Clinical trial NCT05357989
Conditions: Parkinson's Disease, Idiopathic
Keywords: Parkinson's
Sponsor: Annovis Bio Inc.
Start date: 2022-08-03; Completion date: 2023-12-04
Enrollment: 523 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to measure safety and efficacy of buntanetap/posiphen capsules compared with placebo capsules in participants with early PD.

Study details include:

* The study duration will be up to 7-8 months.
* The double-blind treatment duration will be up to 6 months.
* There will be 5 in-clinic visits and 7 phone calls

Detailed description:
450 early Parkinson's Disease (PD) patients will be randomized to 10mg, 20 mg of buntanetap/posiphen or placebo. They will undergo a Screening Visit, and if they provide informed consent and are considered eligible per the inclusion and exclusion criteria, will proceed to participate in the treatment period. Randomized participants will visit the clinic for the first-time dosing in clinic with administration of 10 mg or 20mg of buntanetap/posiphen or placebo, followed by an at home dosing period of 6 months, with daily administration of 10 mg or 20mg of buntanetap/posiphen or Placebo. Participants will be required to visit clinics 1 month, 2 months, 3 months, and 6 months (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 (MDS-United Parkinson's Disease Rating Scale (MDS-UPDRS), Clinical Global Impression of Severity (CGIS), Wechsler Adult Intelligence Scales (WAIS), Mini-Mental State Examination (MMSE)) and Participant Global Impression of Change (PGIC). At the end of blood sampling, the subjects 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 to report.

Buntanetap/posiphen has shown to improve PD subjects' mobility. MDS-UPDRS sum of score of Part II + Part III and Total score of all four parts will be measured to assess its improvement on PD subjects daily living, mobility and complications. PGIC will also be measured to assess its effect.

Buntanetap/posiphen has shown to reduce inflammation and preserve axonal integrity and synaptic functions as well as neurotoxic proteins in previous Phase 2a studies. In this study we plan to measure plasma glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and potentially TDP43.

Reports of adverse events (AEs) and serious adverse events (SAEs) during exposure to buntanetap/posiphen 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/posiphen; therefore, these safety measures will be sufficient in the proposed study.

For clinical, functional, and cognitive assessment measures, The subjects will be administered the Hoehn \& Yahr and the MMSE for determination of inclusion into the study. The MDS-UPDRS and PGIC will be administered for subjects' movement and daily function. The Coding subtest from the WAIS 4th edition will serve as a sensitive measure of Central Nervous System (CNS) dysfunction. MMSE will also be measured to assess subjects' cognitive change.

Arms: arm 1: Buntanetap/posiphen 10 mg oral capsule with daily administration for a period of 6 months arm 2: Buntanetap/posiphen 20 mg oral capsule with daily administration for a period of 6 months arm 3: Placebo oral capsule with daily administration for a period of 6 months
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 documents:
Prot_000.pdf: 
 
 
 
 
 
 
 
 
Cover Page for ClinicalTrials.gov 
 
 
 
Sponsor name:
Annovis Bio, Inc.
NCT number:
NCT05357989
Sponsor trial ID:
ANVS-22001
Official title of study: 
A 6-month prospective, randomized, double-blind, placebo-
controlled clinical trial investigating the efficacy, safety, and 
tolerability of two different doses of buntanetap or placebo in patients 
with early Parkinson’s disease
Document type: 
Protocol
Document date:
August 21, 2023
 


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Page 1 of 60 
 Protocol Title: 
A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial 
investigating the efficacy, safety, and tolerability of two different doses of buntanetap or 
placebo in patients with early Parkinson’s disease 
Protocol Short Title: 
A double-blind study to investigate efficacy and safety of buntanetap compared with 
placebo in participants with early PD  
 
Protocol Number:  ANVS-22001 
 
Sponsor:  Annovis Bio, Inc., Berwyn, Pennsylvania 19312, USA  
 
US IND Number:  159667 
NCT Number: 05357989  
EudraCT Number:  2022-001542-38 
IMP Identifier:  Buntanetap 
 
 
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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SPONSOR SIGNATURE PAGE: 
Protocol Title: 
A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial investigating 
the efficacy, safety, and tolerability of two different doses of buntanetap or placebo in patients 
with early Parkinson’s disease 
Protocol Short Title: 
A double-blind study to investigate efficacy and safety of buntanetap compared with placebo in 
participants with early PD 
 
CONTRACT RESEARCH 
ORGANIZATION 
SPONSOR 
 
TFS Trial Form Support International AB 
together with each of its subsidiaries and 
affiliates (“TFS”) 
Medicon Village Scheeletorget 1  
Byggnad 601 SE – 223 81  
Lund, Sweden 
 
ANNOVIS BIO, Inc. 
1055 Westlakes Drive, Suite 300 
Berwyn, Pennsylvania 19312 USA 
 
Maria L. Maccecchini, PhD 
President & CEO 
maccecchini@Annovisbio.com 
Tel: +1-(610) 727-3710 
 
 
SPONSOR SIGNATURE 
_______________________________________  
___________________ 
Maria Maccecchini, PhD 
 
 
 
Date 
 
 
 


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PRINCIPAL INVESTIGATOR SIGNATURE PAGE: 
Protocol Title: 
A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial investigating 
the efficacy, safety, and tolerability of two different doses of buntanetap or placebo in patients 
with early Parkinson’s disease 
Protocol Short Title: 
A double-blind study to investigate efficacy and safety of buntanetap compared with placebo in 
participants with early PD 
CONTRACT RESEARCH 
ORGANIZATION 
SPONSOR 
 
TFS Trial Form Support International AB 
together with each of its subsidiaries and 
affiliates (“TFS”) 
Medicon Village Scheeletorget 1  
Byggnad 601 SE – 223 81  
Lund, Sweden 
 
ANNOVIS BIO, Inc. 
1055 Westlakes Drive, Suite 300 
Berwyn, Pennsylvania 19312 USA 
 
Maria L. Maccecchini, PhD 
President & CEO 
maccecchini@Annovisbio.com 
Tel: +1-(610)-727-3710 
 
 
I, the undersigned, have carefully reviewed this clinical study protocol and I agree to conduct 
this study in accordance with the ethical principles set forth in the Declaration of Helsinki, the 
International Council for Harmonization guidelines on Good Clinical Practice (ICH E6, R2), and 
any applicable regulations and laws. 
INVESTIGATOR SIGNATURE 
 
___________________________________________ 
 
___________________ 
Signature 
 
 
 
 
 
 
Date 
 
 
Investigator Name: ______________________________________________________ 
 
Institution Name: ______________________________________________________________ 
 
 


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LIST OF ABBREVIATIONS  
5’UTR  
 
5’ untranslated region 
αSYN  
 
Alpha-synuclein 
Aβ 
 
 
Amyloid Beta 
AChE  
 
Acetylcholinesterase 
AD 
 
 
Alzheimer's Disease 
ADAS-Cog 
 
Alzheimer's Disease Assessment Scale – Cognitive Subscale 
ADCS  
 
Alzheimer's Disease Cooperative Study 
AE 
 
 
Adverse Event 
ALP 
 
 
Alkaline phosphatase 
ALT 
 
 
Alanine aminotransferase 
ANOVA 
 
Analysis of variance 
APP 
Aβ Precursor Protein 
AST 
Aspartate Aminotransferase 
AUC 
Area under the curve 
BChE 
Butyrylcholinesterase 
BDNF 
Brain Derived Neurotrophic Factor 
BP 
Blood pressure 
BPM 
Beats per minute 
BSA 
Body surface area 
CA 
Competent authority 
CFR 
Code of Federal Regulations 
CGIS 
Clinical Global Impression of Severity  
cGMP 
Current Good Manufacturing Practice 
CTCAE 
Common Terminology Criteria for Adverse Events 
CLBP 
Chronic low back pain 
Cmax 
Maximum plasma and CSF concentration  
ChE 
Cholinesterase 
CI 
Confidence Interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL 
Clearance  
C-SSRS 
Columbia Suicide Severity Rating Scale 
CNS 
Central Nervous System 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal Fluid 
CV 
Coefficients of variation 
CVD 
Cerebrovascular Dementia 
CYP3A4 
Cytochrome P450 3A4 enzyme 
DNA 
Deoxyribonucleic Acid 
DS 
Down Syndrome 
DSMB 
Data Safety Monitoring Board 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
EC 
European Community 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EU 
European Union 
FCR  
Fractional clearance rate 
FDA 
Food and Drug Administration 


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FSR 
Fractional Synthesis Rate 
FWA 
Federal wide Assurance 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFAP 
Glial Fibrillary Acidic Protein  
GI 
Gastrointestinal 
GRAS  
Generally recognized as safe  
GWAS 
Genome Wide Association Studies 
HEK 293 
Human embryonic kidney cells 
HEENT 
Head/ears/eyes/nose/throat 
hERG 
Human ether-a-go-go related gene  
HbA1c 
Hemoglobin A1C 
HIPAA 
Health Insurance Portability and Accountability Act 
HPMC 
Hydroxypropyl methylcellulose  
H&Y 
Hoehn and Yahr 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone Releasing System 
kg 
kilogram 
MAD 
Multiple Ascending Dose 
MCI 
Mild Cognitive Impairment 
MDS 
Movement Disorder Society 
MDS-UPDRS 
MDS-United Parkinson’s Disease Rating Scale 
MedRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram  
min 
minute 
mITT 
Modified Intent to Treat 
mL 
milliliter  
MMRM 
Mixed Model for Repeated Measures 
MMSE 
Mini-Mental State Examination 
mRNA 
Messenger Ribonucleic Acid 
ms 
milliseconds  
N 
Number of Subjects 
NFL 
Neurofilament Light 
NG 
Neurogranin 
ng.h 
Nanogram per hour 
NIH 
National Institutes of Health 
NOAEL 
No observed adverse effect level 
OHRP 
Office for Human Research Protections 
p-tau  
Phosphorylated tau 
PD 
Parkinson’s disease 
PGIC 
Patients' Global Impression of Change  
pH 
Power of Hydrogen 
PHI 
Protected Health Information 
PI 
Principal Investigator 


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PID 
Patient/Participant ID 
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 
QTcf  
Interval seen in QT (ECG) test 
RA 
Regulatory Authority 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
sAPPa 
soluble APP alpha 
sAPPb 
soluble APP beta 
SARS-CoV-2 
Covid 19 Virus 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SH-SY-5Y 
Human Derived Cell Line 
SILK™ 
Stable Isotope Labeling and Kinetics 
SNCA 
Synuclein Alpha 
SOC 
Standard of Care / System Organ Class 
SNRI 
Selective Norepinephrine Reuptake Inhibitor 
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 
TDP-43 
TAR DNA-binding Protein 43 
TG 
Transgenic 
Tmax 
Time to peak drug concentration 
TMF 
Trial Master File 
ULN 
Upper limit of normal 
US 
United States 
WAIS-IV 
Wechsler Adult Intelligence Scales, 4th edition 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................4 
1.0 
PROTOCOL SYNOPSIS ............................................................................................11 
2.0 
INTRODUCTION ......................................................................................................13 
2.1. 
OBJECTIVES .............................................................................................................14 
2.2. 
ENDPOINTS ..............................................................................................................14 
3.0 
COMPLETED STUDIES ...........................................................................................17 
3.1. 
Summary of Non-Clinical Findings ............................................................................18 
3.2. 
Summary of Clinical Findings ....................................................................................18 
4.0 
BACKGROUND AND STUDY RATIONALE.........................................................20 
4.1. 
Background .................................................................................................................20 
4.2. 
Study Overview...........................................................................................................22 
4.3. 
Outcome Measures ......................................................................................................24 
5.0 
POTENTIAL RISKS AND BENEFITS OF INVESTIGATIONAL PRODUCT AND 
STUDY PROCEDURES ............................................................................................24 
5.1. 
Risks and Benefits Associated with Buntanetap or Placebo .......................................24 
5.2. 
Risk/Benefit Associated with Blood Collections ........................................................25 
6.0 
SAMPLE SIZE AND STATISTICAL PLAN ............................................................25 
6.1. 
Randomization ............................................................................................................26 
6.2. 
Power and Sample Size Determination .......................................................................26 
6.3. 
Safety and Tolerability Analysis .................................................................................26 
6.4. 
PK Analysis.................................................................................................................26 
6.5. 
Criteria for Termination of the Trial ...........................................................................27 
6.6. 
Statistical Analysis ......................................................................................................27 
6.7. 
Study Subjects and Demographics ..............................................................................27 
6.7.1. 
Disposition and Withdrawals ......................................................................................27 
6.7.2. 
Protocol Deviations .....................................................................................................27 
6.7.3. 
Demographics and Other Baseline Characteristics .....................................................27 
6.7.4. 
Medical History and Concomitant Medications .........................................................27 
6.8. 
Analysis of Primary Endpoint .....................................................................................27 
6.9. 
Multiplicity Adjustment ..............................................................................................28 
6.10. 
Interim Analysis ..........................................................................................................28 


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6.11. 
Safety and Tolerability Analyses ................................................................................30 
6.11.1. 
Adverse Events ...........................................................................................................30 
6.11.2. 
Clinical Laboratory Evaluations .................................................................................30 
6.11.3. 
Vital Signs ...................................................................................................................31 
6.11.4. 
Physical/Neurological Examination Findings .............................................................31 
6.11.5. 
Other Safety Parameters:  C-SSRS .............................................................................31 
7.0 
STUDY DRUG AND CONCOMITANT MEDICATIONS ......................................31 
7.1. 
Identity of IP and Comparator ....................................................................................31 
7.2. 
Dosage .........................................................................................................................31 
7.3. 
Packaging/Dispensing/Labeling ..................................................................................31 
7.4. 
Storage ........................................................................................................................32 
7.5. 
Drug Accountability ....................................................................................................32 
7.6. 
Compliance .................................................................................................................32 
7.7. 
Breaking the Blind ......................................................................................................32 
7.8. 
Concomitant Medications ...........................................................................................33 
7.8.1. 
Prohibited Concomitant Medications ..........................................................................33 
7.8.2. 
Permitted Concomitant Medications ...........................................................................33 
8.0 
STUDY POPULATION .............................................................................................34 
8.1. 
Inclusion Criteria.........................................................................................................35 
8.2. 
Exclusion Criteria .......................................................................................................36 
9.0 
DESCRIPTION OF STUDY VISITS .........................................................................38 
9.1. 
Screening Visit ............................................................................................................38 
9.2. 
Baseline Visit ..............................................................................................................39 
9.3. 
Onsite Visit at 1 month, 2 month and 3 months..........................................................41 
9.4. 
4.5 months Telephone Contact ....................................................................................41 
9.5. 
End of Trial Visit ........................................................................................................41 
9.5.1. 
Pre-visit Telephone Contact ........................................................................................41 
9.5.2. 
End of Trial Visit ........................................................................................................41 
9.5.3. 
Post End of Trial Visit 24-Hour Phone Follow-up .....................................................43 
9.5.4. 
After The Trial ............................................................................................................43 
10.0 
EARLY TREATMENT/STUDY DISCONTINUATION ..........................................44 
10.1. 
Reasons for Early Discontinuation .............................................................................44 


