartite Guideline: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting (1994). 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or Sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. 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 participant and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
15.2 
Reporting SAEs 
Collection of serious adverse events will begin once informed consent is signed (regardless of 
study drug exposure) and will be monitored throughout the trial.  All SAEs must be reported to 
the Medical Monitor and the Sponsor within 24 hours of learning of the event. This in turn will 
trigger an alert to the appropriate Coordinating Center personnel and Protocol Project Directors, 
which will lead to the initiation of the creation of the report. A notification will be sent to all 
participating sites and the DSMB once the report is available. Sites will inform their IRB of the 
event based on local IRB requirements. The Sponsor is the IND holder and is responsible for 
submitting any SAEs according to the FDA reporting requirements.   
 
 


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16 SUSPECTED UNEXPECTED SERIOUS, ADVERSE REACTION 
16.1 
Definition 
A suspected unexpected serious adverse reaction (SUSAR) is an AE that is assessed as serious, 
related, and unexpected. 
16.2 
Reporting of Suspected Unexpected Serious Adverse Reactions 
The Sponsor is responsible for informing the FDA and IRB of any individual case reports of SAEs 
that are determined to be reportable by the Sponsor (SUSARs). The Investigator will ensure that 
all relevant information is provided to the Sponsor to allow the Sponsor to meet their obligations 
to report the SUSAR to the FDA and IRB. For a SUSAR that is fatal or life-threatening, this should 
be reported as soon as possible and not later than 7 days after the Sponsor was first advised, for 
any other SUSAR this should be within 15 days. 
17 ADVERSE EVENTS OF SPECIAL INTEREST 
Not applicable. 
18 PRECAUTIONS/OVERDOSE 
If a participant receives a dose exceeding 200 mg of buntanetap, the dose may be considered toxic. 
Since this is a double-blind study, if a participant swallows 7 or more capsules with the assumption 
of them being in the 30mg buntanetap group, this will be considered an overdose, and in such case, 
the information will be collected following the same timeframe and procedures as for a SAE, even 
if the overdose is not associated to any AE/SAE. No specific treatment is recommended apart from 
appropriate supportive measures. 
19 PREGNANCY 
Female participants will be instructed to notify the Investigator immediately if they become 
pregnant during the study. Male participants will be instructed to notify the Investigator 
immediately if their partner becomes pregnant. Pregnant participants will be withdrawn from 
further study treatment. The participants will also be instructed to report pregnancies discovered 
after the last visit, if they believe that conception occurred during their participation in the study.  
A pregnancy as such is not an AE, unless there is a possibility that the study drug has interfered 
with the efficiency of any contraceptive measures. However, the Investigator should report 
pregnancies according to the procedures and timelines described for reporting of SAEs (Section 
15.2). The pregnancy report form should be used instead of the SAE form. 
The pregnant participant or partner will be followed until the end of the pregnancy. Any 
complication during the pregnancy should preferably be reported as an AE or SAE (if it fulfils 
SAE criteria). The outcome of the pregnancy must be reported on the pregnancy report form. Any 
spontaneous abortion, stillbirth, birth defect/congenital anomaly, death, or other serious infant 
condition must be reported and followed up as an SAE. 


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20 DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent DSMB will review the safety information from the study on an ongoing basis. 
The DSMB, will identify the study-specific data parameters and format of the information to be 
reported, as well as the timing of reports based on the enrollment status of the study. The DSMB 
will initially be provided with data blinded to treatment status, but they may request unblinded 
data if there is a safety concern. 
Additionally, the DSMB will be informed of the occurrence of any serious adverse events within 
7 days of being reported to the Coordinating Center. The DSMB may at any time request 
additional information from the Coordinating Center. 
Based on the review of safety data, the DSMB will make recommendations regarding the 
conduct of the study. These may include amending safety monitoring procedures, modifying the 
protocol or consent, terminating the study, or continuing the study as designed. Using the Safety 
Review Process (review of lab data, vitals, and adverse events) and the DSMB, there is 
substantial oversight and case review to alert the investigators, in a timely manner, to any safety 
issues that may arise. Further details will be provided in the DSMB charter. 
21 RECORDING AND COLLECTION OF DATA  
21.1 
Electronic Case Report Form (eCRF) 
The PI or designee will record all data collected (either written or electronic record of data). 
Written or electronic data of record must be entered into the eCRF provided for that purpose. In 
some instances, no prior written or electronic record of data may exist, and data recorded directly 
into the eCRF is considered source data. The site will be suitably trained on the use of the eCRF 
and appropriate site personnel will be authorized to provide electronic signatures. The PI is 
responsible to verify the integrity of the data and acknowledge as such by signature. 
All site entries will be made in a secured eCRF, and the PI will review the record for 
completeness. If corrections are necessary to the eCRFs, the PI or designee will update the eCRF 
and provide documentation for the reason for change. 
Completed eCRFs will be submitted according to provided instructions and reviewed by the 
Coordinating Center to determine their acceptability. If necessary, data correction requests will 
be generated for resolution by the study site.  
 


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21.2 
Study Files and Source Documents 
Participant confidentiality is strictly held in trust by the participating investigators, research staff, 
and the Coordinating Center and/or sponsoring institution and their agents. This confidentiality is 
extended to cover testing of biological samples and genetic tests in addition to the clinical 
information relating to participants. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study, or the data will be released to any 
unauthorized third party, without prior written approval of the sponsoring institution. Authorized 
representatives of the sponsoring institution may inspect all documents and records required to 
be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. Any data, specimens, forms, reports, video/audio recordings, and 
other records that leave the site will be identified only by a participant identification number 
(Participant ID, PID) to maintain confidentiality. All records will be kept in a locked file cabinet. 
All computer entry and networking programs will be done using PIDs only. Information will not 
be released without written permission of the participant, except as necessary for trial-related 
monitoring, audits, IRB review, and regulatory inspection(s), where direct access to source 
data/documents will be provided. 
Information about study participants will be kept confidential and managed according to the 
requirements of the General Data Protection Regulation (GDPR) of 2018, and the Health 
Insurance Portability and Accountability Act (HIPAA) of 1996.  
If a participant revokes authorization to collect or use protected health information (PHI), the 
investigator, by regulation, retains the ability to use all information collected prior to the 
revocation of participant authorization. Each site PI, under the guidance of his/her IRB, is 
responsible for ensuring that all applicable GDPR/HIPAA regulations and laws are met. 
22 ETHICS AND REGULATORY CONSIDERATIONS 
22.1 
Good Clinical Practice 
This study will be conducted in compliance with the protocol and accordance with Good Clinical 
Practice (GCP) guidelines, as defined by the International Conference on Harmonization (ICH) 
Guideline, Topic E6, the ethical principles of the latest revision of the Declaration of Helsinki as 
adopted by the World Medical Association, and all other applicable local regulatory 
requirements and laws. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s) in accordance with GCP. 
No study document shall be destroyed without prior written agreement between the Coordinating 
Center and the investigator. Should the investigator wish to assign study records to another party 


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or move them to another location, he/she may do so only with the prior written consent of the 
Coordinating Center. 
22.2 
Institutional Review Board (IRB) 
In the US, IRBs must be constituted, and their authority delegated through the institution’s 
normal process of governance according to applicable State and Federal requirements for each 
participating location. Each participating institution must provide for the review and approval of 
this protocol and the associated informed consent documents and recruitment material by an 
appropriate IRB registered with the OHRP. Any amendments to the protocol or consent materials 
must also be approved before they are placed into use. In the US, only institutions holding a 
current US Federal wide Assurance (FWA) issued by OHRP may participate. 
The investigator must obtain approval from the IRB for all subsequent protocol amendments and, 
when warranted, changes to the informed consent document. Protocol and informed consent 
form amendments can be made only with the prior approval of the Coordinating Center. The 
investigator shall notify the IRB of deviations from the protocol or SAEs occurring at the site, in 
accordance with local procedures. 
22.3 
Informed Consent and Health Insurance and Portability and Accountability Act 
(HIPAA) Compliance 
Informed consent will be obtained in accordance with 21CFR§50.25, and ICH GCP. Applicable 
HIPAA privacy notifications will be implemented, and HIPAA/GDPR authorizations signed 
before protocol procedures are conducted. Information should be given in both oral and written 
form as deemed appropriate by the Site’s IRB.  
Prior to the beginning of the trial, the investigator must obtain the IRB’s written approval of the 
informed consent form and any other written information to be provided to participants and their 
LAR if LAR is required. Consent forms must be in a language fully comprehensible to the 
prospective participants. Participants and their LARs if LAR is required will be given ample 
opportunity to inquire about the details of the study. Prior to a participant’s participation in the 
trial, the written informed consent form should be signed and personally dated by the participant 
or their LAR if LAR is required and by the person who conducted the informed consent 
discussion. Participants will be provided a copy of the signed ICF. 
The informed consent will not only cover consent for the trial itself, but for the genetic 
samples/data/storage and biomarker samples/data/storage as well. Consent forms will specify 
that DNA and biomarker samples are for research purposes only; the tests on the DNA and 
biomarker samples are not diagnostic in nature, and are part of the study analysis, and 
participants will never receive results. 
 