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11.0 
STUDY-SPECIFIC INSTRUMENTS ........................................................................44 
12.0 
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 
13.0 
PERSONNEL REQUIREMENTS ..............................................................................47 
14.0 
ADVERSE EVENTS (AES) .......................................................................................47 
14.1. 
Definition ....................................................................................................................47 
14.2. 
Following Up on AEs .................................................................................................48 
15.0 
SERIOUS ADVERSE EVENTS (SAE) .....................................................................48 
15.1. 
Definition ....................................................................................................................48 
15.2. 
Reporting SAEs...........................................................................................................48 
16.0 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION .........................49 
16.1. 
Definition ....................................................................................................................49 
16.2. 
Reporting of Suspected Unexpected Serious Adverse Reactions ...............................49 
17.0 
ADVERSE EVENTS OF SPECIAL INTEREST .......................................................49 
18.0 
PRECAUTIONS/OVERDOSE ...................................................................................49 
19.0 
PREGNANCY ............................................................................................................49 
20.0 
DATA AND SAFETY MONITORING BOARD (DSMB) .......................................50 
21.0 
RECORDING AND COLLECTION OF DATA .......................................................50 
21.1. 
Electronic Case Report Form (eCRF) .........................................................................50 
21.2. 
Study Files and Source Documents ............................................................................51 
22.0 
ETHICS AND REGULATORY CONSIDERATIONS .............................................51 
22.1. 
Good Clinical Practice ................................................................................................51 
22.2. 
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) ................52 
22.3. 
Informed Consent and Health Insurance and Portability and Accountability Act 
(HIPAA) Compliance .................................................................................................52 
23.0 
STUDY MONITORING.............................................................................................53 
24.0 
AUDIT ........................................................................................................................53 


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25.0 
RECORD RETENTION .............................................................................................54 
26.0 
LITERATURE CITED ...............................................................................................55 
APPENDIX 1: SCHEDULE OF EVENTS ...................................................................................57 
APPENDIX 2:  INSTRUMENTS USED IN THE STUDY ..........................................................60 
 
 
 
 


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1.0 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
A 6-month prospective, randomized, double-blind, placebo-controlled 
clinical trial investigating the efficacy, safety, and tolerability of two 
different doses of buntanetap or placebo in patients with early 
Parkinson’s disease 
STUDY DESIGN 
The study will be 6-month placebo-controlled and double-blinded: 
subjects, investigators and the sponsor will be blinded to the subjects’ 
treatment.  
Qualified subjects will be randomly assigned at a 1:1:1 ratio to one of 
three treatment arms: buntanetap 10 mg, buntanetap 20 mg, and 
placebo, through an Interactive Randomization System, after a 
screening period of up to 42 days.  
MDS-UPDRS, PGIC, CGIS, WAIS coding, 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 subjects will be assessed by the same clinician throughout 
the study.  Participants should stop SOC Parkinson’s medications 12 
hrs before clinical visits to ensure clinical OFF-state during visit.  
DURATION OF STUDY 
PARTICIPATION 
Each subject will have up to a 42-day screening period, a baseline 
visit, followed by 6 months of treatment at home, followed by an in-
clinic visit. The total duration of study participation will be 7-8 
months.  
SUMMARY OF 
INVESTIGATIONAL 
PRODUCT 
Buntanetap 10mg, 20 mg, or placebo capsules, taken orally once a day 
for 6 months. 
SUMMARY OF KEY 
ELIGIBILITY 
CRITERIA  
 Diagnosis of idiopathic PD  
 Age 40 to 85 
 MMSE 22-30 
 Hoehn & Yahr =1,2,3 during ON-state & OFF-state < 2hrs per day 
PRIMARY OUTCOME 
MEASURES 
Aim 1. Change from baseline to Month 6 in MDS-UPDRS Part II 
(OFF-state) 
Aim 2.  Safety and Tolerability 
SECONDARY 
OUTCOME MEASURES 
Aim 1.  Change from baseline to Month 6 in the sum of MDS-
UPDRS Part II+III (OFF-state) 
Aim 2. Change from baseline to Month 6 in the MDS-UPDRS Part 
III (OFF-state) 
Aim 3. Change from baseline to Month 6 in the total MDS-UPDRS 
score (OFF-state) 
Aim 4.  Percentage of Responders with "Much Improved" or "Very 
Much Improved" on Participant Global Impression of Change 
(PGIC) (ON-state) 
Aim 5. Change from baseline to Month 6 on Clinical Global 
Impression of Severity of illness (CGIS) (OFF-state) 
EXPLORATORY 
OUTCOME MEASURES 
Aim 1.  Change from baseline to Month 6 in the plasma biomarkers 
measured 


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Aim 2.  Change from baseline to Month 6 in WAIS Coding Test 
(OFF-state) 
Aim 3.  Change from baseline to Month 6 in MMSE (OFF-state) 
Aim 4.  Pharmacokinetics (PK) 
 
 


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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 patients, 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 
development of combination therapies that target 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 
αSYN, APP, its fragments, and tau. All three proteins have been implicated in the pathogenesis 
of PD. Furthermore, at older ages, there is a high incidence of PD patients with mixed 
pathologies, such as PD dementia.  Therefore, it is reasonable to hypothesize that inhibiting 
expression of all three proteins should lead to a better efficacy outcome in PD patients than 
inhibiting just one. 
αSYN, APP, and tau 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 colonic motility in a human SNCAA53T 
and SNCAA30T transgenic (tg) mice models of early PD, 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’s safety has been established in three Phase 1 clinical studies by Maccecchini et al 
(2012). Importantly, buntanetap normalized levels of αSYN, APP, and tau as well as 
inflammatory markers in the cerebrospinal fluid (CSF) of mildly cognitively impaired (MCI) 
subjects 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 subjects (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 PD, 54 subjects 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 neurofilament light (NFL) and improved synaptic density shown by 
neurogranin (NG). Although sample size was not powered to see efficacy, buntanetap improved 
PD subjects WAIS coding scores at all doses including 5mg QD. Buntanetap also improved PD 
subjects MDS-UPDRS Part II, III, IV and Total score.  
In this study, we want to confirm buntanetap’s efficacy in early PD subjects. During the dose-
finding Phase 2a study, we saw a dose-response curve between 0 and 10/20 mg QD. Therefore, 
we decided to dose subjects with 10 and 20 mg QD.  
2.1. 
OBJECTIVES 
Study objectives include assessing buntanetap’ s efficacy and safety in early PD subjects.   
Study drugs will be 10 mg, 20mg of buntanetap, or matching placebo capsules, taken once per 
day in the morning before food. Eligible subjects will be randomly assigned at a 1:1:1 ratio to 
one of the three treatment arms: buntanetap 10 mg, buntanetap 20 mg, and placebo, through an 
Interactive Randomization System, after a screening period of up to 42 days. The total duration 
of the study will be 7-8 months. MDS-UPDRS, PGIC, CGIS and WAIS coding will be assessed 
by clinicians who have successfully completed the requisite certifications/trainings for each 
assessment. All efforts will be made to ensure subjects will be assessed by the same clinician 
throughout the study.  Participants should stop SOC Parkinson’s medications 12 hrs before 
clinical visit to ensure clinical OFF-state during visit.  
2.2. 
ENDPOINTS 
Primary Endpoints: 
1. Change From Baseline to Month 6 in MDS-UPDRS Part II (OFF-state) 


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Change in the Score from the MDS- Unified Parkinson's Disease Rating Scale (UPDRS) Parts II 
from Baseline to the End of Trial. MDS-UPDRS Part II (Motor experiences of daily living) has 
13 items and the score ranges from 0–52, with higher score reflecting greater severity. 
 
 


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2. Safety and Tolerability 
 Adverse Events (AE)  
 Severity of AEs 
 Drug related AEs 
 AEs leading to study discontinuation 
 Electrocardiogram findings 
 Clinical laboratory test results 
 Vital sign measurements 
 Physical and neurological examination findings 
Secondary Endpoints: 
1. Change from Baseline to Month 6 in the sum of MDS-UPDRS Part II+III (OFF-
state) 
Change in the Sum of the Score from the Activities of Daily Living (ADL) Scale and 
Motor Examination in the MDS-UPDRS (Parts II+III, a UPDRS Subtotal) from Baseline 
to the End of Trial.  
MDS-UPDRS Part II (Motor experiences of daily living) has 13 items and the score 
ranges from 0–52, with higher score reflecting greater severity MDS-
UPDRS Part III (motor examination) has 18 items and ranges from 0-132, with higher 
scores reflecting greater severity. The sum of Part II+III will be 0-184, with higher scores 
reflecting greater severity. 
2. Change from Baseline to Month 6 in the MDS-UPDRS Part III (OFF-state) 
MDS-UPDRS Part III (motor examination) has 18 items and ranges from 0-132, with 
higher scores reflecting greater severity. 
3. Change From Baseline to Month 6 in The Sum of MDS-UPDRS Total Score (OFF-
state) 
The MDS-Unified Parkinson's Disease Rating Scale (UPDRS) is a 50-item rating scale 
designed to assess Parkinson's disease-related disability and impairment. The scale 
comprises four parts: Part I evaluates mentation, behavior, and mood symptoms; Part II 
evaluates activities of daily living (ADL); Part III evaluates motor function; and Part IV 
evaluates complications of dopaminergic therapy. The Total score is the sum of the 
subscale scores for Parts I to III and ranges from 0 to 236, with higher scores reflecting 
greater severity. 
4. Percentage of Responders with "Much Improved" or "Very Much Improved" on 
Participant Global Impression of Change (PGIC) (ON-state) 


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The PGIC is the participant-reported outcome. The qualitative assessment of 
meaningful change will be determined by the participant in response to the question, 
"Compared to your condition at the beginning of treatment, how much has your 
condition changed?" Scores are: 1=very much improved; 2=much improved; 
3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; and 7=very 
much worse. Percentage of responders with much improved and very much 
improved on PGIC scale will be assessed. PGIC will be taken at home while the subject 
is during ON-state (with their SOC for Parkinson disease). 
5. Change From Baseline to Month 6 on Change on Clinical Global Impression of 
Severity (CGIS) (OFF-state) 
The Clinical Global Impressions Scale on the severity of movement impairment as assessed 
by the site rater. Site raters will be asked: Considering your total clinical experience with the 
Parkinson disease population, how ill is the patient at this time? Answers were based on a 7-
point scale, with 1=not assessed, 2= very mild, 3= mild, 4= moderate, 5= moderate severe, 
6= severe, 7=extremely severe. 
 
Exploratory Endpoints: 
1. Changes From Baseline to Month 6 in The Plasma Biomarker Measured 
Potential biomarkers to be measured in plasma are Neurofilament Light (NFL), Glial fibrillary 
acidic protein (GFAP) and TDP43. 
2. Change From Baseline to Month 6 in WAIS Coding Test (OFF-state) 
In the digital symbol coding test 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. 
3. Change From Baseline to Month 6 in MMSE (OFF-state) 
The Mini-Mental State Exam (MMSE) is a 30-point test, widely used test of cognitive function. 
4. Pharmacokinetics 
The following PK parameters will be determined, as data permit: Area under the curve (AUC), 
Cmax, Tmax, t½, and CL. 
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. 


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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. These plasma levels are 
attainable with low oral dosing in humans (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 
2021). In summary, buntanetap is a translational inhibitor of APP and aSYN and fully restores 
function at doses that are very low and very safe. 
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.  
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. Buntanetap readily crosses the blood-
brain barrier. 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 obtained from mild cognitively 
impaired participants (Protocol QR12001). One Phase1/2 study (Discover) was to test the safety, 
tolerability, PK and PD of  buntanetap in subjects with early Alzheimer's disease  (Protocol 


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QR12005). The other Phase 2a study was a double study for both early AD and early PD subjects 
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 subjects 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 
disproportionately 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 subject 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 disproportionally 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 AD 
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 
level of the N8-metabolite reached about 20 to 25% of the buntanetap levels measured in plasma.  
Because a substantial proportion of the adverse events observed in AD subjects treated with 
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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 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 sAPP, tau, αSYN and a series of inflammatory markers. 
The concentration and persistence of buntanetap in the brain suggest 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 the first part, 
early AD and PD subjects were given 80 mg QD buntanetap or placebo for 25 days.  In the 
second part, early PD subjects were given 5 mg, 10 mg, 20 mg, 40 mg QD buntanetap or placebo 
for 25 days. In all doses and in both AD and PD subjects, 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 
disproportionally 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 subjects’ CSF levels of 
sAPPa, sAPPb, 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 subjects’ CSF levels of αSYN and a series of inflammatory 
markers (YKL-40, GFAP, sTREM2, Complement C3). Buntanetap also improved PD subjects’ 
axonal integrity shown by NFL and synaptic function shown by NG.  
Further, buntanetap treatment improved AD subjects’ cognition shown by ADAS-Cog11 and 
WAIS coding test and improved PD subjects’ movement shown by MDS-UPDRS and WAIS 
coding test. 
4.0 
BACKGROUND AND STUDY RATIONALE 
4.1. 
Background 
A major pathological hallmark of PD is the appearance in the gut and in the brain of aSYN 
aggregates that form Lewy bodies. These aggregates are thought to occur one or two decades 
prior to overt symptom development. Recent research has shown that soluble forms of 
phosphorylated tau (p-tau) and other neurotoxic proteins such as TDP43 may also contribute to 
neuropathology of PD. A high load of inflammation and microglia activating factors that 
contribute to neurodegeneration are also common in PD. 


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Buntanetap is the (+) enantiomer of phenserine, an orally available small molecule. 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 also decreased aSYN and sAPP 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 aSYN and APP, as well as other neurotoxic aggregating 
proteins, it might have a broader spectrum of activity than PD and AD. By protecting neurons 
from dying, it has a disease-modifying effect in PD, AD as well as other neurodegenerative 
disorders.  
 
 


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4.2. 
Study Overview 
Study population: The study will be conducted in subjects with early PD. 
Dose selection: Qualified subjects will be randomly assigned at a 1:1:1 ratio to one of the three 
treatment arms: buntanetap 10 mg, buntanetap 20 mg, and placebo.  
Study Design:  450 early PD subjects will be randomized to 10 mg, 20 mg of buntanetap QD or 
placebo.  They will undergo a Screening Visit, and if they provide informed consent and are 
considered eligible per the inclusion and exclusion criteria, will proceed to participate in the 
treatment period.  Randomized participants will visit the clinic for the first-time dosing with 
administration of 10 mg or 20 mg of buntanetap or placebo, followed by an at home dosing 
period of 6 months, with daily administration of 10 mg or 20 mg of buntanetap or placebo.  
Participants will be required to attend clinic visits at 1 month, 2 months, 3 months, and 6 months 
(end-of-trial) time points, 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), psychometric tests 
(MDS-UPDRS, WAIS, MMSE) and PGIC and CGIS. 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 
clinic visits to assess the participants current condition and if there are any additional adverse 
events to report.   
Subjects who drop out during the initial 5 months at home treatment period will be discontinued 
and should complete an Early Discontinuation visit as soon as possible following 
discontinuation. Subjects that drop out after the initial 5 months, will be scheduled for an End of 
Trial visit. If 4 subjects are discontinued due to serious adverse events, a safety review will be 
conducted without interrupting the study. Unscheduled visits are allowed and investigators will 
perform safety assessments and AE/SAE and concomitant medication reviews as needed.  
The following figure shows how many times and when these procedures will be performed 
throughout the approximately 7 months of the study duration: 


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4.3. 
Outcome Measures 
Efficacy outcome measures: Buntanetap has shown to improve PD subjects’ mobility. MDS-
UPDRS sum of scores of Part II, Part III, Part II+III, and total score of first three parts will be 
measured to assess its improvement on PD subjects.  
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 subjects will be administered the 
Hoehn & Yahr (1967) and the MMSE (Folstein 1975) for determination of inclusion into the 
study. The MDS-UPDRS (Goetz 2008), Clinical Global Impression of Severity (CGIS, Hurst 
2004), and Participant Global Impression of Change (PGIC, Hurst 2004) will be administered for 
subjects’ movement and daily function.  The Coding subtest from the Wechsler Adult 
Intelligence Scales, 4th edition (WAIS-IV; Wechsler 2008) will serve as a sensitive measure of 
CNS dysfunction. MMSE will also be measured to assess subjects’ cognitive change. 
Exploratory measures: Buntanetap has shown to reduce inflammation and preserve axonal 
integrity and synaptic functions as well as neurotoxic proteins in previous Phase 2a studies. In 
this study we plan to measure plasma GFAP, NFL and potentially TDP43 depending on assay 
availability. 
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 subjects other than receiving medical and selective functional and 
cognitive evaluations. 
The clinical investigator must advise all potential subjects 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 


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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). 
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, potentially cholinergic based side effects, which 
resulted in the decision not to test higher single doses. 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 also 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 one 
month 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 and one month after.  Male study 
participants should not donate sperm and female study participants should not donate eggs 
during the whole duration of the trial and one month after.  
At this time, there is no controlled clinical data available for anyone receiving SARS-CoV-2 
(COVID-19) 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 subjects participating in 
this study who have received SARS-CoV-2 (COVID-19) vaccination or who are planning to 
receive the vaccination. As such, SARS-CoV-2 (COVID-19) vaccination is not prohibited. If 
appropriate, SARS-CoV-2 (COVID-19) vaccination should be considered as a concomitant 
medication (see Section 7.8.2). 
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 450 subjects (1:1:1 randomized to 10mg, 20mg buntanetap and placebo 
respectively) is planned.  
Definitions of the analysis populations and a detailed description of the analysis rules will be 
presented in a separate Statistical Analysis Plan (SAP). 