 


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23 STUDY MONITORING  
The clinical monitor is responsible for inspecting the case report forms (CRFs) and source 
documentation at specific time points throughout the study to verify adherence to the protocol, 
completeness and accuracy of the data, and adherence to local regulations on the conduct of 
clinical research. 
The monitor will visit the study site on a regular basis to ensure that the study is conducted and 
documented in accordance with this protocol, ICH GCP guidelines, regulatory requirements, and 
any study specific documents such as CRF completion guidelines.  Monitoring visits will be 
conducted to confirm that e.g.: 
• The investigational team is adhering to the study protocol 
• Informed consent has been obtained from all participants 
• AEs have been reported as required 
• Data are being accurately recorded in the CRF 
• Study drug is being stored correctly and drug accountability is being performed on an on-going basis 
• Facilities are, and remain, acceptable throughout the study 
• The Investigator and the site are receiving sufficient information and support throughout the study 
Moreover, during monitoring visits the data recorded in the CRF, source documents and other 
study-related records will be compared against each other to ensure accurate data that reflect the 
actual existence of the participant in the study, i.e., source data verification. The Site Investigator 
will cooperate in the monitoring process by ensuring the availability of the CRF, source 
documents and other necessary documents at the time of the monitoring visits. Site Investigator 
will promptly address any matters brought to his/her attention by the monitor. 
24 AUDIT 
In accordance with ICH E6 R2 (Good Clinical Practices) representatives of the Contract 
Research Organization (CRO) and/or Sponsor and/or regulatory agency may select this study for 
audit. The investigator and study staff are responsible for maintaining the site master file 
containing all study-related regulatory documentation that will be suitable for inspection at any 
time by the CRO, the Sponsor, its designees, a regulatory authority (i.e., FDA) and/or an IRB. 
Inspection of site facilities (e.g., pharmacy, laboratories) to evaluate the trial conduct and 
compliance with the protocol may also occur. 
25 RECORD RETENTION 
The Sponsor shall retain the records and reports required for 2 years after a marketing 
application is approved for the drug; or, if an application is not approved for the drug, until 2 
years after shipment and delivery of the drug for investigational use is discontinued and FDA has 
been so notified (21CFR§312.57). 
 


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26 LITERATURE CITED 
Chen XQ, S.A., Pearn M, Maccecchini M, Mobley W, Targeting increased levels of APP in 
Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal 
phenotypes in the Ts65Dn mouse model. Alzheimer's & dementia, 2020. 
Fang C, Hernandez P, Liow K, Damiano E, Zetterberg H, Blennow K, Maccecchini M. (2022). 
Buntanetap, a novel translational inhibitor of multiple neurotoxic proteins, proves to be safe and 
promising in both Alzheimer’s and Parkinson’s patients. Journal of Prevention of Alzheimer’s 
Disease. 2022. 
Folstein M.F., Folstein, S.E., McHugh, P.R. (1975). “Mini-mental state”. A practical method for 
grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12(3), 
189-198. 
Kadir A., Andreasen N., Almkvist O., Wall A., Forsberg A., Engler H., HagmanG., Lärksäter 
M.,Winblad B., Zetterberg H., Blennow K., Längström B., Nordberg A. (2008). Effect of 
Phenserine Treatment on Brain Functional Activity and amyloid in Alzheimer ’s disease. Ann 
Neurol 621-631. 
Kuo YM, Nwankwo EI, Nussbaum RL, Rogers J, Maccecchini ML (2019). Translational 
inhibition of α-synuclein by Posiphen normalizes distal colon motility in transgenic Parkinson 
mice. Am J Neurodegener Dis 8(1):1-15. 
Lilja A.M., Röjdner J., Mustafiz T., Thome C.M., Storelli E., Gonzalez D., Lithner C.U., Greig 
N.H., Nordberg A., Marutle A. (2013) Age-Dependent Neuroplasticity Mechanisms in 
Alzheimer Tg2576 Mice Following Modulation of Brain Amyloid-β Levels.  PLoS ONE 8(3): 
e58752. doi:10.1371/journal.pone.0058752. 
Maccecchini ML, Chang MY, Pan C, John V, Zetterberg H, Greig N (2012). Posiphen as a 
candidate drug to lower CSF amyloid precursor protein, amyloid-b peptide and s levels: target 
engagement, tolerability and pharmacokinetics in humans. J Neurol Neurosurg Psychiatry, 
83:894-902.  
 
Marutle A, Ohmitsu M, Nilbratt M, Grieg NH, Nordberg A, Sugaya K (2007). Modulation of 
human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. 
PNAS 104(30). 
 
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas GH, Klunk WE, 
Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, Rossor MN, Scheltens P, Carrillo 
MC, Thies B, Weintraub S, Phelps CH (2011). The diagnosis of dementia due to Alzheimer’s 
disease: recommendations from the National Institute on Aging- Alzheimer’s Association 
workgroups on diagnostic guidelines for Alzheimer’s disease. Alzeheimrs Dement 7(3):263-9. 
 


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Teich AF, Sharma E, Barnwell E, Zhang H, Staniszewski A, Utsuki T, Padmaraju V, Mazell C, 
Tzekou A, Sambamurti K, Arancio O, Maccecchini ML (2018). Translational inhibition of APP 
by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse. 
Alzheimers Dement Transl Res Clin Interv 4:37–45. 
 
Wechsler D (2008). Wechsler Adult Intelligence Scale—Fourth Edition Administration and 
Scoring Manual. San Antonio, TX: Pearson (only available under license agreement) 
Yu QS, Reale M, Kamal M.A., Holloway H.W., Luo W., Sambamurti K., Ray B., Lahiri D.K., 
Rogers JT, Greig NH (2013). Synthesis of the Alzheimer drug posiphen into its primary 
metabolic products (+)-N1-norposiphen, (+)-N8-norposiphen and (+)-N1,N8-bisnorposiphen, 
their inhibition of amyloid precursor protein, a Synuclein synthesis, interleukin-1β release and 
cholinergic action. Antiinflamm Antiallergy Agents Med Chem. 12:117-28. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med. 2011;30(28):3267-3284. 
Chen YH, DeMets DL, Lan KK. Increasing the sample size when the unblinded interim result is 
promising. Statistics in Medicine. 2004; 23(7): 1023-1038 
Y.H. Joshua Chen, Shuai S. Yuan & Xiaoming Li (2018). Statistical Inference following sample 
size adjustment based on the 50%-conditional-power principle. Journal of Biopharmaceutical 
Statistics. 28:3, 575-587, DOI: 10.1080/10543406.2017.1372766 
 
 
 


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APPENDIX 1: SCHEDULE OF EVENTS  
Study Period 
Screening/Baseline 
At-Home Treatment 
Unscheduled 
Visitk 
Early 
Discontinuation 
Visit 
Visit Timing 
Day -42 to 0 
6 weeks ± 7 days 
12 weeks ± 7 days 
(end-of-trial) b 
 
 
Procedure 
Screening j 
(up to 42 days 
before Day 0) 
Baseline (Day 
0) 
Clinic Visit 
- 
Clinic Visit 
- 
Clinic Visit 
 
Clinic Visit 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Demography information 
X 
 
 
 
 
 
Full physical and neurological 
examination 
X 
X 
X 
X 
X 
X 
Height, Weight, BMI 
X 
 
 
 
 
 
Medical and psychiatric history (includes 
substance use) 
X 
 
 
 
 
 