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6.1. 
Randomization 
Subjects 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 ratio. 
6.2. 
Power and Sample Size Determination 
Qualified subjects will be randomized at a 1:1:1 to one of the following three treatment groups: 
10 mg, 20 mg QD buntanetap and placebo. A sample size of 360 (120 per treatment group) will 
have 90% power to detect a treatment difference at a two-sided 0.025 significance level. In the 
sample size calculation, it was assumed a treatment difference of 2.55 and a common standard 
deviation of 5.59 based on historical data of MDS-UPDRS Part II+III (details will be provided in 
the Statistical Analysis Plan (SAP).  Approximately 450 subjects will be randomized 
(approximately 150 per arm) to account for 112 patients calculated from the power analysis plus 
screen failures and dropout rates.  
Based on FDA recommendations, the primary endpoint was changed into MDS-UPDRS Part II 
after enrollment ended. The current enrolled subject number gives us 90% power to detect a 
treatment difference of 3 points and a common standard deviation of 8 points of MDS-UPDRS 
Part II. 
6.3. 
Safety and Tolerability Analysis 
Safety and tolerability will be assessed with physical/neurological 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.  
Subjects who dropout during the initial 5 months at-home treatment period will be scheduled 
early discontinuation visit.  Subjects who drop out after the initial 5 monthswill be scheduled for 
an end-of-trial visit. If 4 subjects are discontinued due to serious adverse events a 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 subjects’ 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 subjects (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-subject coefficients of variation (CV) will be calculated. 


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6.5. 
Criteria for Termination of the Trial  
The trial may be terminated by the Project Directors and/or the Sponsor based on issues of 
safety, futility, and Data Safety Monitoring Board (DSMB) recommendations. 
6.6. 
Statistical Analysis 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a p value of less than or equal to 0.05 will be considered statistically significant. 
Furthermore, the baseline will be the last assessment before the first dosing of the study drug. 
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum. For categorical variables, these 
statistics will typically include the number and percentage of subjects in each category. 
6.7. 
Study Subjects and Demographics 
6.7.1. 
Disposition and Withdrawals 
The numbers of subjects 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 subjects in each analysis population will be reported. 
6.7.2. 
Protocol Deviations 
Major protocol deviations will be classified and documented by TFS before database lock and will 
be discussed in the CSR. All protocol deviations, both minors and majors, will be presented in a 
data listing. 
6.7.3. 
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. 
6.7.4. 
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 subjects taking each medication, classified using World 
Health Organization (WHO) Drug Dictionary Anatomical Therapeutic Chemical (ATC) classes 
and preferred terms. 
6.8. 
Analysis of Primary Endpoint 
The primary endpoint is the change from baseline to Month 6 in of MDS-UPDRS Part II scores. 
The primary endpoint will be analyzed via a mixed model for repeated measures (MMRM). The 
model will include treatment, timepoint, treatment-by-timepoint interaction as the fixed effects 


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and baseline MDS-UPDRS Part II as the covariate. The covariate will assume to be unstructured. 
The treatment effects and the differences of the treatment effects will be estimated. The two-
sided 95% confidence intervals of the treatment differences will be presented. 
6.9. 
Multiplicity Adjustment 
There are two active treatment groups (10 mg and 20 mg) in the study. Each of the two active 
treatments will be compared to the control (two hypothesis tests for the primary endpoint). 
Hochberg step-up procedure will be used to control the familywise Type I Error. Details are 
described in the SAP. 
6.10. 
Interim Analysis 
An interim sample size review will be performed after in total 𝑛1 = 150 evaluable patients (50 
patients per treatment group) have primary endpoint data, i.e., MDS-UPDRS part II+III at month 
2. Evaluable patients are defined as randomized and having received at least once treatment with 
the study drug. The aim of the interim sample size review is to re-assess the size of the estimated 
mean and standard deviations of the primary effectiveness variable (MDS-UPDRS part II+III).  
No interim analyses are planned for the purpose of stopping the study early for futility. 
The initial sample size estimation provides statistical power to demonstrate effectiveness among 
patients treated with buntanetap. A potential sample size adjustment is to assure that this trial 
will have the intended precision. The decision of sample size adjustment will be made based 
upon the estimates of MDS-UPDRS part II+III at baseline and after two months of treatment 
calculated for the first 150 evaluable patients with primary endpoint data. Sample size will not be 
decreased regardless of the results of this evaluation. To warrant the originally intended >90% 
power of the study at the 0.025 alpha level (2-sided), the evaluable sample size may be increased 
to a maximum of nmax=200 enrolled patients per treatment group. The sample size re-estimation 
will be evaluated for the efficacy endpoint based on the observed interim mean and standard 
deviation of treatment difference of the MDS-UPDRS part II+III score. 
The sample size re-estimation method is based on evaluation of conditional power in relationship 
to pre-specified decision rules defined by ranges of attainable conditional power values. Only an 
increase in sample size is possible under this approach when observed conditional power falls 
within the ‘promising zone’ as described below (Mehta and Pocock 2011). 
The conditional power at the interim analysis (𝐶𝑃𝛿̂1 (𝑧1, 𝑛̃2)) can be defined by the following 
equation from Mehta and Pocock (2011): 
 
𝐶𝑃𝛿̂1 (𝑧1, 𝑛̃2) = 1 − Φ(((𝑧𝛼/2√𝑛2 − 𝑧1√𝑛1)/√𝑛̃2) – (𝑧1√𝑛̃2/√𝑛1)) + Φ(((−𝑧𝛼/2√𝑛2 − 𝑧1√𝑛1)/ √𝑛̃2)) – 
(𝑧1√𝑛̃2 √𝑛1) 
 
where 𝑛̃2 = 𝑛2 − 𝑛1, 𝑧𝛼/2 = Φ-1(1 - 𝛼/2), and 𝑧1 is the value of the cumulative Wald statistic as 
computed at the interim analysis of 𝑛1= 50, 𝑛2= 150 evaluable patients. Define the estimated 
treatment difference, 𝛿̂1 = 𝜇̂1 − 𝜇0 at interim analysis, where 𝜇̂1 is mean and proportion at interim 
analysis and 𝜇0 is the null hypothesis correspondingly. 
The targeted conditional power at the first interim review is 90%, however we pre-specify a 
range of conditional power values below 90% that would deem our interim results promising and 


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warrant a sample size re-estimation. Table 1 provides cut-off values from Mehta and Pocock 
(2011) for the lower bound of the promising zone, 𝐶𝑃𝑚𝑖𝑛, under some typical two-stage adaptive 
designs. 𝐶𝑃𝑚𝑖𝑛 is 0.42 (42%) for the parameter choices (nmax/n2 = 1.5, n1/n2 = 0.33) in this study.  
  
Table 1. 𝐶𝑃𝑚𝑖𝑛 cut-off values for some typical two-stage adaptive designs with no early stopping 
either for efficacy or futility 
Sample size ratios 
CPmin values for targeted conditional 
power 
Maximum allowed 
(nmax / n2) 
At interim look      
(n1 / n2) 
80 per cent 
90 per cent 
1.5 
0.25 
0.42 
0.42 
1.5 
0.5 
0.41 
0.41 
1.5 
0.75 
0.38 
0.38 
2 
0.25 
0.37 
0.37 
2 
0.5 
0.36 
0.36 
2 
0.75 
0.33 
0.33 
3 
0.25 
0.32 
0.32 
3 
0.5 
0.31 
0.31 
3 
0.75 
0.30 
0.27 
∞ 
0.25 
0.32 
0.28 
∞ 
0.5 
0.31 
0.27 
∞ 
0.75 
0.30 
0.25 
 
Table 2 summarizes the sample size re-estimation decision based on the conditional power 
observed at interim analysis. The sample size is re-estimated when the interim conditional power 
falls within the promising zone of 0.42 to 0.90 (42% to 90%).   
 
Table 2. Sample Size Re-Estimation Decision  
Conditional power 
Decision 
Less than 42% 
“Unfavorable zone” – No change to sample size 
42% to 90% 
“Promising zone” – Increase sample size 
At least 90% 
“Favorable zone” – No change to sample size 
 
The re-estimated cumulative final sample size (𝑛2∗) is computed using the following equation 
(equation (9) from Mehta and Pocock (2011)) and will be increased by a factor based on a re-
assessed attrition rate as per the initial sample size calculation:  
𝑛2∗ = min(𝑛2′ , 𝑛𝑚𝑎𝑥) , where ñ2′ satisfies the condition 𝐶𝑃𝛿̂1 (𝑧1, ñ2′ ) = 1 − β, β = 90%, 
and n2′ is the estimated new sample size computed as n1 + ñ2′. 
  
Based on Mehta and Pocock (2011), this condition is satisfied by the function:  


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𝑛̃2′ = ([𝑛1/𝑧12][(𝑧𝛼/2√𝑛2− 𝑧1√𝑛1 √𝑛2− 𝑛1 + 𝑧𝛽]2), where 𝑧𝛼/2 = Φ-1(1- 𝛼/2), 𝑧𝛽 = Φ-1(1- 𝛽), 
and 𝑧1 is the cumulative Wald statistic as computed at the interim analysis. 
The new sample size s increased to: 
𝑛2∗ = min(𝑛2′, 𝑛𝑚𝑎𝑥) ,  
where ñ2′ satisfies the condition 𝐶𝑃𝛿̂1 (𝑧1, ñ2′) = 1 − β, β = 90%, and n2′ is the estimated 
new sample size computed as n1 + ñ2′ (Details see SAP). 
The study team at the Sponsor will be blinded to interim results. A blinded Sponsor clinical 
scientist may have access to blinded subject-level and aggregated MDS-UPDRS 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 
Safety analyses will be conducted using data from the Safety Population.  
Safety and tolerability will be assessed through TEAEs; hematologic, biochemical, and 
urinalysis laboratory parameters; physical/neurological examination findings; and vital signs 
measurements.  
No formal statistical comparisons will be performed for safety endpoints. 
6.11.1. 
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities reporting system. The number and percentage of subjects 
with TEAEs will be displayed for each treatment group by SOC and preferred term. 
Additionally, TEAEs will be tabulated for each treatment group by severity and by relationship 
to the study drug. A listing of SAEs will be provided if applicable. 
6.11.2. 
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.  
Additionally, clinical laboratory parameters will be categorized as low, normal, or high 
according to laboratory range specifications and the number and percentage of subjects 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. 


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6.11.3. 
Vital Signs 
Descriptive summaries (mean, SD, 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. 
6.11.4. 
Physical/Neurological Examination Findings 
Physical/neurological examination data will be presented in the listings. 
6.11.5. 
Other Safety Parameters:  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. The distribution of responses for most severe 
suicidal ideation and most severe suicidal behavior during the subject’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 listings will be provided and will include 
the subject 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 subjects who have suicidal ideation or suicidal 
behavior will also be provided. 
7.0 
STUDY DRUG AND CONCOMITANT MEDICATIONS 
7.1. 
Identity of IP and Comparator 
Buntanetap will be provided in size 1 white opaque hydroxypropyl methylcellulose (HPMC, 
vegetarian source) capsule shells.  Capsules contain buntanetap (either 10mg or 20mg) 
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 6 months at home.  
Participants are encouraged to take a minimum of 80% of all doses (across 6 months).  Returned 
IMP will be examined at each clinic visit to assess compliance overall.  
7.3. 
Packaging/Dispensing/Labeling 
The study drug (buntanetap capsules and placebo capsules) has been manufactured under cGMP, 
in a manner to preserve the blind, i.e., identical color and shape white opaque HPMC hard capsule 
shells and packaged 40 capsules per bottle.  
The investigational drug supply will be shipped directly to the clinical sites to dispense to 
participants.  


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Sites should order IP only after successful confirmation of eligibility criteria (usually after receipt 
of positive 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 
caregiver before dispensing the study drug.  
All packaging and labelling as well as the production of study medication will be in accordance 
with US FDA regulations and EudraLex volume 4, Annex 13 “Good manufacturing practices for 
Medicinal products for human and veterinary use” and applicable local regulatory requirements. 
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 subjects.  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 relevant study visits. Participants are encouraged to take a 
minimum of 80% of all doses at home (6 months) depending on the end of trial date. Site 
personnel will count capsules and evaluate compliance from the bottle at each clinic visit.  
Prior to the end of trial visit, site personnel will also contact the participant to remind them of the 
dose regimen, to ensure that the necessary level of compliance has been achieved to continue 
with the end-of-trial visit procedures. It is possible that subjects will be discontinued early from 
the study due to insufficient study drug compliance. 
Site personnel will assess compliance at each clinic visit and again at the time of admission for 
the end of trial visit. . 
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 


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the blind to be unmasked for a subject for SAE, the investigator can open the blind without prior 
consulting with the Medical Monitor and the Project Directors. 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.  
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 Project Directors 
and 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 FDA guidance on drug development and drug interactions. 
CYP3A4 
inhibitors 
Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil 
CYP3A4 
inducers 
Rifampicin 
 
7.8.2. 
Permitted Concomitant Medications 
This protocol allows concomitant treatment with anti-parkinsonian medications at stable doses 
for 4 weeks or greater prior to screening. 
Use of the following medications is allowed only if the patients have been stable on them 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 prescribed dose must be equal to 
or less than the following doses for each listed medication: quetiapine 50 mg/day, 
risperidone 1.5 mg/day, olanzapine 5 mg/day, 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 study is discouraged 
and should consult with the Medical Director and Sponsor for further guidance. 
If subjects 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 allowed. 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 subjects 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 (COVID-19) vaccination is not prohibited. 
8.0 
STUDY POPULATION 
Participants in this study must be in accordance with the criteria specified below. Subjects who 
do not meet all inclusion criteria, disease diagnostic criteria, or who meet any exclusion criteria 
will not be included in the clinical trial.  Membership in the analysis populations will be 
determined before unblinding. 
The following analysis populations are planned for this study:  
 Enrolled Population:  The enrolled population will include all subjects who signed 
Informed Consent and meet all inclusion and exclusion criteria. 
 Randomized Population:  The randomized population will include all subjects who are 
randomized to a treatment arm. 
 Modified Intent-to-Treat (mITT) Population:  the mITT will consist of all subjects who 
are randomized, take at least 1 dose of the study drug, and have at least 1 post-Baseline 
assessment.  The mITT population will be analyzed to support the primary efficacy 
analyses. 
 Intent-to-Treat (ITT) Population: the ITT will consist of all subjects who are randomized. 
The primary efficacy analysis will be based on the ITT population. 
 Safety Population:  The Safety Population will be the primary safety analysis population 
and will include all subjects who receive at least 1 dose of the study drug.  The safety 
analyses will be based on the Safety Population. 


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 Per Protocol Population:  The Per Protocol Population will include all mITT subjects who 
do not have any major protocol deviations. 
8.1. 
Inclusion Criteria 
Subjects must meet the following criteria:  
1. 
Diagnosis of idiopathic PD according to MDS Clinical Diagnostic Criteria for Parkinson’s 
Disease (Postuma 2015). 
2. 
H&Y score =1, 2 or 3 during ON-state & OFF-state <2hrs per day. 
3. 
Male or female aged 40 – 85 years.  
4. 
MMSE score between the range of 22-30 during screening visit (ON-state) and subjects can 
live independently without a caregiver. 
5. 
Female subjects 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. 


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6. 
Male subjects 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 subject 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 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion   
7. 
General cognition and functional performance sufficiently preserved that the subject can 
provide written informed consent.  
8. 
No evidence of current suicidal ideation or previous suicide attempt in the past month as 
evaluated in the Columbia Suicide Severity Rating Scale.  
9. 
Stability of permitted medications prior to screening for at least 4 weeks.  
10. At screening subjects do not need to but may be on the following medication:  
 
Standard of Care anti-parkinsonian medication   
 
Anticonvulsant medications used for epilepsy or mood stabilization, neuropathic 
pain indications  
 
Mood-stabilizing psychotropic agents, including, but not limited to, lithium.  
 
11. Adequate visual and hearing ability (physical ability to perform all the study assessments).  
 
12. Good general health with no disease expected to interfere with the study.  
 
13. Subjects previously exposed to buntanetap can still be included in the study after a 28- day 
wash out period. 
8.2. 
Exclusion Criteria 
Subjects 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.  


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2. 
History of a seizure disorder, if stable on medication is acceptable.  
 
3. 
Has a history or current evidence of long QT syndrome, Fridericia's formula corrected QT 
(QTcF) interval ≥ 450 ms for men and 460ms for women, or torsades de pointes.  
 
4. 
Has bradycardia (<50 bpm) or tachycardia (>100 bpm) on the ECG at screening.  
 
5. 
Has uncontrolled Type-1 or Type-2 diabetes. A subject with HbA1c levels up to 7.5% can 
be enrolled if the investigator believes the subject's diabetes is under control.  
 
6. 
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).  
 
7. 
Has any clinically significant abnormal laboratory values. Subjects with liver function tests 
(aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) greater than twice 
the upper limit of normal will be excluded.  
 
8. 
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. Subjects 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.  
 
9. 
Has cancer or has had a malignant tumor within the past year, except subjects who 
underwent potentially curative therapy with no evidence of recurrence. (Subjects with 
stable untreated prostate cancer or skin cancers are not excluded).  
10. Alcohol / Substance use disorder, moderate to severe, in the last 5 years according to the 
most current version DSM.  
 
11. Participation in another clinical trial with an investigational agent and have taken at least 
one dose of study medication, unless unblinded on placebo, within 60 days prior to the start 
of screening. The end of a previous investigational trial is the date the last dose of an 
investigational agent was taken, or five half-lives of the investigational drug, whichever is 
greater.  
 
12. Subjects with learning disability or developmental delay.  
 
13. Subjects whom the site PI deems to be otherwise ineligible.  
 
14. Subjects with a known allergy to the investigational drug or any of its components. Here 
are all the inactive ingredients of the IMP:  


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Silicified Microcrystalline Cellulose 
Dibasic Calcium Phosphate Dihydrate 
Mannitol 
Magnesium Stearate 
Hypromellose (capsule shells structure) 
Titanium Dioxide (opacifier of the capsule shells) 
 
 
15. Subject is currently pregnant, breast-feeding and/or lactating. 
16. Subject is currently taking strong or moderate CYP3A4 inhibitors and/or inducers. See 
examples below: 
CYP3A4 
inhibitors 
Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil 
CYP3A4 
inducers 
Rifampicin 
 
17. Subject is currently receiving deep brain stimulation treatment. 
9.0 
DESCRIPTION OF STUDY VISITS 
Each subject will have a 42-day screening period followed by 6 months 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. Participants do not need to stop their 
Parkinson’s disease SOC medications for screening visit.  
Potential participants must sign an informed consent form prior to administration of any study-
related procedures. Information regarding the subject’s demographics, concurrent medications, 
and medical history will be collected along with cognitive assessments, physical examination, 
and neurological examination. With investigator’s permission, lab re-testing is allowed within a 
month. If investigator deems re-screening is justified, they must contact Medical Monitor and 
sponsor for discussion at case-by-case basis.  
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 


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pregnancy test will be completed for female subjects. Fasting is required for safety laboratory 
tests. 
Cognitive and functional assessments should not be administered when the subject 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 subject’s 
eligibility before proceeding to Baseline. 
9.2. 
Baseline Visit 
Baseline procedures include functional, cognitive, and behavioral assessments, safety 
assessments, and review of concurrent medications and potential adverse events that might 
occur. Fasting is required for safety laboratory tests. Participants should stop all Parkinson’s 
disease SOC 12 hours prior to the visit to ensure a clinical OFF-state. For patients who are not on 
any Parkinson’s disease SOC, their natural state will be considered OFF-state and since they 
won’t have ON-state, it should be documented accordingly in the source documents. 
Baseline visit should be completed in one day except for the intense PK sub-group. 
Day 1: 
Subjects 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, patients will be provided low-fat light meal before completing functional and 
cognitive evaluations (completed in an OFF state after holding PD meds for 12 hours prior to 
arrival at site), a physical and neurological exam, collecting vital signs, ECG, and reviewing and 
recording adverse events and concurrent medications. Sites should take detailed notes of contents 
of all meals provided to the patients. Following completion of all these procedures, subjects who 
continue to meet all protocol inclusion criteria and no exclusion criteria should be randomized. 
Patients can take their SOC medication at this point if needed. 
For sparse PK group (i.e. any subject that is not participating in the intense PK sub-study), if no 
medical or compliance concerns are identified, the subject will move on to the PK sampling 
phase, which will entail the following procedures: 
1) Collect initial samples of blood (hour 0) with venipuncture unless PI deems 
inappropriate. 
2) Administer first dose of assigned study drug after the hour 0 sampling. 
3) Collect blood (10mL) at the 1.5hr timepoint. Blood should be taken within ± 10 mins of 
times. 
4) Perform the final safety monitoring.  


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For sparse PK group, prior to discharge from the clinic, vital signs should be recorded, and a 
review of AE(s) and concomitant medications should be conducted as the final safety 
monitoring. Patients will be educated of the study drug compliance and study drug return. Upon 
determination by the Investigator (or qualified designee) that the subject is stable, the participant 
will be discharged. If a participant experiences an unstable AE, the PI shall manage the event 
without prior consulting with the Medical Monitor. The MM shall be informed as soon as 
possible, and the management of the AE shall be reported in the Study documents. 
For intense PK group, if no medical or compliance concerns are identified following the Day 1 
procedures, subjects will be scheduled for the next day PK sampling, unless patients prefer to 
finish PK in one day.  
Day 2 (Intense PK group only) 
Patient should arrive in clinic fasted in the morning after an overnight fast but does not need to 
be in OFF state.  The subject will start PK sampling phase, which entails the following 
procedures.  
1. Place an intravenous line for blood sampling.   
2. Collect initial sample of blood (hour 0).  
3. Administer first dose of assigned study drug after the hour 0 sampling. 
a. For 16 subjects per group, blood samples (10mL) will be collected at 1hr, 1.5hr, 
2hr, 3hr, 4hr, 5hr, 6hr,7hr, 8hr, 9hr, and 10hr timepoints. Blood should be 
collected within ± 10 mins of scheduled times. 
b. Perform periodic safety monitoring during the collection period. Participants 
should be asked about pain, redness or swelling at the blood collection site.  
c. Patients will be provided low-fat light meals after 2hr, 6hr and 10hr PK sampling. 
Sites should take detailed notes of contents of all meals provided to the patients. 
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 as the final safety monitoring. Patients will be 
educated of the study drug compliance and study drug return. Upon determination by the 
Investigator (or qualified designee) that the subject is stable, the participant will be discharged. If 
a participant experiences an unstable AE, the PI shall manage the event without prior consulting 
with the Medical Monitor. The MM shall be informed as soon as possible, and the management 
of the AE shall be reported in the Study documents. 
 


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9.3. 
ONSITE VISIT AT 1 MONTH, 2 MONTH AND 3 MONTHS 
At 1 month, 2 months and 3 months (+/- 7 days) from the baseline visit, a clinic visit should 
occur. Participants should stop all Parkinson’s disease SOC 12 hours prior to the visit to ensure a 
clinical OFF-state. Clinic visit procedures include functional, and behavioral assessments, safety 
assessments, and review of concurrent medications and adverse events that occur in clinic and 
during blood collection. Fasting is required for safety laboratory tests.  After safety lab, patients 
will be provided low-fat light meal before completing functional and cognitive evaluations 
(completed in an OFF state after withholding PD meds for 12 hours prior to arrival at site), a 
physical and neurological exam, collecting vital signs, ECG, and reviewing and recording 
adverse events and concurrent medications. Sites should take detailed notes of contents of all 
meals provided to the patients. 
Study medication compliance will be reviewed and discussed, and reminders given about the 
upcoming end of trial visit.  
 A post-visit safety phone follow up will be conducted approximately 24 hours following each 
clinic visit.  
9.4. 
4.5 months Telephone Contact  
A telephone call will be conducted at 4.5 months +/- 7 days from the baseline visit to assess for 
any changes in status, adverse events, or concomitant medications. Study medication compliance 
will be discussed, and reminders given about the upcoming end of trial visit.  
9.5. 
End of Trial Visit 
End of trial is when the last subject of the study finishes last clinical visit. End of trial visit is 
each subject’s last clinical visit during the study. The end of trial visit should occur 6 months +/- 
7 days 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 behavioral 
assessments, safety assessments, and review of concurrent medications and adverse events that 
occur in clinic and blood collection. Participants should stop all Parkinson’s disease SOC 12 
hours prior to the visit to ensure a clinical OFF-state. 
9.5.1. 
Pre-visit Telephone Contact  
A telephone call will be conducted at 1-3 days prior to end of trial to assess for any changes in 
status, adverse events, or concomitant medications.  Study medication compliance will be 
discussed, and reminders given about the upcoming end of trial visit.  
9.5.2. 
End of Trial Visit 
This constitutes the subjects’ last clinical visit during the study for all patients who have 
participated over 5 months. Early drop-out patients will be invited to participate early discontinuation 
visit. The end of trial visit will consist of the following: admission procedures, Time 0 blood 


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sampling, administration of last dose of study drug, 1.5hr after-dose blood sampling except for 
the subgroup of subjects participating in the intense PK sub-study, who will have PK samples for 
10 hours, all psychometric and safety tests, and discharge procedures. Fasting is required for 
safety laboratory tests. End of trial visit should be done in one day except for the intense PK 
subgroup. 
For the subgroup of subjects who will have intense PK samples, blood samples will be drawn at 
0hr, 1hr, 1.5hr, 2hr, 3hr, 4hr, 5hr, 6hr, 7hr, 8hr, 9hr, and 10hr timepoints. 
Day 1: 
Subjects 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, patients will be provided low-fat light meal before completing functional and 
cognitive evaluations (completed in an OFF state after holding PD meds for 12 hours prior to 
arrival at site), a physical and neurological exam, collecting vital signs, ECG, and reviewing and 
recording adverse events and concurrent medications. Sites should take detailed notes of contents 
of all meals provided to the patients. Patients can take their SOC medication at this point if 
needed. 
For sparse PK group, if no medical or compliance concerns are identified, the subject will move 
on to the PK sampling phase, which will entail the following procedures: 
1) Collect initial samples of blood (hour 0) by venipuncture unless PI deems inappropriate. 
2) Administer last dose of assigned study drug after the hour 0 sampling. 
3) Collect blood (10mL) at the 1.5hr timepoint. Blood should be taken within ± 10 mins of 
times. 
4) Perform the final safety monitoring.  
For sparse PK group, 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 subject is stable, the participant will be discharged. If 
a participant experiences an unstable AE, the PI shall manage the event without prior consulting 
with the Medical Monitor. The MM shall be informed as soon as possible, and the management 
of the AE shall be reported in the Study documents. 
For intense PK group, if no medical or compliance concerns are identified, the subject will be 
scheduled for the next day PK sampling unless patients prefer to complete end-of-trial visit in 
one day.  
Day 2 (Intense PK only) 


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Patient should arrive in clinic fasted in the morning after an overnight fast but do not need to be 
in OFF state.  The subject will start PK sampling phase, which entails the following procedures.  
5. Place an intravenous line for blood sampling for the subgroup that will collect 10-hour 
blood samples.   
6. Collect initial samples of blood (hour 0). 
7. Administer last dose of assigned study drug after the hour 0 sampling. 
a. For 16 subjects per group, their blood samples (10mL) will be collected at 1hr, 
1.5hr, 2hr, 3hr, 4hr, 5hr, 6hr,7hr, 8hr, 9hr, and 10hr. Blood should be taken within 
± 10 mins of times. 
b. Perform periodic safety monitoring during the collection period. Participants 
should be asked about pain, redness or swelling at the blood collection site in the 
arm.  
c. Patients will be provided low-fat light meal after 2hr, 6hr and 10hr PK sampling. 
Sites should take detailed notes of contents of all meals provided to the patients. 
 
8. 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 as the final safety monitoring. Upon determination 
by the Investigator (or qualified designee) that the subject is stable, the participant will be 
discharged. If a participant experiences an unstable AE, the PI shall manage the event without 
prior consulting with the Medical Monitor. The MM shall be informed as soon as possible, and 
the management of the AE shall be reported in the Study documents. 
9.5.3. 
Post End of Trial Visit 24-Hour Phone Follow-up 
Approximately 24 hours following the end of trial visit the subject will be contacted by phone to 
confirm the subject’s well-being and to query about any new AEs. 
9.5.4. 
After The Trial 
The subject will continue the standard of care of Parkinson’s disease under the supervision of the 
treating physician.   
 


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10.0 
EARLY TREATMENT/STUDY DISCONTINUATION 
The investigators at each site will make every reasonable effort to maximize subject retention. 
However, if an investigator removes a subject from treatment or study, or if a subject declines 
further treatment or study participation, an early discontinuation visit will be completed as soon 
as possible following discontinuation. 
10.1. 
Reasons for Early Discontinuation 
Participants 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 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 or others 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 participant 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. 
11.0 
STUDY-SPECIFIC INSTRUMENTS  
The following instruments will be employed to measure states of function, dementia, and 
movement.  Copies of the instruments are provided in Appendix 2. 
 Mini-Mental State Examination (MMSE) 
 Patients' Global Impression of Change (PGIC) 
 Clinical Global Impression of Severity (CGIS) 
 Wechsler Adult Intelligence Scales, 4th edition (WAIS-IV)  


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 Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease 
Rating Scale (MDS-UPDRS). 
12.0 
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 subjects 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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12.1.3. 
Clinical Laboratory Evaluations 
Blood and urine samples will be obtained for clinical safety lab assessments as described in the 
Schedule of Events (Appendix 1).  The following table lists the clinical safety lab tests that will 
be assessed by the central lab at these time points: the screening visit, each clinical visit (1 
month, 2 months and 3 months), and the end of trial visit.  Refer to the Laboratory Manual for 
additional details. 
 