Urine pregnancy test (WOCBP only) 
X 
X 
X 
X 
X 
X 
MMSE  l 
X 
X 
 
X 
 
X 
ADCS-CGIC 
 
Xd 
Xe 
Xe 
 
Xe 
ADAS-Cog11 
 
X 
X 
X 
 
X 
ADCS-ADL 
 
X 
X 
X 
 
X 
DSST 
 
X 
X 
X 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
Safety laboratory tests c 
X 
X 
X 
X 
X  
X 
12-lead ECG 
X 
X 
X 
X 
 
X 
Vital signsa 
X 
X 
X 
X 
X 
X 


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Study Period 
Screening/Baseline 
At-Home Treatment 
Unscheduled 
Visitk 
Early 
Discontinuation 
Visit 
Visit Timing 
Day -42 to 0 
6 weeks ± 7 days 
12 weeks ± 7 days 
(end-of-trial) b 
 
 
Procedure 
Screening j 
(up to 42 days 
before Day 0) 
Baseline (Day 
0) 
Clinic Visit 
- 
Clinic Visit 
- 
Clinic Visit 
 
Clinic Visit 
Randomization 
 
X 
 
 
 
 
Genetic sample (ApoE) 
 
X 
 
 
 
 
Study intervention 
 
Xg 
Xh 
XI 
 
 
Study intervention compliance review 
 
 
X 
X 
 
 
AE/SAE review  
X 
X 
X 
X 
X 
X 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
PK sampling  
 
X 
 
X 
 
 
Sampling for blood biomarkers 
 
X 
 
X 
 
 
24-hour phone follow-up 
 
X 
X 
X 
X 
X 
a Vital sign will include sitting blood pressure, pulse, temperature, respiration rate. 
b Participants that drop out before the initial 9 weeks of study treatment will complete the Early Discontinuation visit and participants that drop out after 
the initial 9 weeks of study treatment will complete the End-of-Trial visit. 
c Safety labs should be taken fasted. 
d ADCS-CGIC evaluation only. 
e ADCS-CGIC evaluation and scoring the scale. 
g Participants are given one pill during the visit after taking pre-dose (0h) blood samples and the pills for the remaining 6 weeks at the end of the visit. 
h Participants are given pills for the remaining 6 weeks at the end of the visit. 
I Participants are given one pill during the visit after taking pre-dose (0h) blood samples. 
J At PI’s discretion, re-testing can be done within 30 days. If the investigator deems re-screening is justified, they must contact Medical Monitor and 
sponsor for discussion on a case-by-case basis. If/when rescreening MMSE, the test must be done at least 3 weeks apart from the previous one. 
K Investigator will determine the extra assessment if any is needed. 
l To avoid the learning effect, all MMSEs should be done at least 3 weeks apart. 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Cover Page for ClinicalTrials.gov 
 
 
 
Sponsor name: 
Annovis Bio, Inc. 
NCT number: 
NCT05686044 
Sponsor trial ID: 
ANVS-22002 
Official title of study: 
A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, 
Multicenter Study of Buntanetap in Participants with Mild to 
Moderate Alzheimer’s Disease 
Document type: 
Statistical Analysis Plan 
Document date: 
February 27, 2024 
 




ANNOVIS BIO, INC. 
CONFIDENTIAL 
Statistical Analysis Plan 
ANVS-22002                                                                                                            Version 2.0, 27 February 2024 
 
 
Page 2 of 25 
 
Contents 
 
 
Abbreviations ................................................................................................................................. 4 
 
Document Version History ............................................................................................................. 6 
 
Introduction .................................................................................................................................... 6 
 
Study Objectives and Endpoints.................................................................................................... 7 
 
Overall Study Design ..................................................................................................................... 9 
 
Determination of Sample Size ....................................................................................................... 9 
 
Data Sets to be Analyzed .............................................................................................................. 9 
 
Statistical and Analytical Plans .................................................................................................... 10 
8.1 
Changes to the Planned Analyses ...................................................................................... 10 
8.2 
Hypothesis and Statistical Methods .................................................................................... 10 
8.2.1 
Level of Significance, Multiple Comparisons and Multiplicity .......................................... 10 
8.2.2 
Definitions ........................................................................................................................ 11 
8.2.3 
Summary Statistics .......................................................................................................... 12 
8.2.4 
Patient/Subject Data Listings ........................................................................................... 13 
8.2.5 
Subject Disposition .......................................................................................................... 13 
8.2.6 
Demographic and Other Baseline Characteristics .......................................................... 13 
8.2.7 
Primary Analysis .............................................................................................................. 13 
8.2.8 
Secondary Analysis ......................................................................................................... 14 
8.2.9 
Exploratory Analysis ........................................................................................................ 15 
8.2.10 
Exposure to Treatment ................................................................................................ 15 
8.2.11 
Medical History and Concomitant Medications ........................................................... 15 
8.2.11.1 
Prohibited concomitant medication ...................................................................... 15 
8.2.11.2 
Permitted concomitant medication ...................................................................... 16 
8.2.11.3 
Coding and imputation of incomplete dates ........................................................ 16 
8.3 
Safety Assessment .............................................................................................................. 17 
8.3.1 
Adverse Events................................................................................................................ 17 
8.3.2 
Vital Signs ........................................................................................................................ 18 
8.3.3 
Clinical Laboratory Measurements .................................................................................. 19 
8.3.4 
Physical Examination ...................................................................................................... 19 
8.3.5 
Neurological Examination ................................................................................................ 20 
8.3.6 
Cardiac Assessments ...................................................................................................... 20 
8.3.7 
Columbia Suicide Severity Rating Scale (C-SSRS) ........................................................ 20 
8.4 
Plasma Biomarkers and Pharmacokinetic Analysis ............................................................ 21 
8.5 
Multicenter Studies .............................................................................................................. 21 
8.6 
Adjustment for Covariates ................................................................................................... 21 
8.7 
Examination of Subgroups .................................................................................................. 21 
8.8 
Handling of Dropouts, Intercurrent Events, and Missing Data ............................................ 21 
8.9 
Interim Analysis ................................................................................................................... 22 
8.10 
Data Monitoring ................................................................................................................... 22 


ANNOVIS BIO, INC. 
CONFIDENTIAL 
Statistical Analysis Plan 
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8.11 
Reporting Conventions ........................................................................................................ 23 
APPENDIX 1: SCHEDULE OF EVENTS ............................................................................................ 24 
 
 
 


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Abbreviations 
αSYN 
Alpha-synuclein 
Aβ 
Amyloid beta 
AD 
Alzheimer’s disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale–Cognitive Subscale 
ADCS-ADL 
Alzheimer's Disease Cooperative Study–Activities of Daily Living Scale 
ADCS-CGIC 
Alzheimer’s Disease Cooperative Study–Clinical Global Impression of 
Change 
AE 
Adverse Event 
APP 
Amyloid β Precursor Protein 
AR(1) 
First-order Autoregressive 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve  
Cmax 
Maximum plasma and CSF concentration 
CI 
Confidence interval 
CL 
Clearance  
CM 
Concomitant medication  
CSF 
Cerebrospinal Fluid 
CSP 
Clinical Study Protocol 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficients of variation 
DSMB 
Data Safety Monitoring Board  
DSST 
Digital Symbol Substitution Test 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ES 
Enrolled set  
FDA 
Food and Drug Administration 
GFAP 
Glial Fibrillary Acidic Protein 
IC 
Informed Consent 
IMP 
Investigational Medicinal Product 
iSAP 
interim Statistical Analysis Plan 
ITT 
Intent-to-Treat set  
LSM 
Least Square Mean 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat set 
MMRM 
Mixed Model for Repeated Measures 
MMSE 
Mini-Mental State Examination 


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MNAR 
Missing Not at Random 
NFL 
Neurofilament Light 
p-tau 
Phosphorylated tau 
PD 
Parkinson’s disease 
PK 
Pharmacokinetic 
PPS 
Per-protocol set 
PT 
Preferred Term 
QD 
Once a Day 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class  
TEAE 
Treatment-Emergent Adverse Event 
T½ 
Half-life  
tau 
Tau protein 
TDP-43 
TAR DNA-binding Protein 43 
tmax 
Time to peak drug concentration 
TOEPH 
Heterogeneous Toeplitz 
UN 
Unstructured 
WHO 
World Health Organization 
 
 
 




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Study Objectives and Endpoints 
Objective 
Endpoint 
Primary 
 
The primary objective is to assess 
efficacy and safety of buntanetap in 
participants with mild to moderate AD. 
1. Alzheimer’s Disease Assessment Scale-
Cognitive Subscale 11 (ADAS-Cog 11) 
Change in ADAS-Cog 11 from Baseline to Week 
12. 
ADAS-Cog 11 is an 11-item score measuring 
cognitive functions and non-cognitive functions 
such as mood and behavior. Total scores range 
from 0-70, with higher scores indicating greater 
cognitive impairment.  
 