Lab reports will be reviewed, signed, and dated by the site PI (or a medically qualified individual 
delegated by the PI). If a value is outside of the laboratory’s normal range, the clinician will 
indicate if the value has clinical significance. Those results that are deemed clinically significant 
may need to be repeated and may require follow up with the subject’s primary care physician for 
further evaluation.  
12.2. 
Biofluids 
12.2.1. 
Plasma for Biomarkers and Pharmacokinetics 
Plasma samples will be collected at the baseline visit, and during the end of trial visit for analysis 
of biomarkers and PK, as described in the Laboratory Manual.  
CLINICAL SAFETY LAB TESTS 
METABOLIC PANEL 
COMPLETE BLOOD COUNT 
URINALYSIS 
Sodium (Na) 
Potassium (K) 
Chloride (Cl) 
Carbon Dioxide (CO2) 
Blood Urea Nitrogen (BUN) 
Glucose  
Calcium (Ca)  
Creatinine (Crn) 
Bilirubin (direct and Total) 
Albumin 
Protein - Total 
Glutamic-Oxaloacetic 
Transferase (AST, SGOT) 
Glutamic-PyruvateTransferase 
(ALT, SGPT) 
Alkaline Phosphatase (ALP) 
eGFR (estimated Glomerular 
Filtration Rate) 
White Blood Cell Count (absolute and 
percentage): basophils, eosinophils, 
lymphocytes, monocytes, neutrophils 
Red Blood Cell Count (RBC) 
Hemoglobin (Hb) 
Hematocrit (HCT) 
Mean Corpuscular Volume (MCV) 
Mean Corpuscular Hemoglobin (MCH) 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
Red Blood Cell Distribution Width 
(RDW) 
Mean Platelet Volume (MPV) 
Platelet Count (PLT) 
 
                 Screening Only 
Hemoglobin A1C (HbA1c) 
 
Color 
Appearance 
Specific Gravity 
pH 
Blood 
Glucose 
Protein 
Ketones 
Leukocyte Esterase  
Nitrite 
Urobilinogen 
Bilirubin (total) 
 


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13.0 
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. Additionally, the PI will perform or supervise clinical evaluation of all 
subjects and ensure protocol adherence. Additional key personnel will be required, as outlined in 
the procedure manual.  
14.0 
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 subject or clinical investigation subject administered a 
pharmaceutical product and 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 subject 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) Subject 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 Subject 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 Subject’s 
records, in accordance with the investigator’s normal clinical practice, and on the AE electronic 
case report form (eCRF). 


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14.2. 
Following Up on AEs 
The investigator is obliged to follow subjects with AEs until the events have subsided, the 
conditions are considered medically stable, or the subjects are no longer available for follow up. 
Subjects 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. 
15.0 
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 subject 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.  The Sponsor will work with 
the Coordinating Center personnel to submit any SAEs according to the EU local country 
requirements. 


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16.0 
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 Competent Authority (CA), the European Medicines 
Agency and the IECs as well as the Regulatory Authority (RA), the FDA and IRB of any individual 
case reports of SAEs that are determined to be reportable by the Sponsor (SUSARs) in Europe and 
the US, respectively. 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 CA/RA and 
IEC/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. 
17.0 
ADVERSE EVENTS OF SPECIAL INTEREST 
Not applicable. 
18.0 
PRECAUTIONS/OVERDOSE 
If a subject receives a dose exceeding 200 mg of buntanetap, the dose may be considered toxic. 
Since this is a double-blind study, if a subject swallows more than 10 capsules with the assumption 
of them being in the 20mg 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. 
19.0 
PREGNANCY 
Female subjects will be instructed to notify the Investigator immediately if they become pregnant 
during the study. Male subjects will be instructed to notify the Investigator immediately if their 
partner becomes pregnant. Pregnant subjects will be withdrawn from further study treatment. The 
subjects 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 IMP 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 subject 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). 


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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. 
20.0 
DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent Data and Safety Monitoring Board (DSMB) will be formed to safeguard the 
subjects’ wellbeing. The responsibilities of DSMB will be established in the DSMB Charter. The 
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. First DSMB meeting will be when 75 patients (17% of the targeted sample size) 
received 1 month of treatment. 
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. 
21.0 
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 
Subject 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 subjects. 
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 subjects 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 subject identification number (Subject 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 subject, except as necessary for trial-related monitoring, audits, 
IRB/IEC review, and regulatory inspection(s), where direct access to source data/documents will 
be provided. 
Information about study subjects 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.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. Each site PI, under the guidance of his/her IRB/IEC, is responsible for ensuring 
that all applicable GDPR/HIPAA regulations and applicable laws are met. 
22.0 
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) / Independent Ethics Committee (IEC) 
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 United States, 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. 
In Europe, this protocol and any amendments will be submitted to a properly constituted IEC and 
Competent Authority (if applicable), in accordance with the International Conference on 
Harmonization (ICH) guidelines, the applicable European Directives and local legal 
requirements, for approval/favorable opinion of the study. Approval/favorable opinion must be 
obtained in writing before the first subject can be recruited. 
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 Good Clinical 
Practice. 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 subjects. Consent 
forms must be in a language fully comprehensible to the prospective subjects. Subjects and their 
relatives will be given ample opportunity to inquire about the details of the study. Prior to a 
subject’s participation in the trial, the written informed consent form should be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion. Subjects 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 subjects 
will never receive results. 


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23.0 
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. 
Centralized monitoring of the original electronic source records will take place where available, 
however on-site monitoring inspections will continue to take place to perform monitoring 
activities that cannot be performed remotely.  
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 include but not be limited to confirming: 
 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 CRFs 
 IMP 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 CRFs, source documents and other 
study-related records will be compared against each other to ensure accurate data that reflect the 
actual existence of the subject in the study, i.e., source data verification. The Site Investigator 
will cooperate in the monitoring process by ensuring the availability of the CRFs, 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. 
24.0 
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 RA/CA and/or an IRB/IEC. Inspection of site 
facilities (e.g., pharmacy, laboratories) to evaluate the trial conduct and compliance with the 
protocol may also occur. 


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25.0 
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 (US 21CFR§312.57). 
Trials in which data are used to support a marketing authorization have additional requirements 
and the TMF must be retained for at least 15 years after completion or suspension of the trial or 
at least two years after the last marketing authorization has been granted in the European 
Community (where no marketing authorization applications are pending or foreseen in the EC) 
or at least two years after the formal suspension of the clinical development of the investigational 
product (Directive 2003/63/EC). 


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26.0 
LITERATURE CITED 
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. 
Goetz CG, Tilley BC, Shaftman SR, Stebbin GT, et al. (2008). Movement Disorder Society-
Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Scale 
Presentation and Clinimetric Testing Results.  Movement Disorders. Vol. 23, No. 15, pp. 2129–
2170. 
Hoehn MM, Yahr MD (1967). Parkinsonism:  onset, progression, and mortality.  Neurology. 
Vol. 17. No. 5.   
Hurst H, Bolton J (2004). Assessing the clinical significance of change scores recorded on 
subjective outcome measures.  J Manipulative Physiol Ther 27:26-35. 
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. 
 
Li X, Herrmann C, Rauch G (2020). Optimality criteria for futility stopping boundaries for group 
sequential designs with a continuous endpoint. BMC Med Res Methodol 20, 274. 
Lilja AM, Röjdner J, Mustafiz T, Thome CM, Storelli E, Gonzalez D, Lithner CU, Greig NH, 
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). 
 
Mehta, C. R., & Pocock, S. J. (2011). Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30(28), 3267-3284. 


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Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, Obeso J, Marke K, Litvan I, 
Lang AE, Halliday G, Goetz CG, Gasser T, Duboie B, Chan P, Bloem BR, Adler CH, Deuschl G 
(2015).  MDS Clinical Diagnostic Criteria for Parkinson’s Disease.  Movement Disorders, Vol. 
30, No. 12, p1591-1599. 
 
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. 
 


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APPENDIX 1: SCHEDULE OF EVENTS  
Study Period 
Screening/Baseline 
Up to 42 Days 
Double-Blind Trial Treatment Period 6 Monthse 
Unscheduled 
Visit h 
(USV) 
Early 
Discontinuation 
Visit  
Visit Timing 
Day -42 to 0 
1 month 
 ± 7 days 
2 
months  
± 7 days 
3 
months 
± 7 days 
4.5 
months 
± 7 days 
1-3 
days 
prior 
to end 
of trial 
visit 
6 months  
± 7 days 
(end of trial 
visit) J 
 
 
Procedure 
ScreeningI  
(up to 42 
days 
before 
Day 0) 
Base 
line J 
(Day 
0) 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Phone 
Clinic Visit 
 
 
Clinic Visit 
 
 
Clinic Visit 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
Demography 
information 
X 
 
 
 
 
 
 
 
 
 
Full physical 
examination 
and 
neurological 
examination 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Height, Weight, 
BMI 
X 
 
 
 
 
 
 
 
 
 
Medical and 
psychiatric 
history 
(includes 
substance use) 
X 
 
 
 
 
 
 
 
 
 


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Study Period 
Screening/Baseline 
Up to 42 Days 
Double-Blind Trial Treatment Period 6 Monthse 
Unscheduled 
Visit h 
(USV) 
Early 
Discontinuation 
Visit  
Visit Timing 
Day -42 to 0 
1 month 
 ± 7 days 
2 
months  
± 7 days 
3 
months 
± 7 days 
4.5 
months 
± 7 days 
1-3 
days 
prior 
to end 
of trial 
visit 
6 months  
± 7 days 
(end of trial 
visit) J 
 
 
Procedure 
ScreeningI  
(up to 42 
days 
before 
Day 0) 
Base 
line J 
(Day 
0) 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Phone 
Clinic Visit 
 
 
Clinic Visit 
 
 
Clinic Visit 
Urine 
pregnancy test  
(WOCBP only) 
X 
X 
X 
X 
X 
 
 
X 
 
X 
 
X 
Hoehn & Yahr 
Stage 
X 
 
 
 
 
 
 
 
 
 
MMSE 
X 
X 
 
 
 
 
 
X 
 
 
PGIC 
 
 
X 
X 
X 
 
 
X 
 
 
CGIS 
 
X 
X 
X 
X 
 
 
X 
 
 
WAIS-IV 
 
X 
 
X 
 
 
 
X 
 
 
MDS-UPDRS 
 
X 
X 
X 
X 
 
 
X 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Laboratory 
safety testsd&g 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
 
 
X 
X 
             X 
Vital signsa 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study 
intervention 
dispensed 
 
X 
X 
X 
X 
 
 
Xf 
 
 


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Study Period 
Screening/Baseline 
Up to 42 Days 
Double-Blind Trial Treatment Period 6 Monthse 
Unscheduled 
Visit h 
(USV) 
Early 
Discontinuation 
Visit  
Visit Timing 
Day -42 to 0 
1 month 
 ± 7 days 
2 
months  
± 7 days 
3 
months 
± 7 days 
4.5 
months 
± 7 days 
1-3 
days 
prior 
to end 
of trial 
visit 
6 months  
± 7 days 
(end of trial 
visit) J 
 
 
Procedure 
ScreeningI  
(up to 42 
days 
before 
Day 0) 
Base 
line J 
(Day 
0) 
Clinic 
Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Phone 
Clinic Visit 
 
 
Clinic Visit 
 
 
Clinic Visit 
Study 
intervention 
compliance 
review 
 
 
X 
X 
X 
X 
X 
X 
 
X 
AE/SAE 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
PK samplingc 
 
X 
 
 
 
 
 
X 
 
 
Sampling for 
blood 
biomarkers 
 
X 
 
 
 
 
 
X 
 
 
24-hour phone 
follow-upb 
 
X 
X 
X 
X 
 
 
X 
X 
X 
a=Vital signs include sitting blood pressure, pulse, temperature, respiration rate. 
b=Phone follow-up should occur approximately 24 hours after baseline, each clinic visit and after discharge from the end of trial or early 
discontinuation visits. 
c=Sampling Times:  0 (pre-dosing) and 1.5hrs after dosing, except for 16-people per group who will go through 10hr sampling timepoints at 
0, 1hr, 1.5hr, 2hr, 3hr, 4hr,5hr, 6hr, 7hr, 8hr, 9hr, and 10hr (±10 mins for all collection timepoints).  Intense PK subgroup is only in the US. 
d=Safety labs at all clinic visits should be taken fasted. 


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e=Subjects who drop out after the initial 5 months of study treatment will complete the full End of Trial visit.  Subjects who dropped out 
prior to the initial 5 months of study treatment will complete the Early Discontinuation Visit assessments. 
f=The study intervention dispensing on the end of trial visit is only for the one pill given on that day. 
g=Blood and urine samples will be obtained for clinical safety lab assessments as described in the Laboratory Manual. 
h= Investigator will determine the extra assessment if any is needed. 
i= With investigator’s permission, lab re-testing is allowed within a month. 
j= For the intense PK subgroup participants, baseline visit and end-of-trial visit can be done in 2 days. 
 
APPENDIX 2:  INSTRUMENTS USED IN THE STUDY  
Copies of the following instruments used in the study are provided here. 
 Mini-Mental State Examination (MMSE) 
 Patients' Global Impression of Change (PGIC) 
 Clinical Global Impression of Severity (CGIS) 
 Wechsler Adult Intelligence Scales, 4th edition (WAIS-IV)  
 Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
Cover Page for ClinicalTrials.gov 
 
 
 
Sponsor name:
Annovis Bio, Inc.
NCT number:
NCT05357989
Sponsor trial ID:
ANVS-22001
Official title of study: 
A 6-month prospective, randomized, double-blind, placebo-
controlled clinical trial investigating the efficacy, safety, and 
tolerability of two different doses of buntanetap or placebo in patients 
with early Parkinson’s disease
Document type: 
Statistical Analysis Plan
Document date:
January 11, 2024
 


ANNOVIS BIO, INC. 
CONFIDENTIAL 
Statistical Analysis Plan 
ANVS-22001                                                                                                              Version 2.1, 11 January 2024 
 
 
 
 
 
Page 1 of 28 
 
Statistical Analysis Plan 
for  
 
A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial investigating the 
efficacy, safety, and tolerability of two different doses of buntanetap or placebo in patients with early 
Parkinson’s disease 
 
Sponsor 
ANNOVIS BIO, INC., USA 
Product/Compound 
ANVS-22001 
Phase of the study 
III 
EudraCT number 
2022-001542-38 
 
 
Name, Title, Affiliation 
Signature & Date 
Written by 
 
Wenxin Lu, PhD 
Senior Statistician I, 
Statistics 
Pharmapace, Inc. 
 
Approved by Sponsor 
Representative 
Maria Luisa Maccecchini 
President and CEO 
ANNOVIS BIO, INC. 
 