2. Alzheimer’s Disease Cooperative Study-
Clinical Global Impression of Change (ADCS-
CGIC) 
ADCS-CGIC is a validated categorical measure of 
change in the participant’s clinical condition 
between baseline and follow-up visits. It 
measures whether the effects of active treatment 
are substantial enough to be detected by a skilled 
and experienced clinician on the basis of a clinical 
interview and examination. It relies on both direct 
examination of the participant and an interview of 
the study partner. A skilled and experienced 
clinician who is blinded to treatment assignment 
rates the participant on a 7-point Likert scale, 
ranging from 1 (marked improvement) to 7 
(marked worsening). Lower scores indicate better 
improvement. 
 
3. Safety and tolerability 
 
Adverse events (AE) 
 
Severity of AEs 
 
Drug related AEs 
 
AEs leading to study discontinuation 
 
Electrocardiogram (ECG) findings 
 
Clinical laboratory test results 
 
Vital sign measurements 
 
Physical examination findings 


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Objective 
Endpoint 
Secondary 
 
Assess improvement on AD 
participants’ daily living and cognitive 
functions 
1. Alzheimer’s Disease Cooperative Study-
Instrumental Activities of Daily Living Scale 
(ADCS-ADL) 
The ADCS-ADL is a 23-item inventory developed 
as a rater-administered questionnaire answered 
by the participant‘s study partner. The ADCS-ADL 
measures both basic and instrumental activities 
(instrumental activity items 6a, 7-23) of daily living 
by participants with a lower score indicating 
greater severity. 
 
2. Mini Mental State Examination (MMSE) Score 
MMSE is a brief screening instrument used to 
assess cognitive function (orientation, memory, 
attention, ability to name objects, follow 
verbal/written commands, write a sentence, and 
copy figures). Total score ranges from 0 to 30 with 
a lower score indicating greater disease severity. 
 
3. Digital Symbol Substitution Test (DSST) 
In the DSST individuals are asked to record 
associations between different symbols and 
numbers within time limits. The total score is the 
sum of all the correctly coded numbers and higher 
scores indicate better performance. 
 
 
 
 
 
  
 
 
Exploratory 
 
Investigate change after buntanetap in 
potential biomarkers  
1. Plasma biomarkers 
Potential biomarkers to be measured in plasma 
are A42/40 ratio, phosphorylated tau 181 
(pTau181), pTau217, Neurofilament Light (NFL), 
Glial fibrillary acidic protein (GFAP) and TAR 
DNA-binding protein 43 (TDP43). 
 
2. Pharmacokinetics (PK) Analysis 
The following PK parameters will be determined: 
Area under the curve (AUC), Cmax, Tmax, t½, and 
CL. 
 
 
 
 
 


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Overall Study Design 
This is a 12-week randomized, double-blind, placebo-controlled, dose-ranging, multicenter clinical trial 
investigating the efficacy, safety, and tolerability of three different doses of buntanetap or placebo in 
participants with mild to moderate AD. 
Qualified participants will be randomly assigned at a 1:1:1:1 ratio to one of the four treatment arms: 
buntanetap 7.5 mg, buntanetap 15 mg, buntanetap 30 mg, and placebo after a screening period of up 
to 42 days.  
ADAS-Cog 11, ADCS-CGIC, ADCS-ADL, DSST, and MMSE will be assessed by clinicians who have 
successfully completed the requisite certifications/trainings for each assessment. All efforts will be 
made to ensure participants will be assessed by the same clinician throughout the study. 
320 mild to moderate AD participants will be randomized to 7.5 mg, 15 mg, 30 mg of buntanetap QD 
or placebo. 
Participants who have signed an informed consent and meet screening eligibility requirements will be 
randomly assigned at a 1:1:1:1 ratio to one of the four treatment arms: buntanetap 7.5 mg, buntanetap 
15 mg, buntanetap 30 mg, and placebo, through an Interactive Randomization System, after a 
screening period of up to 42 days, followed by an at home dosing period of 12 weeks. Participants will 
be required to visit clinics at Day 0 (baseline), 6 weeks, and 12 weeks (end-of-trial), where they will 
undergo study procedures that include safety assessments (AE and concomitant medication 
monitoring, 
12-lead 
ECGs, 
clinical 
laboratory 
testing, 
vital 
signs 
assessments, 
and 
physical/neurological examinations), and psychometric tests (ADAS-Cog11, ADCS-CGIC, ADCS-
ADL, DSST, MMSE).  
The Schedule of Events is shown in Appendix 1. 
 
Determination of Sample Size 
A sample size of up to 320 participants (1:1:1:1 randomized to 7.5 mg, 15 mg, 30 mg buntanetap and 
placebo respectively) is planned to be randomized. 
Qualified participants will be randomized at a 1:1:1:1 ratio to one of the following four treatment groups: 
7.5 mg, 15 mg, 30 mg QD buntanetap and placebo. A sample size of 280 (210 combining all three 
buntanetap-treatment groups and 70 in control) will have 90% power to detect a treatment difference 
for the co-primary efficacy variable ADAS-Cog11 at a two-sided significance level of 0.05, assuming a 
delta of 2.7 between the treatment (pooling all three treatment arms together) and placebo, and a 
common standard deviation (SD) of 6.0. This sample size will also have an 89% power to detect a 
significant difference for the co-primary efficacy variable ADCS-CGIC at a two-sided significance level 
of 0.05, assuming a delta difference 0.23 between the treatment (pooling all three treatment arms 
together) and placebo, and a common SD of 0.5. Approximately 320 participants will be randomized 
(approximately 80 per arm) to account for an expected 12.5% dropout rate. 
 
Data Sets to be Analyzed 
The following analysis sets will be used for the statistical analysis and presentation of data:  
 
The Enrolled analysis set (ES) will include all participants who signed IC and meet all inclusion 
and exclusion criteria. All data collected from ES will be presented in listings and if relevant in 
tables and/or graphs. Screening failures will have selected data be presented in a separate 
listing if needed.  
 
The Intent-to-Treat set (ITT) will consist of all participants who are randomized. The primary 
efficacy analyses will be based on the ITT. 
 
The Modified Intent-to-Treat set (mITT) will consist of all participants who are randomized, 
receive at least one dose of study drug, and have both a baseline and at least one post-
baseline assessment value for the ADAS-Cog11 or ADCS-CGIC score after taking study drug. 
The mITT will be used to support the primary efficacy analyses. 
 
The Safety analysis set (SAF) will consist of all randomized participants who receive at least 
one dose of study drug. The safety analyses will be based on the SAF. 


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 
The Per-protocol set (PPS) will consist of all participants in the mITT who complete at least 67 
days treatment exposure (Last dose date - First dose date + 1 >= 67 days) without any major 
protocol deviations that potentially could impact the primary efficacy endpoint. The 
membership of this analysis set will be determined prior to database lock. The PPS will be 
used to support the primary and secondary endpoints as supportive analyses. 
 
The PK set will analyze all available data from safety participants receiving buntanetap and 
with at least one sampling profile allowing derivation of at least one PK parameter. 
Protocol deviations leading to exclusions from PPS include but are not limited to the following: 
 
Non-fulfilment of all inclusion criteria  
 
Fulfilment of at least one exclusion criterion 
 
Use of certain concomitant medications (for details see section 8.3.11) 
 
The final criteria for the PPS, regarding which protocol deviations that warrant exclusion, will be 
determined before breaking the blind.  
Baseline presentations will be based on the SAF.  
Safety presentations will be based on the SAF. 
Exposure to study drug will be given for the SAF. 
The ITT and mITT will be analyzed according to randomized (planned) treatment. Safety and PPS will 
be analyzed on actual treatment. 
Plasma concentration-time data for buntanetap will be based on the SAF. PK parameters derivations 
and statistical analyses are described in a separate PK SAP and will be based on the PK set (see 
Section 8.5). 
 