ANNOVIS BIO, INC. 
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Statistical Analysis Plan 
ANVS-22001                                                                                                              Version 2.1, 11 January 2024 
 
 
Page 2 of 28 
 
Contents 
 
 
Abbreviations ................................................................................................................................. 3 
 
Document Version History ............................................................................................................. 5 
 
Introduction .................................................................................................................................... 5 
 
Study Objectives and Endpoints.................................................................................................... 6 
 
Overall Study Design ..................................................................................................................... 8 
 
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 
Pre-Analysis Review ............................................................................................................ 10 
8.3 
Hypothesis and Statistical Methods .................................................................................... 10 
8.3.1 
Level of Significance, Multiple Comparisons and Multiplicity .......................................... 10 
8.3.2 
Definitions ........................................................................................................................ 11 
8.3.3 
Summary Statistics .......................................................................................................... 12 
8.3.4 
Patient/Subject Data Listings ........................................................................................... 13 
8.3.5 
Subject Disposition .......................................................................................................... 13 
8.3.6 
Demographic and Other Baseline Characteristics .......................................................... 13 
8.3.7 
Primary Analysis .............................................................................................................. 14 
8.3.8 
Secondary Analysis ......................................................................................................... 14 
8.3.9 
Exploratory Analysis ........................................................................................................ 15 
8.3.10 
Exposure to Treatment ................................................................................................ 16 
8.3.11 
Medical History and Concomitant Medications ........................................................... 16 
8.3.11.1 
Prohibited concomitant medication ...................................................................... 16 
8.3.11.2 
Permitted concomitant medication ...................................................................... 17 
8.3.11.3 
Coding and imputation of incomplete dates ........................................................ 17 
8.3.12 
Adverse Events............................................................................................................ 18 
8.4 
Other Safety Assessment .................................................................................................... 19 
8.5 
Plasma Biomarkers and Pharmacokinetic Analysis ............................................................ 22 
8.6 
Multicenter Studies .............................................................................................................. 22 
8.7 
Adjustment for Covariates ................................................................................................... 22 
8.8 
Examination of Subgroups .................................................................................................. 22 
8.9 
Handling of Dropouts, Intercurrent Events, and Missing Data ............................................ 22 
8.10 
Interim Analysis ................................................................................................................... 23 
8.10.1 
Re-estimation of Sample Size ..................................................................................... 23 
8.10.2 
Clarifications Based on Food and Drug Administration (FDA)’s Feedback................. 24 
8.11 
Data Monitoring ................................................................................................................... 25 
8.12 
Reporting Conventions ........................................................................................................ 25 
8.13 
References .......................................................................................................................... 25 
APPENDIX 1: SCHEDULE OF EVENTS ............................................................................................ 26 


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Statistical Analysis Plan 
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Page 3 of 28 
 
 
 
Abbreviations 
αSYN 
Alpha-synuclein 
Aβ 
Amyloid beta 
AD 
Alzheimer’s disease 
ADL 
Activities of daily living 
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 
CGIS 
Clinical Global Impression of Severity 
CI 
Confidence interval 
CL 
Clearance  
CM 
Concomitant medication  
CP 
Conditional Power 
CSF 
Cerebrospinal Fluid 
CSP 
Clinical Study Protocol 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CV 
Coefficients of variation 
DSMB 
Data Safety Monitoring Board  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ES 
Enrolled set  
FDA 
Food and Drug Administration 
GFAP 
Glial Fibrillary Acidic Protein 
IC 
Informed Consent 
IDMB 
Independent DSMB 
IMP 
Investigational Medicinal Product 
ITT 
Intent-to-Treat set  
LSM 
Least Square Mean 
MAR 
Missing at Random 
MCMC 
Markov Chain Monte Carlo 
MDS-UPDRS 
Movement Disorder Society-United Parkinson’s Disease Rating Scale 
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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Statistical Analysis Plan 
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Page 4 of 28 
 
MNAR 
Missing Not at Random 
NFL 
Neurofilament Light 
PD 
Parkinson’s disease 
PGIC 
Participant Global Impression of Change 
PK 
Pharmacokinetic 
PPS 
Per-protocol set 
PT 
Preferred Term 
QD 
Once a Day 
RCTC 
Rheumatology Common Toxicity Criteria 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class / Standard of care 
T½ 
Half-life  
tau 
Tau protein 
TDP-43 
TAR DNA-binding Protein 43 
TEAE 
Treatment-Emergent Adverse Event 
tmax 
Time to peak drug concentration 
TOEPH 
Heterogeneous Toeplitz 
UN 
Unstructured 
WAIS-IV 
Wechsler Adult Intelligence Scales, 4th edition 
WHO 
World Health Organization 
 
 
 


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Page 5 of 28 
 
 
Document Version History 
Version Number 
Version date 
Section(s) 
Updated 
Change since previous version (with 
reason) 
Draft 0.1 
24-OCT-2022 
All 
First version 
Draft 0.2 
03-NOV-2022 
All 
Internal review comments incorporated 
Draft 0.3 
17-NOV-2022 
All 
Sponsor first review comments 
incorporated 
Final 1.1 
09-DEC-2022 
All 
Final version 
Final 1.1 
Amendment 
25-APR-2023 
All 
Bonferroni method was updated to 
Hochberg method. 
Revised the randomized sample size 
and evaluable sample size as needed 
in the Interim Analysis section for 
consistency with the protocol. 
 
Final 2.0 
Amendment 
07-DEC-2023 
All 
FDA comments incorporated 
Final 2.1 
Amendment 
11-JAN-2024 
Section 7 
Section 8.5 
Study drug exposure was included in 
defining Per-protocol set. 
A separate PK SAP is not needed. 
 
 
Introduction 
This Statistical Analysis Plan (SAP) is based on Clinical Study Protocol (CSP) Global-Version 5.0, 
dated August 21, 2023. In the case where there is a difference between the protocol and the SAP, the 
SAP will be the ruling document. 
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 alpha-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 patients, 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 development of combination therapies 
that target 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 αSYN, APP, 
its fragments, and tau. All three proteins have been implicated in the pathogenesis of PD. Furthermore, 
at older ages, there is a high incidence of PD patients with mixed pathologies, such as PD dementia.  
Therefore, it is reasonable to hypothesize that inhibiting expression of all three proteins should lead to 
a better efficacy outcome in PD patients than inhibiting just one. 
The objective of this study is to confirm efficacy of buntanetap in early PD subjects. During the dose-
finding Phase 2a study, a dose-response curve between 0 and 80 mg once daily (QD) was observed 
with 10 and 20mg QD showing the best benefit. Therefore, decision has been taken to dose subjects 
with 10 and 20 mg QD. 


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Page 6 of 28 
 
 
 
Study Objectives and Endpoints 
Objective 
Endpoint 
Primary 
 
The primary objective is to assess 
efficacy and safety of buntanetap in 
early PD subjects  
1. Change from baseline to Month 6 in MDS-
UPDRS Part II (OFF-state) 
Change in the Score from the Activities of Daily 
Living (ADL) Scale in the Movement Disorder 
Society-Unified Parkinson's Disease Rating 
Scale (MDS-UPDRS) (Part II, a MDS-
UPDRS Subscale) from Baseline to Month 6. 
The MDS-UPDRS is a 50-item rating scale 
designed to assess Parkinson's disease-related 
disability and impairment. The scale comprises 
four parts: Part I evaluates mentation, behavior, 
and mood symptoms; Part II evaluates ADL; Part 
III evaluates motor function; and Part IV evaluates 
complications of dopaminergic therapy. 
Part II contains 13 questions which are to be 
completed by the participant (range 0-52).  A 
higher score indicates more severe symptoms of 
PD. 
 
2. 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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Page 7 of 28 
 
Objective 
Endpoint 
Secondary 
 
Assess improvement on PD subjects’ 
daily living, mobility, and complications 
1. Change from baseline to Month 6 in the sum 
of MDS-UPDRS Part II+III (OFF-state) 
Change in the Sum of the Score from the ADL 
Scale and Motor Examination in the MDS-UPDRS 
(Parts II+III, a MDS-UPDRS Subtotal) from 
Baseline to Month 6. 
Part II contains 13 questions which are to be 
completed by the participant (range 0-52).  Part III 
contains 33 scores based on 18 items (range 0-
132).  MDS-UPDRS Part II and III combined score 
equals the sum of Parts II and III (range 0-184). A 
higher score indicates more severe symptoms of 
PD. 
 
2. Change from baseline to Month 6 in MDS-
UPDRS Part III (OFF-state) 
Part III (motor function) contains 33 scores based 
on 18 items (Range 0-132). A higher score 
indicates more severe symptoms of PD. 
 
3. Change from baseline to Month 6 in the sum 
of MDS-UPDRS Total score (OFF-state) 
The MDS-UPDRS is a 50-item rating scale 
designed to assess Parkinson's disease-related 
disability and impairment. The scale comprises 
four parts: Part I evaluates mentation, behavior, 
and mood symptoms; Part II evaluates ADL; Part 
III evaluates motor function; and Part IV evaluates 
complications of dopaminergic therapy. The Total 
score is the sum of the subscale scores for Parts I 
to III and ranges from 0 to 236, with higher scores 
reflecting greater severity. 
 
 
 
4. Percentage of Responders with "Much 
Improved" or "Very Much Improved" on 
Participant Global Impression of Change 
(PGIC) (ON-state) 
The PGIC is the participant-reported outcome. 
The qualitative assessment of 
meaningful change will be determined by 
the participant in response to the question, 
"Compared to your condition at the beginning of 
treatment, how much has your 
condition changed?" Scores are: 1=very much 
improved; 2=much improved; 3=minimally 
improved; 4=no change; 5=minimally worse; 
6=much worse; and 7=very much 
worse. Percentage of responders with much 
improved and very much improved on PGIC scale 
will be assessed. PGIC will be taken at home 
while the subject is during ON-state (with their 
Standard of care (SOC) for Parkinson disease). 


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Page 8 of 28 
 
Objective 
Endpoint 
 
5. Change from baseline to Month 6 on Clinical 
Global Impression of Severity (CGIS) (OFF-
state) 
The CGIS on the severity of movement 
impairment as assessed by the site rater. Site 
raters will be asked: Considering your total clinical 
experience with the Parkinson disease population, 
how ill is the patient’s movement at this time? 
Answers were based on a 7-point scale, with 
1=not assessed, 2= very mild, 3= mild, 4= 
moderate, 5= moderate severe, 6= severe, 
7=extremely severe.   
 
 
 
 
Exploratory 
 
Investigate change after buntanetap in 
potential biomarkers and improvement 
in cognitive functions 
1. Change from baseline to Month 6 in the 
plasma biomarkers measured 
Potential biomarkers to be measured in plasma 
are Neurofilament Light (NFL), Glial fibrillary 
acidic protein (GFAP) and TAR DNA-binding 
protein 43 (TDP43). 
 
2. Change from baseline to Month 6 in Wechsler 
Adult Intelligence Scale (WAIS IV) coding test 
(OFF-state) 
In the digital symbol coding test 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. The higher score indicates better 
outcome. 
 
3. Change from baseline to Month 6 in Mini-
Mental State Exam (MMSE) (OFF-state) 
The MMSE is a 30-point test widely used for the 
testing of the cognitive function, with a higher 
score indicating better function. A higher score 
indicates better outcome. 
 
4. Pharmacokinetics (PK) Analysis 
The following PK parameters will be determined: 
Area under the curve (AUC), Cmax, Tmax, t½, and 
CL. 
 
 
Overall Study Design 
This is a 6-month prospective, randomized, double-blinded, placebo-controlled clinical trial 
investigating the efficacy, safety, and tolerability of two different doses of buntanetap or placebo in 
patients with early PD. 
Qualified subjects will be randomly assigned at a 1:1:1 ratio to one of three treatment arms: buntanetap 
10 mg, buntanetap 20 mg, and placebo after a screening period of up to 42 days.  
MDS-UPDRS, CGIS, WAIS IV, and MMSE will be assessed in clinical OFF-state during visits, i.e., 
after subjects having stopped medications of SOC Parkinson’s disease 12 hours before clinical visits. 


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PGIC will be assessed in clinical ON-state during visits, i.e., subjects are allowed to take their SOC 
Parkinson medication during buntanetap treatment. 
450 subjects with early PD will be randomized to 10 mg, 20 mg of buntanetap QD or placebo. 
They will undergo a Screening Visit, and if they provide Informed Consent (IC) and are considered 
eligible per the inclusion and exclusion criteria, will proceed to participate in the treatment period.  
Randomized subjects will visit the clinic for the first-time dosing in clinic with administration of 10 mg 
or 20 mg of buntanetap or placebo, followed by an at home dosing period of 6 months, with daily 
administration of 10 mg or 20 mg of buntanetap or placebo. 
Subjects will be required to visit clinics at 1 month, 2 months, 3 months, and 6 months (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), psychometric tests (MDS-UPDRS, WAIS, MMSE), PGIC (ON-
state), and CGIS.  
The Schedule of Events is shown in Appendix 1. 
 
Determination of Sample Size 
A sample size of up to 450 subjects (1:1:1 randomized to 10 mg, 20 mg buntanetap and placebo 
respectively) was determined. 
Qualified subjects will be randomized at a 1:1:1 to one of the following three treatment groups: 
buntanetap 10 mg, 20 mg QD and placebo. A sample size of 360 (120 per treatment group) will have 
90% power to detect a treatment difference at a two-sided 0.025 significance level. In the sample size 
calculation, it was assumed a treatment difference of 2.55 and a common standard deviation (SD) of 
5.59 based on historical data of MDS-UPDRS Part II+III. Approximately 450 subjects will be 
randomized (approximately 150 per arm) to account for 120 subjects calculated from the power 
analysis plus screen failures and dropout rates.   
 
Data Sets to be Analyzed 
Subjects in this study must be in accordance with the criteria specified below. Subjects who do not 
meet all inclusion criteria, disease diagnostic criteria, or who meet any exclusion criteria may not be 
randomized into the study without prior approval from the Project Directors and Medical Monitor.  
Membership in the analysis sets will be determined in a Pre-Analysis review meeting (see Section 8.2) 
before unblinding. 
The following analysis sets will be used for the statistical analysis and presentation of data:  
 
The Enrolled set (ES) will include all subjects 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 subjects who are randomized. The primary 
efficacy analyses will be based on the ITT. 
 
The Modified Intent-to-Treat set (mITT) will consist of all subjects who randomized, take at 
least 1 dose of the study drug, and have at least 1 post-baseline assessment. The mITT will 
be used to support the primary efficacy analyses. 
 
The Safety analysis set (SAF) will be the primary safety analysis set and will consist of all 
randomized subjects who receive at least 1 dose of the study drug. The safety analyses will 
be based on the SAF. 
 
The Per-protocol set (PPS) will consist of all mITT subjects who complete at least 145 days 
treatment exposure (Last dose date - First dose date + 1 >= 145 days) without any major 
protocol deviations that potentially could impact the primary efficacy endpoint. 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 subjects receiving buntanetap and with 
at least one sampling profile allowing derivation of at least one PK parameter. Intense PK 


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subgroup is only in the US. 16-people per group will go through 10hr sampling timepoints at 
0, 1hr, 1.5hr, 2hr, 3hr, 4hr,5hr, 6hr, 7hr, 8hr, 9hr, and 10hr (±10 mins for all collection 
timepoints). 
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 during the pre-analysis review when all data on protocol violations/deviations are available 
and 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 in a separate PK SAP will be based on the PK set. 
 