Statistical and Analytical Plans 
8.1 
Changes to the Planned Analyses 
There have been no changes in the planned analyses in the study protocol. 
8.2 
Hypothesis and Statistical Methods 
For tests of statistical significance on efficacy variables the significance level (p-value) will be provided 
together with the 95 percent confidence intervals (CI) of the mean, minimum, median, first and third 
quartiles and maximum. 
8.2.1 
Level of Significance, Multiple Comparisons and Multiplicity 
The primary study hypothesis is that buntanetap-treatment (pooling three treatment arms together) is 
superior to placebo in reducing the cognitive impairment and function impairment of AD participants, 
as assessed by the two co-primary endpoints: change from baseline in the ADAS-Cog11 score at 12-
week and ADCS-CGIC score at 12-week. The two co-primary endpoints will be tested at a two-sided 
significance level of 5% without multiplicity adjustment. If both test hypotheses are rejected at the 5% 
level, the test will continue onto secondary endpoints in a hierarchical testing order, at a two-sided 
significance level of 5%. If one of the two co-primary endpoints is not statistically significant, the 
hypothesis testing for all subsequent endpoints will be considered exploratory. 
To control for study-wise type 1 error rate, a fixed-sequence hierarchical testing procedure will be 
applied to adjust for multiplicity arising from multiple secondary endpoints. The hierarchical testing 
order for the secondary endpoints are: 
1. ADCS-ADL 
2. MMSE score 
3. DSST 




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Relative day 
The relative day of an event is derived as: 
Relative day = (Start date) - (Date of first administration of 
Investigational Medicinal Product (IMP) + 1 
For events occurring or starting before the date of first administration of 
IMP, the relative day is derived as: 
Relative day = (Start date) - (Date of first administration of IMP) 
In this way, there will be no Day 0. Day 1 is the same day as the day of 
first administration of IMP, and Day -1 is the day before. 
Date format 
All dates in analysis datasets and tables, listings and figures will be in 
the format YYYY-MM-DD 
8.2.3 
Summary Statistics 
Data will be summarized by means of summary statistics. Summary statistics will be provided for the 
variables described in the following sections. 
Categorical data will be presented as counts and percentages, i.e., n (xx.x%). Percentages will be 
based on the number of subjects in the analysis data set used and given as integers. Zero frequencies 
will be given without percentages.  
For continuous variables, these statistics will include the number of subjects, mean, SD, median, 
minimum, and maximum. 
All variables will be analyzed descriptively with appropriate statistical methods: categorical variables 
by frequency tables (absolute and relative frequencies) and continuous variables by sample statistics 
(i.e., number of observations, mean, SD, 95% CI of the mean, minimum, median, first and third 
quartiles and maximum). Minimum and maximum values will be displayed as reported. 
Since the two co-primary endpoints and secondary endpoints are captured at multiple visits, the 
method selected to analyze the endpoints, which are treated as continuous, will be a Mixed Model for 
Repeated Measures (MMRM). For the co-primary endpoint ADAS-Cog11 score and secondary 
endpoints, MMRM will be applied with change from Baseline score as the response (dependent 
variable) and with Baseline value as a covariate and treatment, timepoint, treatment-by-timepoint 
interaction as fixed effects (independent variables). The Model for co-primary endpoint ADCS-CGIC 
score will include treatment, timepoint, treatment-by-timepoint interaction as the fixed effects. 
Estimation of parameters will be done by means of Restricted Maximum Likelihood method. The 
Unstructured (UN) variance-covariance structure will be initially used to explore the variance-
covariance matrix across visits. If the algorithm doesn’t converge, a heterogeneous Toeplitz (TOEPH) 
as the covariance matrix will be tried first, and then first-order autoregressive (AR(1)) to achieve 
convergence. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. The two-sided 95% CI of the treatment differences will be presented. 
The co-primary endpoint ADAS-Cog11 score and secondary endpoints will be analyzed using the 
model explained above as follows:  
<Endpoint>= intercept + Base + T + V + T*V, 
with  
Base: baseline score;  
T: treatment;  
V: post-baseline visit (Week 6, Week 12). 
The co-primary endpoint ADCS-CGIC score will be analyzed using the model explained above as 
follows:  
<Endpoint>= intercept + T + V + T*V, 
      with  
 T: treatment;  


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 V: post-baseline visit (Week 6, Week 12). 
Treatment comparisons (pooled Buntanetap-treatment vs. Placebo) will be carried out by means of 
the contrasts on the treatment factor by visit effect in SAS® Software, using proc mixed. Treatment 
effects will be estimated by means of Least Square Means (LSM) and 95% CI. Differences between 
treatments (pooled Buntanetap-treatment – Placebo) will be estimated and resulting 2-sided p-values 
and associated 95% CI will be presented. 
 
8.2.4 
Patient/Subject Data Listings 
Data collected in the electronic case report form (eCRF) will generally be listed. eCRF check questions 
(e.g., reminders) will not be listed. 
Listings will be sorted by treatment group, study center, patient/subject id, visit and assessment time 
as applicable. If center id is part of patient/subject id, then center could be omitted.  
In CRF modules where a date is recorded, the relative day may be included in the corresponding 
listing. In modules where both a start date and stop date are recorded, the duration may be included 
in the listing. 
8.2.5 
Subject Disposition 
The numbers of subjects screened, enrolled, completed, discontinued, and withdrawn during the study, 
as well as the reasons for all post-enrolment discontinuations will be listed and/or summarized by 
treatment group. Disposition and reason for study discontinuation will also be provided as a by-subject 
listing. 
8.2.6 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment group using appropriate 
descriptive statistics. 
The following summaries will be given by treatment and in total:  
 
Demography  
 
Age (years) 
 
Age (years), categories (55 to <65, 65 to <75, 75 to <85) 
 
Sex (Male or Female) 
 
Race (White, Asian, Black or African American, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
 
Height (cm) 
 
Weight (kg) 
 
BMI (kg/m2) 
8.2.7 
Primary Analysis 
The co-primary endpoints in this clinical trial are the change from baseline to Week 12 in ADAS-Cog11 
score and the ADCS-CGIC score at Week 12 between buntanetap-treatment (pooling three treatment 
arms together) and placebo.  
The statistical hypothesis to be tested for co-primary endpoint ADAS-Cog11 score is described as:  
 
Null Hypothesis (H0):  
The difference in change in ADAS-Cog11 score from baseline to Week 12 between 
buntanetap-treatment (pooling three treatment arms together) and placebo = 0. 
 
Alternative Hypothesis (H1):  


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The difference in change in ADAS-Cog11 score from baseline to Week 12 between 
buntanetap-treatment (pooling three treatment arms together) and placebo ≠ 0. 
The statistical hypothesis to be tested for co-primary endpoint ADCS-CGIC score is described as:  
 
Null Hypothesis (H0):  
The difference in ADCS-CGIC score at Week 12 between buntanetap-treatment (pooling three 
treatment arms together) and placebo = 0. 
 
Alternative Hypothesis (H1):  
The difference in ADCS-CGIC score at Week 12 between buntanetap-treatment (pooling three 
treatment arms together) and placebo ≠ 0. 
The two co-primary endpoints will be analyzed via MMRM. The model for the co-primary endpoint 
ADAS-Cog11 score will include treatment, timepoint, treatment-by-timepoint interaction as the fixed 
effects and baseline as the covariate. The Model for the co-primary endpoint ADCS-CGIC score will 
include treatment, timepoint, treatment-by-timepoint interaction as the fixed effects. The variance-
covariance matrix will be assumed to be UN.  
This analysis will be conducted after all participants have reached Week 12 or early withdrawal, 
whichever comes first. The primary analysis will be conducted in ITT. The mITT and PPS will be used 
to support the primary analysis.  
Descriptive statistics per visit and change from baseline for each visit will be provided. 
As the study is also designed to explore the effectiveness of three buntanetap-treatment dose levels 
on co-primary endpoints, similar MMRM will be applied comparing each buntanetap-treatment dose 
arm with placebo.  
8.2.8 
Secondary Analysis 
Secondary efficacy endpoints in this clinical trial are 
 
Change from baseline to Week 12 in ADCS-ADL 
 
Change from baseline to Week 12 in MMSE score 
 
Change from baseline to Week 12 in DSST 
Change from Baseline to Week 12 in ADCS-ADL 
The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by 
the participant‘s study partner. The ADCS-ADL measures both basic and instrumental activities 
(instrumental activity items 6a, 7-23) of daily living by participants with a lower score indicating greater 
severity.  
ADCS-ADL score will be analyzed by MMRM, similar to the co-primary endpoint ADAS-Cog11 score. 
Change from Baseline to Week 12 in MMSE Score 
MMSE is a brief screening instrument used to assess cognitive function (orientation, memory, 
attention, ability to name objects, follow verbal/written commands, write a sentence, and copy figures). 
Total score ranges from 0 to 30 with a lower score indicating greater disease severity. 
MMSE score will be analyzed by MMRM, similar to the co-primary endpoint ADAS-Cog11 score. 
Change from baseline to Week 12 in DSST 
In the DSST individuals are asked to record associations between different symbols and numbers 
within time limits. The total score is the sum of all the correctly coded numbers and higher scores 
indicate better performance. 
DSST score will be analyzed by MMRM, similar to the co-primary endpoint ADAS-Cog11 score. 
As the study is also designed to explore the effectiveness of three buntanetap-treatment dose levels 
on secondary endpoints, similar MMRM will be applied comparing each buntanetap-treatment dose 
arm with placebo. 