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 
Pre-Analysis Review 
A pre-analysis review meeting will be held prior to database lock. During this meeting, the assignment 
of subjects to the analysis sets will be discussed and decided reviewing 
 
Screen failures with reason for failure 
 
Discontinued subjects with reason for discontinuation 
 
Protocol deviations 
 
Available efficacy data by visit 
 
Preliminary subjects’ classifications of analysis sets as far as possible 
8.3 
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. 
8.3.1 
Level of Significance, Multiple Comparisons and Multiplicity 
There are two active treatment groups (10 mg and 20 mg) in the study. Each of the two active 
treatments will be compared to the control (two hypothesis tests for the primary endpoint). The 
comparison of each of the two treatment groups against control for the primary endpoint will be 
performed using the Hochberg step up procedure, where if the largest p-value is <0.05, then the null 
hypothesis will be rejected for both groups. If the largest p-value is >0.05, then the critical value for the 
second test will be at two-sided 0.025. 


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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. Change from baseline to Month 6 in the sum of MDS-UPDRS Part II+III (OFF-state) 
2. Change from baseline to Month 6 in MDS-UPDRS Part III (OFF-state) 
3. Change from baseline to Month 6 in MDS-UPDRS Total score (OFF-state) 
4. Percentage of Responders with "Much Improved" or "Very Much Improved" on PGIC (ON-state) 
5. Change from baseline to Month 6 on CGIS (OFF-state) 
If the primary endpoint of both dose groups are statistically significant, the secondary endpoints for 
each dose group will be tested in a hierarchical manner at alpha 0.025. If the primary endpoint of a 
specific dose group is statistically significant, the secondary endpoints for that dose group will be tested 
in a hierarchical manner at alpha 0.025. If the primary endpoint of both dose groups are not statistically 
significant, the hypothesis testing for all subsequent endpoints will be considered exploratory. Two 
flowcharts are also presented in the following. 
   
 
 
 
 
 
 
All other exploratory endpoints are considered supportive and no adjustment for multiplicity will be 
applied. 
8.3.2 
Definitions 
MMSE – OFF-
state 
Mini-Mental State Examination is a 30-point test, widely used test of 
cognitive function. 
PGIC – ON-state 
Participant Global Impression of Change is the participant-reported 
outcome.  
The qualitative assessment of meaningful change will be determined by 
the participant in response to the question, "Compared to your condition 
at the beginning of treatment, how much has your condition changed?" 
Scores are 1= very much improved; 2= much improved; 3= minimally 
improved; 4= no change; 5= minimally worse; 6= much worse; 7= very 
much worse 
CGIS – OFF-state 
Clinical Global Impression of Severity is a scale on the severity of 
movement impairment as assessed by the site rater. Site raters will be 
asked: Considering your total clinical experience with the Parkinson 
disease population, how ill is the patient’s movement at this time? 
Answers were based on a 7-point scale, with 1= not assessed, 2= very 
mild, 3= mild, 4= moderate, 5= moderate severe, 6= severe, 
7=extremely severe 
WAIS-IV – OFF-
state 
In the digital symbol Wechsler Adult Intelligence Scales, 4th edition, 
coding test 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. 
The primary endpoint of both dose 
groups are statistically significant  
The secondary endpoints for 
dose A group will be tested 
in a hierarchical manner at 
alpha 0.025. 
The secondary endpoints for 
dose B group will be tested 
in a hierarchical manner at 
alpha 0.025. 
The primary endpoint of dose A 
group is statistically significant  
The secondary endpoints for 
dose A group will be tested 
in a hierarchical manner at 
alpha 0.025. 


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MDS-UPDRS – 
OFF-state 
Movement Disorder Society-Unified Parkinson’s Disease Rating Scale is 
a 50-item rating scale designed to assess Parkinson's disease-related 
disability and impairment comprising the four parts: 
Part I - Non-Motor Aspects of Experiences of Daily Living  
Part II - Motor Aspects of Experiences of Daily Living  
Part III - Motor examination 
Part IV - Motor complications 
Treatment-
Emergent 
Adverse Event  
Treatment emergent adverse events (TEAEs) are defined as undesirable 
events not present prior to medical treatment, or an already present 
event that worsens either in intensity or frequency following the 
treatment. If an AE starts at the same day as the study drug the start 
time of the AE will be compared with the start time of the administration 
of study drug. If the start time of the AE is at or after start time of 
administration of study drug the AE is a TEAE. If no clear assignment is 
possible due to incomplete or missing start dates, the AE will be counted 
as TEAE. 
Baseline 
Baseline will be the last assessment before or up to the first dosing of 
the study drug. This is valid for vital sign, laboratory data, and safety 
data, where a difference from baseline is derived. For diary data and 
questionnaire data, baseline will be the assessment at the baseline visit. 
Height [cm] 
All values collected in inches will be converted to cm as follows: Height 
[cm] = height [feet] * 30.48 
Weight [kg] 
All values collected in pounds will be converted to kg as follows: weight 
[kg] = weight [pounds] * 0.454 
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 
8.3.3 
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 efficacy primary 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 


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Measures (MMRM) 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). 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 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 (Month 1, Month 2, Month 3, Month 6). 
Treatment comparisons (10 mg vs. Placebo / 20 mg 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 (10 mg – Placebo / 20 mg – Placebo) will be estimated and resulting 2-sided p-values and 
associated 95% CI will be presented. 
 
8.3.4 
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. 
8.3.5 
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. 
8.3.6 
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 (40 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) 
 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 


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 
Substance use – tobacco and alcohol 
 
Smoker (Never, Current or Former) 
 
Alcohol user (Never, Current or Former) 
 
Time since diagnosis of Parkinson’s disease 
8.3.7 
Primary Analysis 
The primary efficacy endpoint in this clinical trial is the change from baseline to Month 6 in the score 
for MDS-UPDRS part II (OFF-state) between each of the two regimens of buntanetap and Placebo.  
The statistical hypothesis to be tested for primary efficacy is described as:  
 
Null Hypothesis (H0):  
The difference in change in MDS-UPDRS Part II (OFF-state) scores from Baseline to Month 
6, between treatment (active vs placebo) regimen = 0. 
 
Alternative Hypothesis (H1):  
The difference in change in MDS-UPDRS Part II (OFF-state) scores from Baseline to Month 
6, between treatment (active vs placebo) regimen ≠ 0. 
The primary endpoint will be analyzed via MMRM. The model will include treatment, timepoint, 
treatment-by-timepoint interaction as the fixed effects and baseline as the covariate. The variance-
covariance matrix will be assumed to be unstructured.  
This analysis will be conducted after all subjects have reached Month 6 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. 
8.3.8 
Secondary Analysis 
Secondary efficacy endpoints in this clinical trial are 
 
Change from baseline to Month 6 in the sum of the score of MDS-UPDRS Parts II+III – OFF-
state 
 
Change from baseline to Month 6 in the score of MDS-UPDRS Part III – OFF-state 
 
Change from baseline to Month 6 in the total score for MDS-UPDRS – OFF-state 
 
Percentage of responders with “Much improved” or “Very much improved” on PGIC – ON-
state 
 
Change from baseline to Month 6 on CGIS – OFF-state. 
Change from baseline to Month 6 in the sum of MDS-UPDRS Parts II+III – OFF-state 
The MDS-UPDRS is a 50-item rating scale designed to assess Parkinson's disease-related disability 
and impairment. The scale comprises four parts: Part I evaluates mentation, behavior, and mood 
symptoms; Part II evaluates ADL; Part III evaluates motor function; and Part IV evaluates 
complications of dopaminergic therapy. Part II contains 13 questions which are to be completed by the 
participant (range 0-52).  Part III contains 33 scores based on 18 items (Range 0-132). MDS-UPDRS 
Part II and III combined score equals the sum of Parts II and III (Range 0-184). A higher score indicates 
more severe symptoms of PD.  
MDS-UPDRS Parts II+III will be analyzed by MMRM, similar to the primary efficacy endpoint. 
Change from baseline to Month 6 in the MDS-UPDRS Part III – OFF-state 
Part III contains 33 scores based on 18 items (Range 0-132). 
MDS-UPDRS Part III will be analyzed by MMRM, similar to the primary efficacy endpoint. 
Change from baseline to Month 6 in the MDS-UPDRS Total score – OFF-state 


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The UPDRS is a 50-item rating scale designed to assess Parkinson's disease-related disability and 
impairment. The scale comprises four parts:  
Part I evaluates mentation, behavior, and mood symptoms;  
Part II evaluates ADL; 
Part III evaluates motor function; and  
Part IV evaluates complications of dopaminergic therapy. 
The MDS-UPDRS Total score is the sum of the subscale scores for Parts I to III and ranges from 0 to 
236, with higher scores reflecting greater severity. MDS-UPDRS will be assessed by the investigator 
at baseline and each visit at the clinic (Month 1, Month 2, Month 3, and Month 6). 
MDS-UPDRS Total score will be analyzed by MMRM, similar to the primary efficacy endpoint. 
Percentage of responders with “Much improved” or “Very much improved” on PGIC – ON-state 
The PGIC is the participant-reported outcome. The qualitative assessment of meaningful change will 
be determined by the participant in response to the question, "Compared to your condition at the 
beginning of treatment, how much has your condition changed?" Scores are  
1= very much improved  
2= much improved  
3= minimally improved  
4= no change  
5= minimally worse  
6= much worse  
7= very much worse 
The assessment is done during visits at the clinic (Month 1, Month 2, Month 3, and Month 6) and ON-
state i.e., subjects were allowed to treat the PD with SOC medication.  
For PGIC, responders are defined as responses with score 1 (very much improved) and score 2 (much 
improved). PGIC will be analyzed for responders (scores 1 and 2) using logistic regression method. 
Descriptive statistics for each visit will be produced for the PGIC. 
Change from baseline to Month 6 on CGIS – OFF-state 
The clinical global impressions scale on the severity of movement impairment as assessed by the site 
rater. Site raters will be asked: Considering your total clinical experience with the Parkinson disease 
population, how ill is the patient’s movement at this time? Answers were based on a 7-point scale, with 
1= not assessed, 2= very mild, 3= mild, 4= moderate, 5= moderate severe, 6= severe, 7= extremely 
severe.  
The assessment is done at baseline visit and during visits at the clinic (Month 1, Month 2, Month 3, 
and Month 6) and OFF-state i.e., 12 hours after last intake of medication of standard of care for 
Parkinson’s disease.  
For CGIS, responders are defined as a decrease in CGIS score from baseline to Month 6. CGIS will 
be analyzed for responders using logistic regression method. 
Descriptive statistics and change from baseline for each visit will be produced for the CGIS. 
8.3.9 
Exploratory Analysis 
Exploratory endpoints in this clinical trial are 
 
Change from baseline to Month 6 in the plasma biomarkers measured 
 
Change from baseline to Month 6 in the WAIS coding test – OFF-state 
 
Change from baseline to Month 6 in MMSE – OFF-state 
 
PK analysis. 


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Changes from baseline to Month 6 in the plasma biomarkers measured 
Potential biomarkers to be measured in plasma are Neurofilament Light (NFL), Glial fibrillary acidic 
protein (GFAP) and TDP43. 
Change from baseline to Month 6 in WAIS IV coding test – OFF-state 
In the digital symbol coding test 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. The 
assessment is done by the investigator at baseline, Month 2, and Month 6 and OFF-state i.e., 12 hours 
after last intake of medication of SOC Parkinson’s disease. 
Descriptive statistics and change from baseline for each visit will be produced for the WAIS coding 
test. 
Change from baseline to Month 6 in MMSE - OFF-state. 
The MMSE is a 30-point test, widely used test of cognitive function. The MMSE will be assessed by 
the investigator at screening, baseline, and Month 6. The MMSE comprises sections on orientation to 
place, orientation to time, registration, attention and calculation, recall, naming, repetition, 
comprehension, reading, writing, and drawing. The assessment is done by the investigator at 
screening, at baseline and at end-of-treatment visit and OFF-state i.e., 12 hours after last intake of 
medication of SOC Parkinson’s disease. 
Descriptive statistics and change from baseline for each visit will be produced for the MMSE. 
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 methods. 
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. 
8.3.10 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 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.  
8.3.11 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, 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). 
8.3.11.1 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.  


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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 Project Directors and 
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. 
CYP3A4 
inhibitors 
Itraconazole, Ketoconazole, Azamulin, Troleandomycin, Verapamil 
CYP3A4 
inducers 
Rifampicin 
8.3.11.2 Permitted concomitant medication 
Per protocol concomitant treatment with anti-parkinsonian medications at stable doses for 4 weeks or 
greater prior to screening are allowed.  
Use of the following medications is allowed only if the patients have been stable on them for at least 4 
weeks before screening and will continue to be stable throughout the study: 
 
tricyclic antidepressants  
 
antipsychotics prescribed for any reason, except ≤50 mg quetiapine daily, risperidone 
≤1.5 mg/day, olanzapine ≤5 mg/day, and aripiprazole ≤10 mg/day 
 
psychostimulants 
Discontinuation and/or change of any of the above medication during the study is discouraged and 
should consult with the Medical Director and Sponsor for further guidance. 
 
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.  
The 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 action and 
currently available data for these vaccine candidates and for buntanetap, it is not believed that there 
are specific risks to consider in subjects 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. 
8.3.11.3 Coding and imputation of incomplete dates 
All concomitant medications/therapies will be classified according to ATC level 3 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 the 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. 
8.3.12 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 Subject 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.  
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: 


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 
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 severity according to Rheumatology Common Toxicity Criteria (RCTC) categories 
 
TEAEs leading to treatment discontinuation of study drug 
 
TEAEs leading to withdrawal from study 
 
TEAEs leading to death 
The overall summary presentation will be repeated for:  
 
Severity categories 
 
TEAEs related to study drug 
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.  
Frequent TEAEs are defined as any PT with ≥5% incidence in any of the treatment arms, which will 
be summarized by PT. 
Deaths, other serious AEs (SAEs), and other significant AEs will be listed, these include the following 
TEAEs:  
 
SAEs leading to death 
 
SAEs not leading to death 
 
AEs for which action was taken with study drug 
 
AEs leading to withdrawal from study 
This listing will be divided into sub-listings with criteria as a subheading. An AE can appear in more 
than one sub-listing. 
AE listings will include the relative time/day in relation to date and time of first administration of study 
drug and duration of AEs. If AE start time and time of first study drug administration is available, relative 
time and duration will be given as HH:MM for AEs with onset/duration less than 24 hours after first 
administration of study drug and otherwise as days. For AEs with incomplete dates no relative day or 
duration will be calculated.  
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. 
8.4 
Other Safety Assessment 


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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.  
Clinical Laboratory Measurements 
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. 
 