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8.2.9 
Exploratory Analysis 
Exploratory endpoints in this clinical trial are 
 
Plasma biomarkers 
 
PK analysis. 
Plasma Biomarkers 
Potential biomarkers to be measured in plasma are A42/40 ratio, pTau181, pTau217, NFL, GFAP 
and TDP43. 
PK analysis 
Plasma concentration-time data for buntanetap will be listed and summarized descriptively (number of 
subjects (N), mean, geometric mean, median, SD, coefficients of variation (CV), minimum, and 
maximum) for the SAF. 
Plasma buntanetap PK parameters will be calculated using a non-compartmental method. 
Calculations will be based on the actual sampling times recorded during the study. The following PK 
parameters will minimally be determined, as data permit: Area under the curve (AUC), Cmax, Tmax, t½, 
and CL. A separate PK SAP will include details on PK parameters derivations and statistical analyses 
based on the PK set. 
8.2.10 Exposure to Treatment 
Duration of exposure will be summarized quantitatively using the number of days on study drug for 
each patient, displayed by treatment group. Duration will be calculated as (last dose date – first dose 
date + 1). 
Compliance with treatment will be assessed as the percentage of tablets taken in relation to number 
of tablets expected to be taken. 
Compliance with study drug (%) = 
்௢௧௔௟ ௡௨௠௕௘௥ ௢௙ ௧௔௕௟௘௧௦ ௧௔௞௘௡
ே௨௠௕௘௥ ௢௙ ௧௔௕௟௘௧௦ ௘௫௣௘௖௧௘ௗ 
Exposure and compliance will be presented using summary statistics by treatment group and the 
pooled buntanetap-treatment group.  
8.2.11 Medical History and Concomitant Medications 
Medical history will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Additionally, a listing of the relevant medical history will be provided. 
Prior and concomitant medications will be summarized by treatment group and by the pooled 
buntanetap-treatment group, by the number and percentage of subjects taking each medication, 
classified using World Health Organization (WHO) Drug Dictionary Anatomical Therapeutic Chemical 
(ATC) classes and preferred terms (PT). 
8.2.11.1 Prohibited concomitant medication 
Investigational agents are prohibited 4 weeks or five half-lives, whichever is greater, prior to entry and 
for the duration of the trial.  
Aducanumab/Aduhelm and Lecanemab/Leqembi are prohibited for 4 weeks or five half-lives, 
whichever is greater, prior to entry and for the duration of the trial. 
Initiation of prohibited medications during the course of the study is discouraged, however, if an 
excluded medication is initiated after screening, the site should consult with the Medical Monitor for 
further guidance. 
Buntanetap is mainly metabolized by CYP3A4 in vitro. Therefore, we recommend avoiding 
concomitant use of strong or moderate CYP3A4 inhibitor/inducers, examples see below according to 
Food and Drug Administration (FDA) guidance on drug development and drug interactions. 


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CYP3A4 
inhibitors 
Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil 
CYP3A4 
inducers 
Rifampicin 
8.2.11.2 Permitted concomitant medication 
Use of the following medications is allowed only if the participants have been stabilized for at least 4 
weeks before screening and will continue to be stable throughout the study: 
 
tricyclic antidepressants  
 
antipsychotics prescribed for any reason. However, the dosage must not exceed the 
following for these medications: 
Quetiapine ≤50 mg/day, risperidone ≤1.5 mg/day, olanzapine ≤5 mg/day, and 
aripiprazole ≤10 mg/day  
If the participant is on other antipsychotics besides the ones mentioned above, please consult              
the Medical Monitor before screening the participant. 
 
psychostimulants  
Discontinuation and/or change of any of the above medication during the course of the study is 
discouraged, however, if necessary, the site should consult with the Medical Director and Sponsor 
for further guidance. 
For concomitant treatment with anti-cholinesterase, it is allowed to use for at least 4 weeks prior to 
screening. 
For any anticonvulsant medications used for epilepsy or mood stabilization, neuropathic pain 
indications, dosing must be stable for at least 4 weeks prior to screening.  
For mood-stabilizing psychotropic agents, including but not limited to lithium, dosing must be stable 
for at least 4 weeks prior to Screening.  
Use of short acting benzodiazepines and hypnotics for treatment on an as-needed basis for insomnia 
or daily dosing as anxiolytics is permitted but should be avoided for 8 hours before administration of 
cognitive tests. For sedating medication given for any short-term use, all cognitive assessments must 
be administered at least 24 hours after administration of the sedative.  
At this time, there is no controlled clinical data available for anyone receiving SARS-COVID19 
vaccination while being treated with buntanetap. Based on the intended mechanism of actions and 
currently available data for these vaccine candidates and for buntanetap, it is not believed that there 
are specific risks to consider in participants participating in this study who have received SARS-
COVID19 vaccination or who are planning to receive the vaccination. As such, SARS-COVID19 
vaccination is not prohibited. If appropriate, SARS-COVID19 vaccination should be considered as a 
concomitant medication. 
8.2.11.3 Coding and imputation of incomplete dates 
All concomitant medications/therapies will be classified according to ATC level 2 group text and WHO 
Drug Dictionary PT. The medications will be classified into categories Prior and Concomitant drug 
administration based on start date and end date in relation to IMP exposure. 
 
Prior medications are those for which end dates of the medication/therapy are strictly before 
date of first administration of study drug. 
 
Concomitant medications are those for which the period between their start dates and end 
dates coincide with exposure to study drug and can be further classified into:   
o 
Concomitant medications starting prior to first exposure to study drug having start 
dates strictly before first exposure to study drug and end dates on same date or after 
date of first administration to study drug or are ongoing. 
o 
Concomitant medications starting on the date of first administration of study drug or 
after but before or on the date of last administration of study drug 


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For medication and therapies with partial dates:  
o 
If start date is completely missing, it will be assumed that the medication started before date 
of first administration of study drug. 
o 
If end date is completely missing and ongoing is not ticked, it will be assumed that the 
medication ended before date of first administration of study drug. 
o 
If only the year is available, month 6 will be imputed for the purpose of classification.  
o 
For medications/therapies where only year and month (including imputed dates) are available 
this information will be used in analogy with how complete dates are used for classification, 
e.g.: 
Start date 
End date 
Ongoing 
IMP start date 
IMP end date 
Classification 
2020-07 
2020-07 
 
2020-08-14 
2020-09-13 
Prior 
2020-07 
 
No 
2020-08-14 
2020-09-13 
Prior 
2020-07 
 
Yes 
2020-08-14 
2020-09-13 
CM before 
2020-07 
2020-08 
 
2020-08-14 
2020-09-13 
CM before 
2020-08 
2020-08 
 
2020-08-14 
2020-09-13 
CM before 
2020-08 
 
No or Yes 
2020-08-14 
2020-09-13 
CM before 
2020-08 
2020-09 
 
2020-08-14 
2020-09-13 
CM before 
2020-09 
2020-09 
 
2020-08-14 
2020-09-13 
CM after 
2020-09 
 
No or Yes 
2020-08-14 
2020-09-13 
CM after 
CM: Concomitant Medication 
A relative day will not be calculated for medications with incomplete dates.  
The concomitant medications will be presented in a summary table broken down on timing in relation 
to study drug (i.e., Prior and Concomitant). Each subject will only be counted once for each medication 
and timing category, on a PT level in each period. 
One list for each timing period will be presented for the SAF. In addition, a list of anti-parkinsonian 
medications will be provided. 
8.3 
Safety Assessment 
All safety summary analyses will be performed using the actual treatment for the Safety Analysis by 
each treatment group and by the pooled buntanetap-treatment group. 
8.3.1 
Adverse Events 
Adverse events include but are not limited to:  
 
worsening or change in nature, severity, or frequency of conditions or symptoms present at 
the start of the study;  
 
subject deterioration due to primary illness;  
 
intercurrent illness; 
 
drug interaction.  
An abnormal laboratory value will only be reported as an AE if the investigator considers it clinically 
significant, or if it leads to the participant being withdrawn from the study. 
Symptoms and conditions present at the beginning of the study will be characterized, so that AEs can 
be defined as any new symptom, or any increase in frequency or severity of an existing symptom.  
AEs will be coded according to the most recent version of the MedDRA system and will be tabulated 
by system organ class (SOC) and PT.  


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A TEAE is an undesirable event that is not present prior to medical treatment, or an already present 
event that worsens either in intensity or frequency following the treatment. Only TEAEs will be included 
in summary tables and non-TEAEs will be listed separately. 
Relationship to clinical study treatment will be mapped according to the scheme below: 
 
Potentially related: will include all adverse events with a relationship rating of “definitely”, 
“probably” or “possibly”.  
 
Unlikely/not related: will include all adverse events with a relationship rating of “unlikely” or 
“unrelated”. 
An overall summary table will give 
 
number of events 
 
number of unique events  
 
number of subjects with at least one event  
for: 
 
Overall summary of TEAEs 
 
Serious TEAEs 
 
Serious TEAE related to study drug 
 
TEAEs related to study drug 
 
TEAEs by maximum severity  
 
TEAEs leading to treatment discontinuation and/or Interruption of study drug 
 
TEAEs leading to withdrawal from study 
 
TEAEs leading to death 
The total number and percentage of subjects with at least one TEAE and the total number of TEAEs 
will be presented by SOC and PT. If more than one TEAE occurs with the same PT for the same 
subject, then the subject will be counted only once for that PT using the most severe and most related 
occurrence for the summary. 
Frequent TEAEs are defined as any PT with ≥5% incidence in any of the treatment arms, which will 
be summarized by PT. 
An AE listing by subject will display all events, and will include the verbatim term in addition to the 
MedDRA SOC and PT. This listing will also include all relevant eCRF data associated with the event: 
date of onset, date resolved, date of last dose, severity, frequency, outcome and relationship to study 
drug and action taken with study drug. Separate listings will be presented for subjects with treatment-
emergent serious AEs (SAEs), related TEAEs, TEAEs leading to drug withdrawn, fatal TEAEs (if any). 
If AE start date is incomplete, AEs with start month same as month of first administration of study drug 
will be regarded as TEAEs.  
Adverse events will be reported to Data Safety Monitoring Board (DSMB) (see Section 8.11) per DSMB 
Charter. 
8.3.2 
Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and changes 
from baseline for all visits at which they were assessed will be calculated for systolic blood pressure, 
diastolic blood pressure, pulse, respiratory rate, and oral temperature. 
Shift tables showing the number of subjects who shifted from normal, abnormal not clinically significant 
or abnormal clinically significant at baseline to normal, abnormal not clinically significant or abnormal 
clinically significant at each post-baseline time of assessment will be presented.  




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Shift tables showing the number of subjects who shifted from normal, abnormal not clinically significant 
or abnormal clinically significant at baseline to normal, abnormal not clinically significant or abnormal 
clinically significant at each post-baseline time of assessment will be presented.  
Physical examination data will also be presented in listings. 
8.3.5 
Neurological Examination 
Number and percentage of normal, abnormal but not clinically significant or abnormal and clinically 
significant findings will be tabulated by visit for the body systems  
 
cranial nerves,  
 
strength,  
 
coordination,  
 
reflexes,  
 
sensation,  
 
tremor,  
 
gait,  
 
mental status. 
Shift tables showing the number of subjects who shifted from normal, abnormal not clinically significant 
or abnormal clinically significant at baseline to normal, abnormal not clinically significant or abnormal 
clinically significant at each post-baseline time of assessment will be presented.  
Neurological examination data will also be presented in listings. 
8.3.6 
Cardiac Assessments 
A 12-lead ECG will be performed prior to the administration of study drug at the timepoints of 
assessments. 
The Investigator will enter a signed and dated clinical interpretation of the ECG trace in the eCRF. At 
each timepoint, absolute values and change from Baseline of ECG numeric variables will be 
summarised through descriptive statistics by each treatment group, and the pooled buntanetap-
treatment group. Observed QTc will also be categorized into the following categories (msec) and the 
number and percentage of subjects in each category will be summarized at each timepoint and the 
overall post-baseline maximum:  
 
Observed: <=450, 451-480, 481-500, and >500; >450; >480 
 
Change from Baseline: <=10, 11-30, 31-60, and >60; >30 
For ECG interpretations, the number of available observations and the number of normal, abnormal 
clinically significant and abnormal not clinically significant values (absolute and in percentage) will be 
summarized at each timepoint. The overall post-baseline worst interpretation will also be summarized.   
Shift tables showing the number of subjects who shifted from normal, abnormal not clinically significant 
or abnormal clinically significant at baseline to normal, abnormal not clinically significant or abnormal 
clinically significant at each post-baseline time of assessment will be presented. 
8.3.7 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The number and percentage of subjects with suicidal ideation or suicidal behavior based on the C-
SSRS will be summarized by treatment group and the pooled buntanetap-treatment group. Suicidal 
ideation or behavior are defined as: 
 
 
Suicidal ideation: A “yes” answer at any time during treatment to any one of the five suicidal 
ideation questions (Categories 1-5)  
 
Suicidal behavior: A “yes” answer at any time during treatment to any one of the five suicidal 
behavior questions (Categories 6-10) 
 
Suicidal ideation or behavior: A “yes” answer at any time during treatment to any one of the 
ten suicidal ideation and behavior questions (Categories 1-10)  


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The intensity of most severe suicidal ideation during the participant’s lifetime, during the double-blind 
treatment period, and during the safety follow-up period will also be presented by treatment group and 
the pooled buntanetap-treatment group for the SAF. Intensity of most severe ideation is a sum of the 
5 intensity items (Frequency, Duration, Controllability, Deterrents, and Reasons for Ideation). 
Actual lethality and potential lethality on most lethal attempt will also be summarized by treatment 
group and the pooled buntanetap-treatment group. 
Supportive listings will be provided and will include the participant number, study center number, 
lifetime history, and post-baseline values. Intensity of suicidal ideation, suicidal behavior type, and 
lethality of suicidal behavior will also be included in these listings.  
A listing of all AEs occurring in participants who have suicidal ideation or suicidal behavior will also be 
provided. 
8.4 
Plasma Biomarkers and Pharmacokinetic Analysis 
Biomarkers, including A42/40 ratio, pTau181, pTau217, GFAP, NFL and potentially TDP43, will be 
summarized descriptively for SAF. 
Plasma concentration-time data for buntanetap will be listed and summarized descriptively (number of 
subjects (N), mean, geometric mean, median, SD, coefficients of variation (CV), minimum, and 
maximum) for the SAF. 
Non-compartmental analysis of one analyte (buntanetap) in blood matrix concentrations will be 
performed using validated computer software Phoenix. Results will be tabulated and graphically 
displayed using Phoenix and appropriately interpreted by a PK Scientist. Calculations will be based 
on the actual sampling times recorded during the study. The following PK parameters will minimally 
be determined, as data permit:  
 
Area under the curve (AUC), including AUC0-10hr and AUC0-inf 
 
Maximum concentration (Cmax) and time of maximum concentration (Tmax) 
 
Terminal half-life (t½)  
 
Systemic clearance (CL).  
8.5 
Multicenter Studies 
No per-center analyses are planned. 
8.6 
Adjustment for Covariates 
Baseline value will be used as a covariate in the MMRM analyses for the co-primary endpoint ADAS-
Cog11 score (see Section 8.3.7). 
8.7 
Examination of Subgroups 
No subgroup analyses are planned for this study. 
8.8 
Handling of Dropouts, Intercurrent Events, and Missing Data 
In case of incomplete dates, the following approach will be used: 
 
If only the day is missing and the month and year are different from the month and year of the 
index date, the day will be imputed with 1. In case the month and year are the same as the 
index day the missing day will be imputed with the last day of the month. 
 