Additionally, clinical laboratory parameters will be categorized as low, normal, or high according to 
laboratory range specifications and the number and percentage of subjects in each category will be 
presented in shift tables. 
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.  
Laboratory values that are outside the normal range will also be flagged in the data listings, along with 
corresponding normal ranges. 
If laboratory values are below the limit of quantification, the value corresponding to the limit of 
quantification will be used when summarizing data (e.g. if the result is <x.x, then the value x.x will be 
used in the statistical analysis). 
Physical 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:  
 
skin,  
 
head,  
 
eyes,  
 
ears,  
 
nose,  
 
throat,  
 
pulmonary,  
 
cardiovascular,  
CLINICAL SAFETY LAB TESTS 
METABOLIC PANEL 
COMPLETE BLOOD COUNT 
URINALYSIS 
Sodium (Na) 
Potassium (K) 
Chloride (Cl) 
Carbon Dioxide (CO2) 
Blood Urea Nitrogen (BUN) 
Glucose  
Calcium (Ca)  
Creatinine (Crn) 
Bilirubin (direct and Total) 
Albumin 
Protein - Total 
Glutamic-Oxaloacetic  
Transferase (AST, SGOT) 
Glutamic-PyruvateTransferase (ALT, 
SGPT) 
Alkaline Phosphatase (ALP) 
eGFR (estimated Glomerular 
Filtration Rate) 
White Blood Cell Count (absolute and 
percentage): basophils, eosinophils, 
lymphocytes, monocytes, neutrophils 
Red Blood Cell Count (RBC) 
Hemoglobin (Hb) 
Hematocrit (HCT) 
Mean Corpuscular Volume (MCV) 
Mean Corpuscular Hemoglobin (MCH) 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
Red Blood Cell Distribution Width (RDW) 
Mean Platelet Volume (MPV) 
Platelet Count (PLT) 
 
                 Screening Only 
Hemoglobin A1C (HbA1c) 
Color 
Appearance 
Specific Gravity 
pH 
Blood 
Glucose 
Protein 
Ketones 
Leukocyte 
Esterase  
Nitrite 
Urobilinogen 
Bilirubin (total) 
 


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 
abdomen,  
 
musculoskeletal,  
 
extremities. 
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. 
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. 
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. 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)  
The intensity of most severe suicidal ideation during the subject’s lifetime, during the double-blind 
treatment period, and during the safety follow-up period will also be presented by 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. 
Supportive listings will be provided and will include the subject 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 subjects who have suicidal ideation or suicidal behavior will also be 
provided. 
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. The number of available observations and the number of 


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normal, abnormal clinically significant and abnormal not clinically significant values (absolute and in 
percentage) will be presented.  
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. 
8.5 
Plasma Biomarkers and Pharmacokinetic Analysis 
Biomarkers, including 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).  
8.6 
Multicenter Studies 
No per-center analyses are planned. 
8.7 
Adjustment for Covariates 
Baseline value will be used as a covariate in the MMRM analyses for the primary efficacy endpoint 
(see Section 8.3.7). 
8.8 
Examination of Subgroups 
No subgroup analyses are planned for this study. 
8.9 
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. 
The MMRM analysis of the primary endpoint 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 primary endpoint analysis. 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 


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method for each treatment separately. The variables for the imputation model will include MDS-
UPDRS Part II score at baseline, Month 1, Month 2, Month 3, and Month 6. Approximately 50 datasets 
will be imputed and the same MMRM analysis as the one applied to the primary analysis will be fitted. 
The ROUND, MINIMUM and MAXIMUM options will be utilized to ensure imputed values are clinically 
plausible integers (0 – 52). 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. A random seed number will be selected for the 
multiple imputation procedure and will be retained. 
8.10 Interim Analysis 
An interim sample size review will be performed after in total 𝑛1 = 120 evaluable subjects (40 subjects 
per treatment group) have primary endpoint data, i.e., MDS-UPDRS part II+III at Month 2. Evaluable 
subjects are defined as randomized and having received at least one dose of the study drug. The aim 
of the interim sample size review is to reassess the size of the estimated mean and SD of the primary 
effectiveness variable (MDS-UPDRS part II+III). The sample size will be adjusted accordingly (see 
following section). 
No interim analyses are planned for the purpose of stopping the study early for futility. 
8.10.1 Re-estimation of Sample Size 
The initial sample size estimation provides statistical power to demonstrate effectiveness among 
subjects treated with buntanetap. A potential sample size adjustment is to assure that this trial will 
have the intended precision. The decision of sample size adjustment will be made based upon the 
estimates of MDS-UPDRS part II+III at baseline and after two months of treatment calculated for the 
first 120 evaluable subjects with primary endpoint data. Sample size will not be decreased regardless 
of the results of this evaluation. To warrant the originally intended >90% power of the study at the 
0.025 alpha level (2-sided), the evaluable sample size may be increased from 𝑛2 = 360 (120 per 
treatment group) to a maximum of nmax=540 (180 per treatment group).  Additional subjects will be 
enrolled to account for screen failures and drop-outs.  The sample size re-estimation will be evaluated 
for the efficacy endpoint based on the observed interim mean and SD of treatment difference of the 
MDS-UPDRS part II+III score. 
The sample size re-estimation method is based on evaluation of conditional power in relationship to 
pre-specified decision rules defined by ranges of attainable conditional power values. Only an increase 
in sample size is possible under this approach when observed conditional power falls within the 
‘promising zone’ as described below (Mehta and Pocock 2011). 
The conditional power at the interim analysis is defined by equation (6) from Mehta and Pocock (2011). 
 
The targeted conditional power at the first interim review is 90%, however we pre-specify a range of 
conditional power values below 90% that would deem our interim results promising and warrant 
sample size re-estimation. Table 1 provides cut-off values from Mehta and Pocock (2011) for the lower 
bound of the promising zone, 𝐶𝑃𝑚𝑖𝑛, under some typical two-stage adaptive designs. 𝐶𝑃𝑚𝑖𝑛 is 0.42 
(42%) for the parameter choices (nmax/n2 = 1.5, n1/n2 = 0.33) in this study.  
  
Table 1. 𝐶𝑃𝑚𝑖𝑛 cut-off values for some typical two-stage adaptive designs with no early stopping either 
for efficacy or futility 
Sample size ratios 
CPmin values for targeted conditional power 
Maximum allowed 
(nmax / n2) 
At interim look       
(n1 / n2) 
80 per cent 
90 per cent 
1.5 
0.25 
0.42 
0.42 
1.5 
0.5 
0.41 
0.41 
1.5 
0.75 
0.38 
0.38 
2 
0.25 
0.37 
0.37 
2 
0.5 
0.36 
0.36 
2 
0.75 
0.33 
0.33 
3 
0.25 
0.32 
0.32 


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3 
0.5 
0.31 
0.31 
3 
0.75 
0.30 
0.27 
∞ 
0.25 
0.32 
0.28 
∞ 
0.5 
0.31 
0.27 
∞ 
0.75 
0.30 
0.25 
CP: Conditional Power 
Table 2 summarizes the sample size re-estimation decision based on the conditional power observed 
at interim analysis. The sample size is re-estimated when the interim conditional power falls within the 
promising zone of 0.42 to 0.90 (42% to 90%).   
 
Table 2. Sample Size Re-Estimation Decision  
Conditional power 
Decision 
Less than 42% 
“Unfavorable zone” – No change to sample size 
42% to 90% 
“Promising zone” – Increase sample size 
At least 90% 
“Favorable zone” – No change to sample size 
 
The re-estimated cumulative final sample size (𝑛2∗) is computed using equations (7-9) from Mehta and 
Pocock (2011) and will be increased by a factor based on a re-assessed attrition rate as per the initial 
sample size calculation. 
8.10.2 Clarifications Based on Food and Drug Administration (FDA)’s Feedback 
The interim analysis for sample size re-estimation has been completed in March 2023. Based on the 
interim analysis results and sample size re-estimation decision rules, the results of the interim analysis 
suggested to increase the sample size to 180 randomized subjects per arm. As of June 9, 2023, the 
study has completed enrollment with a total sample size of 522 (174 per arm) subjects.  
The original evaluable sample size was 120 per arm, and a 20% drop out rate was assumed, which 
rendered to a sample size of 150 randomized subjects per arm (120/0.8=150). Based on the blinded 
data review, we noticed a low dropout rate of approximately 6%. With this dropout rate, 180 per arm 
randomized subjects will lead to 170 (180*0.94) evaluable subjects per arm, which is around 42% 
increase from originally calculated sample size of 120 per arm (170/120=1.42). The sample size 
increased was considered reasonably small (42%) based on the Metha and Pocock (2011) paper that 
the overall Type I error rate will not be inflated.  
The sample size re-estimation for our 3-arm study was handled by the worst-case scenario rules in 
Table 3 below. The sample size re-estimation method evaluates the conditional power in relationship 
to a pre-specified decision rule defined by ranges of attainable conditional power values. Only an 
increase in sample size was possible under this approach if observed conditional power was within 
the Promising Zone. 
Table 3. Worst-case Scenario Approach to Sample Size Re-estimation for Multiple Dose 
Comparisons 
Outcome 
Worst-case Scenario Approach 
Both doses Unfavorable 
Study proceeds with originally planned sample size 
One dose Unfavorable 
One dose Promising 
Study proceeds with sample size re-estimation increase 
suggested by one dose comparison in Promising Zone 
One dose Unfavorable 
One dose Favorable 
Study proceeds with originally planned sample size 
Both doses Promising 
Study proceeds with larger of the sample size re-
estimation increases suggested by two dose comparisons 
in Promising Zone 
One dose Promising 
One dose Favorable 
Study proceeds with sample size re-estimation increase 
suggested by one dose comparison in Promising Zone 
Both doses Favorable 
Study proceeds with originally planned sample size 
 
According to Chen, Yuan and Li (2018), the bias and error rate using the original maximum likelihood 
estimator (MLE) point estimator and confidence interval should be small and appropriate to use in the 
final analysis. In addition, the interim analysis was done using the original primary endpoint MDS-
UPDRS Part II+III. Based on the Agency’s feedback, the original primary endpoint is changed to MDS-


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UPDRS Part II, and MDS-UPDRS Part II+III is kept as a secondary endpoint. Thus, the results of 
interim analysis are not relevant to the new primary endpoint. With a sample size of 174 per arm, the 
study will have 90% power to detect a treatment difference of 3 assuming a common SD of 8, based 
on a 2-sided t-test with alpha of 0.025. 
8.11 Data Monitoring 
An independent DSMB (IDMB) will be convened to review the safety information from the study on an 
ongoing basis. The IDMB, 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 IDMB 
will initially be provided with data blinded to treatment status, but they may request unblinded data if 
there is a safety concern. 
Additionally, the IDMB 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 IDMB may at any time request 
additional information from the Coordinating Center. 
The IDMB will consist of at least one statistician and two physicians with experience of IDMBs and 
clinical trials. 
The data to be considered by the IDMB, the process for quality control of reports and data, and the 
documentation of decisions were described in detail in the mutually agreed IDMB charter prior to the 
study start. The primary responsibility of the IDMB will be to protect the safety of the study subjects.  
Based on the review of safety data, the IDMB 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 IDMB, 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 IDMB charter.  
8.12 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. 
8.13 References 
1. Mehta, C. R., & Pocock, S. J. (2011). Adaptive increase in sample size when interim results are 
promising: a practical guide with examples. Statistics in medicine, 30(28), 3267-3284. 
2. Chen YHJ, Yuan SS, Li X. Statistical inference following sample size adjustment based on the 
50%-conditional-power principle. J Biopharm Stat. 2018; 28(3): 575-587


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APPENDIX 1: SCHEDULE OF EVENTS  
Study Period 
Screening/Baseline 
Up to 42 Days 
Double-Blind Trial Treatment Period 6 Monthse 
Unscheduled 
Visit h 
(USV) 
Early 
Discontinuation 
Visit  
Visit Timing 
Day -42 to 0 
1 month 
 ± 7 days 
2 
months  
± 7 days 
3 
months 
± 7 days 
4.5 
months 
± 7 days 
1-3 
days 
prior to 
end of 
trial 
visit 
6 months  
± 7 days 
(end of trial 
visit) J 
 
 
Procedure 
ScreeningI  
(up to 42 
days before 
Day 0) 
Base 
line J 
(Day 0) 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Phone 
Clinic Visit 
 
 
Clinic Visit 
 
 
Clinic Visit 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Demography 
information 
X 
 
 
 
 
 
 
 
 
 
Full physical 
examination and 
neurological 
examination 
X 
X 
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 
 
X 
 
X 
Hoehn & Yahr 
Stage 
X 
 
 
 
 
 
 
 
 
 


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Study Period 
Screening/Baseline 
Up to 42 Days 
Double-Blind Trial Treatment Period 6 Monthse 
Unscheduled 
Visit h 
(USV) 
Early 
Discontinuation 
Visit  
Visit Timing 
Day -42 to 0 
1 month 
 ± 7 days 
2 
months  
± 7 days 
3 
months 
± 7 days 
4.5 
months 
± 7 days 
1-3 
days 
prior to 
end of 
trial 
visit 
6 months  
± 7 days 
(end of trial 
visit) J 
 
 
Procedure 
ScreeningI  
(up to 42 
days before 
Day 0) 
Base 
line J 
(Day 0) 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Phone 
Clinic Visit 
 
 
Clinic Visit 
 
 
Clinic Visit 
MMSE 
X 
X 
 
 
 
 
 
X 
 
 
PGIC 
 
 
X 
X 
X 
 
 
X 
 
 
CGIS 
 
X 
X 
X 
X 
 
 
X 
 
 
WAIS-IV 
 
X 
 
X 
 
 
 
X 
 
 
MDS-UPDRS 
 
X 
X 
X 
X 
 
 
X 
 
 
C-SSRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Laboratory safety 
testsd&g 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
12-lead ECG 
X 
X 
X 
X 
X 
 
 
X 
X 
             X 
Vital signsa 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Study 
intervention 
dispensed 
 
X 
X 
X 
X 
 
 
Xf 
 
 
Study 
intervention 
compliance 
review 
 
 
X 
X 
X 
X 
X 
X 
 
X 
AE/SAE review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medication 
review 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 


ANNOVIS BIO, INC.                                                                                                       CONFIDENTIAL                                                                                                    Statistical Analysis Plan 
ANVS-22001                                                                                                                                                                                                                                        Version 2.1, 11 January 2024 
 
 
Page 28 of 28 
 
Study Period 
Screening/Baseline 
Up to 42 Days 
Double-Blind Trial Treatment Period 6 Monthse 
Unscheduled 
Visit h 
(USV) 
Early 
Discontinuation 
Visit  
Visit Timing 
Day -42 to 0 
1 month 
 ± 7 days 
2 
months  
± 7 days 
3 
months 
± 7 days 
4.5 
months 
± 7 days 
1-3 
days 
prior to 
end of 
trial 
visit 
6 months  
± 7 days 
(end of trial 
visit) J 
 
 
Procedure 
ScreeningI  
(up to 42 
days before 
Day 0) 
Base 
line J 
(Day 0) 
Clinic Visit 
Clinic 
Visit 
Clinic 
Visit 
Phone 
Phone 
Clinic Visit 
 
 
Clinic Visit 
 
 
Clinic Visit 
PK samplingc 
 
X 
 
 
 
 
 
X 
 
 
Sampling for 
blood biomarkers 
 
X 
 
 
 
 
 
X 
 
 
24-hour phone 
follow-upb 
 
X 
X 
X 
X 
 
 
X 
X 
X 
a=Vital signs include sitting blood pressure, pulse, temperature, respiration rate. 
b=Phone follow-up should occur approximately 24 hours after baseline, each clinic visit and after discharge from the end of trial or early discontinuation visits. 
c=Sampling Times:  0 (pre-dosing) and 1.5hrs after dosing, except for 16-people per group who will go through 10hr sampling timepoints at 0, 1hr, 1.5hr, 2hr, 3hr, 4hr,5hr, 
6hr, 7hr, 8hr, 9hr, and 10hr (±10 mins for all collection timepoints).  Intense PK subgroup is only in the US. 
d=Safety labs at all clinic visits should be taken fasted. 
e=Subjects who drop out after the initial 5 months of study treatment will complete the full End of Trial visit.  Subjects who dropped out prior to the initial 5 months of study 
treatment will complete the Early Discontinuation Visit assessments. 
f=The study intervention dispensing on the end of trial visit is only for the one pill given on that day. 
g=Blood and urine samples will be obtained for clinical safety lab assessments as described in the Laboratory Manual. 
h= Investigator will determine the extra assessment if any is needed. 
i= With investigator’s permission, lab re-testing is allowed within a month. 
j= For the intense PK subgroup participants, baseline visit and end-of-trial visit can be done in 2 days.