In case of missing months, they will be imputed  
o 
with July if the year is not the same as the year of the index date  
o 
with the following month as the month of the index date if the year is the same as the 
year of the index date. 
If not indicated otherwise in case of completely missing dates no imputation will be done. 


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For co-primary endpoint ADAS-Cog11, if there are 3 or less missing item scores at a visit, the missing 
item score will be imputed using the group mean score of that item within the same treatment group 
at the same visit. If there are more than 3 item scores missing, the total score will be set as missing. 
The same MMRM analysis as the one applied to the primary analysis will be fitted as a sensitivity 
analysis. 
The MMRM analysis of the two co-primary endpoints assumes that data are missing at random (MAR). 
The analysis will be conducted in ITT set and subjects will be analyzed as randomized. ITT subjects 
discontinue from the study for any reason without completing the study are considered intercurrent 
events. To assess the robustness of this MAR assumption, a conservative control-based multiple 
imputation method based on missing not at random (MNAR) assumption will be applied to impute 
missing data arising from intercurrent events for the two co-primary endpoints analyses. In this MNAR 
approach, subjects who do not complete the study, missing data will be imputed by observed data 
obtained from the placebo group using multiple imputation with Markov Chain Monte Carlo (MCMC) 
simulation method for each treatment separately. For the co-primary endpoint ADAS-Cog11 score, the 
variables for the imputation model will include ADAS-Cog11 score at baseline, Week 6, and Week 12. 
The ROUND, MINIMUM and MAXIMUM options will be utilized to ensure imputed values are clinically 
plausible integers (0 – 70). For the co-primary endpoint ADCS-CGIC score, the variables for the 
imputation model will include ADCS-CGIC score at Week 6 and Week 12. The ROUND, MINIMUM 
and MAXIMUM options will be utilized to ensure imputed values are clinically plausible integers (1 – 
7). Approximately 50 datasets will be imputed and the same MMRM analysis as the one applied to the 
primary analysis will be fitted. The results from these 50 analyses will be combined using Rubin’s rule 
to construct the treatment estimates from the parameter estimates and associated standard errors. 
The difference of the treatment means (active minus placebo) will be presented with the associated 
standard error and two-sided 95% confidence interval. The imputation will be performed for the two 
co-primary endpoints separately. Two random seed numbers will be selected for the multiple 
imputation procedure and will be retained. 
8.9 
Interim Analysis 
An interim sample size re-estimation will be performed after a total of 𝑛1 = 90 evaluable participants 
across four treatment arms have 6 weeks of assessments for the co-primary efficacy endpoints ADAS-
Cog11 and ADCS-CGIC. Evaluable participants are defined as ITT participants who received the study 
drug and have baseline and Week 6 values of both co-primary efficacy endpoints. The aim of the 
interim sample size review is to re-assess the size of the estimated mean difference between the 
treatment (pooling three treatment arms together) and placebo, and SDs of the co-primary endpoints 
ADAS-Cog11 and ADCS-CGIC to ensure sufficient power at the final analyses. No interim analyses 
are planned for the purpose of stopping the study early for success or futility.  
At the time preparing this SAP, the interim sample size re-estimation was done and interim Statistical 
Analysis Plan (iSAP) was signed off in October, 2023. Please refer to iSAP for more details.  
8.10 Data Monitoring 
An independent DSMB will review the safety information from the study on an ongoing basis. The 
DSMB, will identify the study-specific data parameters and format of the information to be reported, as 
well as the timing of reports based on the enrollment status of the study. The DSMB will initially be 
provided with data blinded to treatment status, but they may request unblinded data if there is a safety 
concern. 
Additionally, the DSMB will be informed of the occurrence of any SAEs probably related to the drug 
within 7 days of being reported to the Coordinating Center. The DSMB may at any time request 
additional information from the Coordinating Center. 
The DSMB will consist of at least one statistician and two physicians with experience of DSMBs and 
clinical trials. 
The data to be considered by the DSMB, the process for quality control of reports and data, and the 
documentation of decisions were described in detail in the mutually agreed DSMB charter prior to the 
study start. The primary responsibility of the DSMB will be to protect the safety of the study subjects.  
Based on the review of safety data, the DSMB will make recommendations regarding the conduct of 
the study. These may include amending safety monitoring procedures, modifying the protocol or 


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consent, terminating the study, or continuing the study as designed. Using the Safety Review Process 
(review of lab data, vitals, and adverse events) and the DSMB, there is substantial oversight and case 
review to alert the investigators, in a timely manner, to any safety issues that may arise. Further details 
will be provided in the DSMB charter.  
8.11 Reporting Conventions 
Any p-values 0.001 will be reported to three (3) decimal places; p-values <0.001 will be reported as 
<0.001. PK parameters will be reported to two decimal places. The mean and median will be displayed 
to one decimal place greater than the original value and the measure of variability (e.g., SD) will be 
displayed to two decimal places greater than the original value. 
 


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APPENDIX 1: SCHEDULE OF EVENTS  
Study Period 
Screening/Baseline 
At-Home Treatment 
Unscheduled 
Visitk 
Early 
Discontinuation 
Visit 
Visit Timing 
Day -42 to 0 
6 weeks ± 7 days 
12 weeks ± 7 days 
(end-of-trial) b 
 
 
Procedure 
Screening j 
(up to 42 days 
before Day 0) 
Baseline (Day 
0) 
Clinic Visit 
- 
Clinic Visit 
- 
Clinic Visit 
 
Clinic Visit 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Demography information 
X 
 
 
 
 
 
Full physical and neurological 
examination 
X 
X 
X 
X 
X 
X 
Height, Weight, BMI 
X 
 
 
 
 
 
Medical and psychiatric history (includes 
substance use) 
X 
 
 
 
 
 
Urine pregnancy test (WOCBP only) 
X 
X 
X 
X 
X 
X 
MMSE  l 
X 
X 
 
X 
 
X 
ADCS-CGIC 
 
Xd 
Xe 
Xe 
 
Xe 
ADAS-Cog11 
 
X 
X 
X 
 
X 
ADCS-ADL 
 
X 
X 
X 
 
X 
DSST 
 
X 
X 
X 
 
X 
C-SSRS 
X 
X 
X 
X 
X 
X 
Safety laboratory tests c 
X 
X 
X 
X 
X  
X 
12-lead ECG 
X 
X 
X 
X 
 
X 
Vital signsa 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
Genetic sample (ApoE) 
 
X 
 
 
 
 
Study intervention 
 
Xg 
Xh 
XI 
 
 
Study intervention compliance review 
 
 
X 
X 
 
 
AE/SAE review  
X 
X 
X 
X 
X 
X 


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Study Period 
Screening/Baseline 
At-Home Treatment 
Unscheduled 
Visitk 
Early 
Discontinuation 
Visit 
Visit Timing
Day -42 to 0 
6 weeks ± 7 days 
12 weeks ± 7 days 
(end-of-trial) b 
Procedure 
Screening j 
(up to 42 days 
before Day 0) 
Baseline (Day 
0) 
Clinic Visit 
- 
Clinic Visit 
- 
Clinic Visit 
Clinic Visit 
Concomitant medication review 
X 
X 
X 
X 
X 
X 
PK sampling 
X 
X 
Sampling for blood biomarkers 
X 
X 
24-hour phone follow-up
X 
X 
X 
X 
X 
a Vital sign will include sitting blood pressure, pulse, temperature, respiration rate. 
b Participants that drop out before the initial 9 weeks of study treatment will complete the Early Discontinuation visit and participants that drop out after the initial 9 weeks 
of study treatment will complete the End-of-Trial visit. 
c Safety labs should be taken fasted. 
d ADCS-CGIC evaluation only.
e ADCS-CGIC evaluation and scoring the scale.
g Participants are given one pill during the visit after taking pre-dose (0h) blood samples and the pills for the remaining 6 weeks at the end of the visit. 
h Participants are given pills for the remaining 6 weeks at the end of the visit. 
I Participants are given one pill during the visit after taking pre-dose (0h) blood samples. 
J At PI’s discretion, re-testing can be done within 30 days. If the investigator deems re-screening is justified, they must contact Medical Monitor and sponsor for discussion 
on a case-by-case basis. If/when rescreening MMSE, the test must be done at least 3 weeks apart from the previous one. 
K Investigator will determine the extra assessment if any is needed. 
l To avoid the learning effect, all MMSEs should be done at least 3 weeks apart.